21 CFR 211.3 Definitions.
The definitions set forth in 210.3 of this chapter apply in this
part.
21 CFR 211.3 Subpart B -- Organization and Personnel
21 CFR 211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the
responsibility and authority to approve or reject all components, drug
product containers, closures, in-process materials, packaging material,
labeling, and drug products, and the authority to review production
records to assure that no errors have occurred or, if errors have
occurred, that they have been fully investigated. The quality control
unit shall be responsible for approving or rejecting drug products
manufactured, processed, packed, or held under contract by another
company.
(b) Adequate laboratory facilities for the testing and approval (or
rejection) of components, drug product containers, closures, packaging
materials, in-process materials, and drug products shall be available to
the quality control unit.
(c) The quality control unit shall have the responsibility for
approving or rejecting all procedures or specifications impacting on the
identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality
control unit shall be in writing; such written procedures shall be
followed.
21 CFR 211.25 Personnel qualifications.
(a) Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, and
experience, or any combination thereof, to enable that person to perform
the assigned functions. Training shall be in the particular operations
that the employee performs and in current good manufacturing practice
(including the current good manufacturing practice regulations in this
chapter and written procedures required by these regulations) as they
relate to the employee's functions. Training in current good
manufacturing practice shall be conducted by qualified individuals on a
continuing basis and with sufficient frequency to assure that employees
remain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture,
processing, packing, or holding of a drug product shall have the
education, training, and experience, or any combination thereof, to
perform assigned functions in such a manner as to provide assurance that
the drug product has the safety, identity, strength, quality, and purity
that it purports or is represented to possess.
(c) There shall be an adequate number of qualified personnel to
perform and supervise the manufacture, processing, packing, or holding
of each drug product.
21 CFR 211.28 Personnel responsibilities.
(a) Personnel engaged in the manufacture, processing, packing, or
holding of a drug product shall wear clean clothing appropriate for the
duties they perform. Protective apparel, such as head, face, hand, and
arm coverings, shall be worn as necessary to protect drug products from
contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter
those areas of the buildings and facilities designated as limited-access
areas.
(d) Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions
that may adversely affect the safety or quality of drug products shall
be excluded from direct contact with components, drug product
containers, closures, in-process materials, and drug products until the
condition is corrected or determined by competent medical personnel not
to jeopardize the safety or quality of drug products. All personnel
shall be instructed to report to supervisory personnel any health
conditions that may have an adverse effect on drug products.
21 CFR 211.34 Consultants.
Consultants advising on the manufacture, processing, packing, or
holding of drug products shall have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for
which they are retained. Records shall be maintained stating the name,
address, and qualifications of any consultants and the type of service
they provide.
21 CFR 211.34 Subpart C -- Buildings and Facilities
21 CFR 211.42 Design and construction features.
(a) Any building or buildings used in the manufacture, processing,
packing, or holding of a drug product shall be of suitable size,
construction and location to facilitate cleaning, maintenance, and
proper operations.
(b) Any such building shall have adequate space for the orderly
placement of equipment and materials to prevent mixups between different
components, drug product containers, closures, labeling, in-process
materials, or drug products, and to prevent contamination. The flow of
components, drug product containers, closures, labeling, in-process
materials, and drug products through the building or buildings shall be
designed to prevent contamination.
(c) Operations shall be performed within specifically defined areas
of adequate size. There shall be separate or defined areas for the
firm's operations to prevent contamination or mixups as follows:
(1) Receipt, identification, storage, and withholding from use of
components, drug product containers, closures, and labeling, pending the
appropriate sampling, testing, or examination by the quality control
unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product containers, closures,
and labeling before disposition;
(3) Storage of released components, drug product containers,
closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
(10) Aseptic processing, which includes as appropriate:
(i) Floors, walls, and ceilings of smooth, hard surfaces that are
easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through high-efficiency particulate air
filters under positive pressure, regardless of whether flow is laminar
or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions;
(vi) A system for maintaining any equipment used to control the
aseptic conditions.
(d) Operations relating to the manufacture, processing, and packing
of penicillin shall be performed in facilities separate from those used
for other drug products for human use.
21 CFR 211.44 Lighting.
Adequate lighting shall be provided in all areas.
21 CFR 211.46 Ventilation, air filtration, air heating and cooling.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure,
micro-organisms, dust, humidity, and temperature shall be provided when
appropriate for the manufacture, processing, packing, or holding of a
drug product.
(c) Air filtration systems, including prefilters and particulate
matter air filters, shall be used when appropriate on air supplies to
production areas. If air is recirculated to production areas, measures
shall be taken to control recirculation of dust from production. In
areas where air contamination occurs during production, there shall be
adequate exhaust systems or other systems adequate to control
contaminants.
(d) Air-handling systems for the manufacture, processing, and packing
of penicillin shall be completely separate from those for other drug
products for human use.
21 CFR 211.48 Plumbing.
(a) Potable water shall be supplied under continuous positive
pressure in a plumbing system free of defects that could contribute
contamination to any drug product. Potable water shall meet the
standards prescribed in the Environmental Protection Agency's Primary
Drinking Water Regulations set forth in 40 CFR part 141. Water not
meeting such standards shall not be permitted in the potable water
system.
(b) Drains shall be of adequate size and, where connected directly to
a sewer, shall be provided with an air break or other mechanical device
to prevent back-siphonage.
(43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426, Mar. 18,
1983)
21 CFR 211.50 Sewage and refuse.
Sewage, trash, and other refuse in and from the building and
immediate premises shall be disposed of in a safe and sanitary manner.
21 CFR 211.52 Washing and toilet facilities.
Adequate washing facilities shall be provided, including hot and cold
water, soap or detergent, air driers or single-service towels, and clean
toilet facilities easily accesible to working areas.
21 CFR 211.56 Sanitation.
(a) Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a clean and sanitary
condition, Any such building shall be free of infestation by rodents,
birds, insects, and other vermin (other than laboratory animals). Trash
and organic waste matter shall be held and disposed of in a timely and
sanitary manner.
(b) There shall be written procedures assigning responsibility for
sanitation and describing in sufficient detail the cleaning schedules,
methods, equipment, and materials to be used in cleaning the buildings
and facilities; such written procedures shall be followed.
(c) There shall be written procedures for use of suitable
rodenticides, insecticides, fungicides, fumigating agents, and cleaning
and sanitizing agents. Such written procedures shall be designed to
prevent the contamination of equipment, components, drug product
containers, closures, packaging, labeling materials, or drug products
and shall be followed. Rodenticides, insecticides, and fungicides shall
not be used unless registered and used in accordance with the Federal
Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).
(d) Sanitation procedures shall apply to work performed by
contractors or temporary employees as well as work performed by
full-time employees during the ordinary course of operations.
21 CFR 211.58 Maintenance.
Any building used in the manufacture, processing, packing, or holding
of a drug product shall be maintained in a good state of repair.
21 CFR 211.58 Subpart D -- Equipment
21 CFR 211.63 Equipment design, size, and location.
Equipment used in the manufacture, processing, packing, or holding of
a drug product shall be of appropriate design, adequate size, and
suitably located to facilitate operations for its intended use and for
its cleaning and maintenance.
21 CFR 211.65 Equipment construction.
(a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
(b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, drug product
containers, closures, in-process materials, or drug products so as to
alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.
21 CFR 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and
sanitized at appropriate intervals to prevent malfunctions or
contamination that would alter the safety, identity, strength, quality,
or purity of the drug product beyond the official or other established
requirements.
(b) Written procedures shall be established and followed for cleaning
and maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of a drug product. These
procedures shall include, but are not necessarily limited to, the
following:
(1) Assignment of responsibility for cleaning and maintaining
equipment;
(2) Maintenance and cleaning schedules, including, where appropriate,
sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment, and
materials used in cleaning and maintenance operations, and the methods
of disassembling and reassembling equipment as necessary to assure
proper cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and
inspection as specified in 211.180 and 211.182.
21 CFR 211.68 Automatic, mechanical, and electronic equipment.
(a) Automatic, mechanical, or electronic equipment or other types of
equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing,
packing, and holding of a drug product. If such equipment is so used,
it shall be routinely calibrated, inspected, or checked according to a
written program designed to assure proper performance. Written records
of those calibration checks and inspections shall be maintained.
(b) Appropriate controls shall be exercised over computer or related
systems to assure that changes in master production and control records
or other records are instituted only by authorized personnel. Input to
and output from the computer or related system of formulas or other
records or data shall be checked for accuracy. A backup file of data
entered into the computer or related system shall be maintained except
where certain data, such as calculations performed in connection with
laboratory analysis, are eliminated by computerization or other
automated processes. In such instances a written record of the program
shall be maintained along with appropriate validation data. Hard copy
or alternative systems, such as duplicates, tapes, or microfilm,
designed to assure that backup data are exact and complete and that it
is secure from alteration, inadvertent erasures, or loss shall be
maintained.
21 CFR 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing, or
packing of injectable drug products intended for human use shall not
release fibers into such products. Fiber-releasing filters may not be
used in the manufacture, processing, or packing of these injectable drug
products unless it is not possible to manufacture such drug products
without the use of such filters. If use of a fiber-releasing filter is
necessary, an additional non-fiber-releasing filter of 0.22 micron
maximum mean porosity (0.45 micron if the manufacturing conditions so
dictate) shall subsequently be used to reduce the content of particles
in the injectable drug product. Use of an asbestos-containing filter,
with or without subsequent use of a specific non-fiber-releasing filter,
is permissible only upon submission of proof to the appropriate bureau
of the Food and Drug Administration that use of a non-fiber-releasing
filter will, or is likely to, compromise the safety or effectiveness of
the injectable drug product.
21 CFR 211.72 Subpart E -- Control of Components and Drug Product Containers and Closures
21 CFR 211.80 General requirements.
(a) There shall be written procedures describing in sufficient detail
the receipt, identification, storage, handling, sampling, testing, and
approval or rejection of components and drug product containers and
closures; such written procedures shall be followed.
(b) Components and drug product containers and closures shall at all
times be handled and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers, or
closures shall be stored off the floor and suitably spaced to permit
cleaning and inspection.
(d) Each container or grouping of containers for components or drug
product containers, or closures shall be identified with a distinctive
code for each lot in each shipment received. This code shall be used in
recording the disposition of each lot. Each lot shall be appropriately
identified as to its status (i.e., quarantined, approved, or rejected).
21 CFR 211.82 Receipt and storage of untested components, drug product
containers, and closures.
(a) Upon receipt and before acceptance, each container or grouping of
containers of components, drug product containers, and closures shall be
examined visually for appropriate labeling as to contents, container
damage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be stored
under quarantine until they have been tested or examined, as
appropriate, and released. Storage within the area shall conform to the
requirements of 211.80.
21 CFR 211.84 Testing and approval or rejection of components, drug
product containers, and closures.
(a) Each lot of components, drug product containers, and closures
shall be withheld from use until the lot has been sampled, tested, or
examined, as appropriate, and released for use by the quality control
unit.
(b) Representative samples of each shipment of each lot shall be
collected for testing or examination. The number of containers to be
sampled, and the amount of material to be taken from each container,
shall be based upon appropriate criteria such as statistical criteria
for component variability, confidence levels, and degree of precision
desired, the past quality history of the supplier, and the quantity
needed for analysis and reserve where required by 211.170.
(c) Samples shall be collected in accordance with the following
procedures:
(1) The containers of components selected shall be cleaned where
necessary, by appropriate means.
(2) The containers shall be opened, sampled, and resealed in a manner
designed to prevent contamination of their contents and contamination of
other components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used
when necessary.
(4) If it is necessary to sample a component from the top, middle,
and bottom of its container, such sample subdivisions shall not be
composited for testing.
(5) Sample containers shall be identified so that the following
information can be determined: name of the material sampled, the lot
number, the container from which the sample was taken, the data on which
the sample was taken, and the name of the person who collected the
sample.
(6) Containers from which samples have been taken shall be marked to
show that samples have been removed from them.
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of
each component of a drug product. Specific identity tests, if they
exist, shall be used.
(2) Each component shall be tested for conformity with all
appropriate written specifications for purity, strength, and quality.
In lieu of such testing by the manufacturer, a report of analysis may be
accepted from the supplier of a component, provided that at least one
specific identity test is conducted on such component by the
manufacturer, and provided that the manufacturer establishes the
reliability of the supplier's analyses through appropriate validation of
the supplier's test results at appropriate intervals.
(3) Containers and closures shall be tested for conformance with all
appropriate written procedures. In lieu of such testing by the
manufacturer, a certificate of testing may be accepted from the
supplier, provided that at least a visual identification is conducted on
such containers/closures by the manufacturer and provided that the
manufacturer establishes the reliability of the supplier's test results
through appropriate validation of the supplier's test results at
appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that
is liable to contamination with filth, insect infestation, or other
extraneous adulterant shall be examined against established
specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that
is liable to microbiological contamination that is objectionable in view
of its intended use shall be subjected to microbiological tests before
use.
(e) Any lot of components, drug product containers, or closures that
meets the appropriate written specifications of identity, strength,
quality, and purity and related tests under paragraph (d) of this
section may be approved and released for use. Any lot of such material
that does not meet such specifications shall be rejected.
21 CFR 211.86 Use of approved components, drug product containers, and
closures.
Components, drug product containers, and closures approved for use
shall be rotated so that the oldest approved stock is used first.
Deviation from this requirement is permitted if such deviation is
temporary and appropriate.
21 CFR 211.87 Retesting of approved components, drug product
containers, and closures.
Components, drug product containers, and closures shall be retested
or reexamined, as appropriate, for identity, strength, quality, and
purity and approved or rejected by the quality control unit in
accordance with 211.84 as necessary, e.g., after storage for long
periods or after exposure to air, heat or other conditions that might
adversely affect the component, drug product container, or closure.
21 CFR 211.89 Rejected components, drug product containers, and
closures.
Rejected components, drug product containers, and closures shall be
identified and controlled under a quarantine system designed to prevent
their use in manufacturing or processing operations for which they are
unsuitable.
21 CFR 211.94 Drug product containers and closures.
(a) Drug product containers and closures shall not be reactive,
additive, or absorptive so as to alter the safety, identity, strength,
quality, or purity of the drug beyond the official or established
requirements.
(b) Container closure systems shall provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product.
(c) Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to remove
pyrogenic properties to assure that they are suitable for their intended
use.
(d) Standards or specifications, methods of testing, and, where
indicated, methods of cleaning, sterilizing, and processing to remove
pyrogenic properties shall be written and followed for drug product
containers and closures.
21 CFR 211.94 Subpart F -- Production and Process Controls
21 CFR 211.100 Written procedures; deviations.
(a) There shall be written procedures for production and process
control designed to assure that the drug products have the identity,
strength, quality, and purity they purport or are represented to
possess. Such procedures shall include all requirements in this
subpart. These written procedures, including any changes, shall be
drafted, reviewed, and approved by the appropriate organizational units
and reviewed and approved by the quality control unit.
(b) Written production and process control procedures shall be
followed in the execution of the various production and process control
functions and shall be documented at the time of performance. Any
deviation from the written procedures shall be recorded and justified.
21 CFR 211.101 Charge-in of components.
Written production and control procedures shall include the
following, which are designed to assure that the drug products produced
have the identity, strength, quality, and purity they purport or are
represented to possess:
(a) The batch shall be formulated with the intent to provide not less
than 100 percent of the labeled or established amount of active
ingredient.
(b) Components for drug product manufacturing shall be weighed,
measured, or subdivided as appropriate. If a component is removed from
the original container to another, the new container shall be identified
with the following information:
(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components
shall be adequately supervised. Each container of component dispensed
to manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit;
(2) The weight or measure is correct as stated in the batch
production records;
(3) The containers are properly identified.
(d) Each component shall be added to the batch by one person and
verified by a second person.
21 CFR 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be
determined at the conclusion of each appropriate phase of manufacturing,
processing, packaging, or holding of the drug product. Such
calculations shall be performed by one person and independently verified
by a second person.
21 CFR 211.105 Equipment identification.
(a) All compounding and storage containers, processing lines, and
major equipment used during the production of a batch of a drug product
shall be properly identified at all times to indicate their contents
and, when necessary, the phase of processing of the batch.
(b) Major equipment shall be identified by a distinctive
identification number or code that shall be recorded in the batch
production record to show the specific equipment used in the manufacture
of each batch of a drug product. In cases where only one of a
particular type of equipment exists in a manufacturing facility, the
name of the equipment may be used in lieu of a distinctive
identification number or code.
21 CFR 211.110 Sampling and testing of in-process materials and drug
products.
(a) To assure batch uniformity and integrity of drug products,
written procedures shall be established and followed that describe the
in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material
and the drug product. Such control procedures shall include, but are
not limited to, the following, where appropriate:
(1) Tablet or capsule weight variation;
(2) Disintegration time;
(3) Adequacy of mixing to assure uniformity and homogeneity;
(4) Dissolution time and rate;
(5) Clarity, completeness, or pH of solutions.
(b) Valid in-process specifications for such characteristics shall be
consistent with drug product final specifications and shall be derived
from previous acceptable process average and process variability
estimates where possible and determined by the application of suitable
statistical procedures where appropriate. Examination and testing of
samples shall assure that the drug product and in-process material
conform to specifications.
(c) In-process materials shall be tested for identity, strength,
quality, and purity as appropriate, and approved or rejected by the
quality control unit, during the production process, e.g., at
commencement or completion of significant phases or after storage for
long periods.
(d) Rejected in-process materials shall be identified and controlled
under a quarantine system designed to prevent their use in manufacturing
or processing operations for which they are unsuitable.
21 CFR 211.111 Time limitations on production.
When appropriate, time limits for the completion of each phase of
production shall be established to assure the quality of the drug
product. Deviation from established time limits may be acceptable if
such deviation does not compromise the quality of the drug product.
Such deviation shall be justified and documented.
21 CFR 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable
microorganisms in drug products not required to be sterile, shall be
established and followed.
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to be sterile,
shall be established and followed. Such procedures shall include
validation of any sterilization process.
21 CFR 211.115 Reprocessing.
(a) Written procedures shall be established and followed prescribing
a system for reprocessing batches that do not conform to standards or
specifications and the steps to be taken to insure that the reprocessed
batches will conform with all established standards, specifications, and
characteristics.
(b) Reprocessing shall not be performed without the review and
approval of the quality control unit.
21 CFR 211.115 Subpart G -- Packaging and Labeling Control
21 CFR 211.122 Materials examination and usage criteria.
(a) There shall be written procedures describing in sufficient detail
the receipt, identification, storage, handling, sampling, examination,
and/or testing of labeling and packaging materials; such written
procedures shall be followed. Labeling and packaging materials shall be
representatively sampled, and examined or tested upon receipt and before
use in packaging or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Any labeling or
packaging materials that do not meet such specifications shall be
rejected to prevent their use in operations for which they are
unsuitable.
(c) Records shall be maintained for each shipment received of each
different labeling and packaging material indicating receipt,
examination or testing, and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug
product, strength, dosage form, or quantity of contents shall be stored
separately with suitable identification. Access to the storage area
shall be limited to authorized personnel.
(e) Obsolete and outdated labels, labeling, and other packaging
materials shall be destroyed.
(f) Gang printing of labeling to be used for different drug products
or different strengths of the same drug product (or labeling of the same
size and identical or similar format and/or color schemes) shall be
minimized. If gang printing is employed, packaging and labeling
operations shall provide for special control procedures, taking into
consideration sheet layout, stacking, cutting, and handling during and
after printing.
(g) Printing devices on, or associated with, manufacturing lines used
to imprint labeling upon the drug product unit label or case shall be
monitored to assure that all imprinting conforms to the print specified
in the batch production record.
21 CFR 211.125 Labeling issuance.
(a) Strict control shall be exercised over labeling issued for use in
drug product labeling operations.
(b) Labeling materials issued for a batch shall be carefully examined
for identity and conformity to the labeling specified in the master or
batch production records.
(c) Procedures shall be utilized to reconcile the quantities of
labeling issued, used, and returned, and shall require evaluation of
discrepancies found between the quantity of drug product finished and
the quantity of labeling issued when such discrepancies are outside
narrow preset limits based on historical operating data. Such
discrepancies shall be investigated in accordance with 211.192.
(d) All excess labeling bearing lot or control numbers shall be
destroyed.
(e) Returned labeling shall be maintained and stored in a manner to
prevent mixups and provide proper identification.
(f) Procedures shall be written describing in sufficient detail the
control procedures employed for the issuance of labeling; such written
procedures shall be followed.
21 CFR 211.130 Packaging and labeling operations.
There shall be written procedures designed to assure that correct
labels, labeling, and packaging materials are used for drug products;
such written procedures shall be followed. These procedures shall
incorporate the following features:
(a) Prevention of mixups and cross-contamination by physical or
spatial separation from operations on other drug products.
(b) Identification of the drug product with a lot or control number
that permits determination of the history of the manufacture and control
of the batch.
(c) Examination of packaging and labeling materials for suitability
and correctness before packaging operations, and documentation of such
examination in the batch production record.
(d) Inspection of the packaging and labeling facilities immediately
before use to assure that all drug products have been removed from
previous operations. Inspection shall also be made to assure that
packaging and labeling materials not suitable for subsequent operations
have been removed. Results of inspection shall be documented in the
batch production records.
21 CFR 211.132 Tamper-resistant packaging requirements for
over-the-counter (OTC) human drug products.
(a) General. The Food and Drug Administration has the authority
under the Federal Food, Drug, and Cosmetic Act (the act) to establish a
uniform national requirement for tamper-resistant packaging of OTC drug
products that will improve the security of OTC drug packaging and help
assure the safety and effectiveness of OTC drug products. An OTC drug
product (except a dermatological, dentifrice, insulin, or throat lozenge
product) for retail sale that is not packaged in a tamper-resistant
package or that is not properly labeled under this section is
adulterated under section 501 of the act or misbranded under section 502
of the act, or both.
(b) Requirement for tamper-resistant package. Each manufacturer and
packer who packages an OTC drug product (except a dermatological,
dentifrice, insulin, or throat lozenge product) for retail sale shall
package the product in a tamper-resistant package, if this product is
accessible to the public while held for sale. A tamper-resistant
package is one having one or more indicators or barriers to entry which,
if breached or missing, can reasonably be expected to provide visible
evidence to consumers that tampering has occurred. To reduce the
likelihood of successful tampering and to increase the likelihood that
consumers will discover if a product has been tampered with, the package
is required to be distinctive by design (e.g., an aerosol product
container) or by the use of one or more indicators or barriers to entry
that employ an identifying characteristic (e.g., a pattern, name,
registered trademark, logo, or picture). For purposes of this section,
the term ''distinctive by design'' means the packaging cannot be
duplicated with commonly available materials or through commonly
available processes. For purposes of this section, the term ''aerosol
product'' means a product which depends upon the power of a liquified or
compressed gas to expel the contents from the container. A
tamper-resistant package may involve an immediate-container and closure
system or secondary-container or carton system or any combination of
systems intended to provide a visual indication of package integrity.
The tamper-resistant feature shall be designed to and shall remain
intact when handled in a reasonable manner during manufacture,
distribution, and retail display.
(1) For two-piece, hard gelatin capsule products subject to this
requirement, a minimum of two tamper-resistant packaging features is
required, unless the capsules are sealed by a tamper-resistant
technology.
(2) For all other products subject to this requirement, including
two-piece, hard gelatin capsules that are sealed by a tamper-resistant
technology, a minimum of one tamper-resistant feature is required.
(c) Labeling. Each retail package of an OTC drug product covered by
this section, except ammonia inhalant in crushable glass ampules,
aerosol products as defined in paragraph (b) of this section, or
containers of compressed medical oxygen, is required to bear a statement
that is prominently placed so that consumers are alerted to the specific
tamper-resistant feature of the package. The labeling statement is also
required to be so placed that it will be unaffected if the
tamper-resistant feature of the package is breached or missing. If the
tamper-resistant feature chosen to meet the requirement in paragraph (b)
of this section is one that uses an identifying characteristic, that
characteristic is required to be referred to in the labeling statement.
For example, the labeling statement on a bottle with a shrink band could
say ''For your protection, this bottle has an imprinted seal around the
neck.''
(d) Request for exemptions from packaging and labeling requirements.
A manufacturer or packer may request an exemption from the packaging and
labeling requirements of this section. A request for an exemption is
required to be submitted in the form of a citizen petition under 10.30
of this chapter and should be clearly identified on the envelope as a
''Request for Exemption from Tamper-Resistant Rule.'' The petition is
required to contain the following:
(1) The name of the drug product or, if the petition seeks an
exemption for a drug class, the name of the drug class, and a list of
products within that class.
(2) The reasons that the drug product's compliance with the
tamper-resistant packaging or labeling requirements of this section is
unnecessary or cannot be achieved.
(3) A description of alternative steps that are available, or that
the petitioner has already taken, to reduce the likelihood that the
product or drug class will be the subject of malicious adulteration.
(4) Other information justifying an exemption.
(e) OTC drug products subject to approved new drug applications.
Holders of approved new drug applications for OTC drug products are
required under 314.70 of this chapter to provide the agency with
notification of changes in packaging and labeling to comply with the
requirements of this section. Changes in packaging and labeling
required by this regulation may be made before FDA approval, as provided
under 314.70(c) of this chapter. Manufacturing changes by which
capsules are to be sealed require prior FDA approval under 314.70(b) of
this chapter.
(f) Poison Prevention Packaging Act of 1970. This section does not
affect any requirements for ''special packaging'' as defined under
310.3(l) of this chapter and required under the Poison Prevention
Packaging Act of 1970.
(Approved by the Office of Management and Budget under OMB control
number 0910-0149)
(54 FR 5228, Feb. 2, 1989)
21 CFR 211.134 Drug product inspection.
(a) Packaged and labeled products shall be examined during finishing
operations to provide assurance that containers and packages in the lot
have the correct label.
(b) A representative sample of units shall be collected at the
completion of finishing operations and shall be visually examined for
correct labeling.
(c) Results of these examinations shall be recorded in the batch
production or control records.
21 CFR 211.137 Expiration dating.
(a) To assure that a drug product meets applicable standards of
identity, strength, quality, and purity at the time of use, it shall
bear an expiration date determined by appropriate stability testing
described in 211.166.
(b) Expiration dates shall be related to any storage conditions
stated on the labeling, as determined by stability studies described in
211.166.
(c) If the drug product is to be reconstituted at the time of
dispensing, its labeling shall bear expiration information for both the
reconstituted and unreconstituted drug products.
(d) Expiration dates shall appear on labeling in accordance with the
requirements of 201.17 of this chapter.
(e) Homeopathic drug products shall be exempt from the requirements
of this section.
(f) Allergenic extracts that are labeled ''No U.S. Standard of
Potency'' are exempt from the requirements of this section.
(g) Pending consideration of a proposed exemption, published in the
Federal Register of September 29, 1978, the requirements in this section
shall not be enforced for human OTC drug products if their labeling does
not bear dosage limitations and they are stable for at least 3 years as
supported by appropriate stability data.
(43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17,
1981)
21 CFR 211.137 Subpart H -- Holding and Distribution
21 CFR 211.142 Warehousing procedures.
Written procedures describing the warehousing of drug products shall
be established and followed. They shall include:
(a) Quarantine of drug products before release by the quality control
unit.
(b) Storage of drug products under appropriate conditions of
temperature, humidity, and light so that the identity, strength,
quality, and purity of the drug products are not affected.
21 CFR 211.150 Distribution procedures.
Written procedures shall be established, and followed, describing the
distribution of drug products. They shall include:
(a) A procedure whereby the oldest approved stock of a drug product
is distributed first. Deviation from this requirement is permitted if
such deviation is temporary and appropriate.
(b) A system by which the distribution of each lot of drug product
can be readily determined to facilitate its recall if necessary.
21 CFR 211.150 Subpart I -- Laboratory Controls
21 CFR 211.160 General requirements.
(a) The establishment of any specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms required
by this subpart, including any change in such specifications, standards,
sampling plans, test procedures, or other laboratory control mechanisms,
shall be drafted by the appropriate organizational unit and reviewed and
approved by the quality control unit. The requirements in this subpart
shall be followed and shall be documented at the time of performance.
Any deviation from the written specifications, standards, sampling
plans, test procedures, or other laboratory control mechanisms shall be
recorded and justified.
(b) Laboratory controls shall include the establishment of
scientifically sound and appropriate specifications, standards, sampling
plans, and test procedures designed to assure that components, drug
product containers, closures, in-process materials, labeling, and drug
products conform to appropriate standards of identity, strength,
quality, and purity. Laboratory controls shall include:
(1) Determination of conformance to appropriate written
specifications for the acceptance of each lot within each shipment of
components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products. The
specifications shall include a description of the sampling and testing
procedures used. Samples shall be representative and adequately
identified. Such procedures shall also require appropriate retesting of
any component, drug product container, or closure that is subject to
deterioration.
(2) Determination of conformance to written specifications and a
description of sampling and testing procedures for in-process materials.
Such samples shall be representative and properly identified.
(3) Determination of conformance to written descriptions of sampling
procedures and appropriate specifications for drug products. Such
samples shall be representative and properly identified.
(4) The calibration of instruments, apparatus, gauges, and recording
devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy
and precision, and provisions for remedial action in the event accuracy
and/or precision limits are not met. Instruments, apparatus, gauges,
and recording devices not meeting established specifications shall not
be used.
21 CFR 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate
laboratory determination of satisfactory conformance to final
specifications for the drug product, including the identity and strength
of each active ingredient, prior to release. Where sterility and/or
pyrogen testing are conducted on specific batches of shortlived
radiopharmaceuticals, such batches may be released prior to completion
of sterility and/or pyrogen testing, provided such testing is completed
as soon as possible.
(b) There shall be appropriate laboratory testing, as necessary, of
each batch of drug product required to be free of objectionable
microorganisms.
(c) Any sampling and testing plans shall be described in written
procedures that shall include the method of sampling and the number of
units per batch to be tested; such written procedure shall be followed.
(d) Acceptance criteria for the sampling and testing conducted by the
quality control unit shall be adequate to assure that batches of drug
products meet each appropriate specification and appropriate statistical
quality control criteria as a condition for their approval and release.
The statistical quality control criteria shall include appropriate
acceptance levels and/or appropriate rejection levels.
(e) The accuracy, sensitivity, specificity, and reproducibility of
test methods employed by the firm shall be established and documented.
Such validation and documentation may be accomplished in accordance with
211.194(a)(2).
(f) Drug products failing to meet established standards or
specifications and any other relevant quality control criteria shall be
rejected. Reprocessing may be performed. Prior to acceptance and use,
reprocessed material must meet appropriate standards, specifications,
and any other relevant critieria.
21 CFR 211.166 Stability testing.
(a) There shall be a written testing program designed to assess the
stability characteristics of drug products. The results of such
stability testing shall be used in determining appropriate storage
conditions and expiration dates. The written program shall be followed
and shall include:
(1) Sample size and test intervals based on statistical criteria for
each attribute examined to assure valid estimates of stability;
(2) Storage conditions for samples retained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product in the same container-closure system
as that in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of
dispensing (as directed in the labeling) as well as after they are
reconstituted.
(b) An adequate number of batches of each drug product shall be
tested to determine an appropriate expiration date and a record of such
data shall be maintained. Accelerated studies, combined with basic
stability information on the components, drug products, and
container-closure system, may be used to support tentative expiration
dates provided full shelf life studies are not available and are being
conducted. Where data from accelerated studies are used to project a
tentative expiration date that is beyond a date supported by actual
shelf life studies, there must be stability studies conducted, including
drug product testing at appropriate intervals, until the tentative
expiration date is verified or the appropriate expiration date
determined.
(c) For homeopathic drug products, the requirements of this section
are as follows:
(1) There shall be a written assessment of stability based at least
on testing or examination of the drug product for compatibility of the
ingredients, and based on marketing experience with the drug product to
indicate that there is no degradation of the product for the normal or
expected period of use.
(2) Evaluation of stability shall be based on the same
container-closure system in which the drug product is being marketed.
(d) Allergenic extracts that are labeled ''No U.S. Standard of
Potency'' are exempt from the requirements of this section.
(43 FR 45077, Sept. 29, 1978, as amended at 46 FR 56412, Nov. 17,
1981)
21 CFR 211.167 Special testing requirements.
(a) For each batch of drug product purporting to be sterile and/or
pyrogen-free, there shall be appropriate laboratory testing to determine
conformance to such requirements. The test procedures shall be in
writing and shall be followed.
(b) For each batch of ophthalmic ointment, there shall be appropriate
testing to determine conformance to specifications regarding the
presence of foreign particles and harsh or abrasive substances. The
test procedures shall be in writing and shall be followed.
(c) For each batch of controlled-release dosage form, there shall be
appropriate laboratory testing to determine conformance to the
specifications for the rate of release of each active ingredient. The
test procedures shall be in writing and shall be followed.
21 CFR 211.170 Reserve samples.
(a) An appropriately identified reserve sample that is representative
of each lot in each shipment of each active ingredient shall be
retained. The reserve sample consists of at least twice the quantity
necessary for all tests required to determine whether the active
ingredient meets its established specifications, except for sterility
and pyrogen testing. The retention time is as follows:
(1) For an active ingredient in a drug product other than those
described in paragraphs (a) (2) and (3) of this section, the reserve
sample shall be retained for 1 year after the expiration date of the
last lot of the drug product containing the active ingredient.
(2) For an active ingredient in a radioactive drug product, except
for nonradioactive reagent kits, the reserve sample shall be retained
for:
(i) Three months after the expiration date of the last lot of the
drug product containing the active ingredient if the expiration dating
period of the drug product is 30 days or less; or
(ii) Six months after the expiration date of the last lot of the drug
product containing the active ingredient if the expiration dating period
of the drug product is more than 30 days.
(3) For an active ingredient in an OTC drug product that is exempt
from bearing an expiration date under 211.137, the reserve sample shall
be retained for 3 years after distribution of the last lot of the drug
product containing the active ingredient.
(b) An appropriately identified reserve sample that is representative
of each lot or batch of drug product shall be retained and stored under
conditions consistent with product labeling. The reserve sample shall
be stored in the same immediate container-closure system in which the
drug product is marketed or in one that has essentially the same
characteristics. The reserve sample consists of at least twice the
quantity necessary to perform all the required tests, except those for
sterility and pyrogens. Reserve samples, except those drugs products
described in paragraph (b)(2), shall be examined visually at least once
a year for evidence of deterioration unless visual examination would
affect the integrity of the reserve samples. Any evidence of reserve
sample deterioration shall be investigated in accordance with 211.192.
The results of the examination shall be recorded and maintained with
other stability data on the drug product. Reserve samples of compressed
medical gases need not be retained. The retention time is as follows:
(1) For a drug product other than those described in paragraphs (b)
(2) and (3) of this section, the reserve sample shall be retained for 1
year after the expiration date of the drug product.
(2) For a radioactive drug product, except for nonradioactive reagent
kits, the reserve sample shall be retained for:
(i) Three months after the expiration date of the drug product if the
expiration dating period of the drug product is 30 days or less; or
(ii) Six months after the expiration date of the drug product if the
expiration dating period of the drug product is more than 30 days.
(3) For an OTC drug product that is exempt for bearing an expiration
date under 211.137, the reserve sample must be retained for 3 years
after the lot or batch of drug product is distributed.
(48 FR 13025, Mar. 29, 1983)
21 CFR 211.173 Laboratory animals.
Animals used in testing components, in-process materials, or drug
products for compliance with established specifications shall be
maintained and controlled in a manner that assures their suitability for
their intended use. They shall be identified, and adequate records
shall be maintained showing the history of their use.
21 CFR 211.176 Penicillin contamination.
If a reasonable possibility exists that a non-penicillin drug product
has been exposed to cross-contamination with penicillin, the
non-penicillin drug product shall be tested for the presence of
penicillin. Such drug product shall not be marketed if detectable
levels are found when tested according to procedures specified in
'Procedures for Detecting and Measuring Penicillin Contamination in
Drugs,' which is incorporated by reference. Copies are available from
the Division of Research and Testing (HFD-470), Center for Drug
Evaluation and Research, Food and Drug Administration, 200 C St. SW.,
Washington, DC 20204, or available for inspection at the Office of the
Federal Register, 1100 L St. NW., Washington, DC 20408.
(43 FR 45077, Sept. 29, 1978, as amended at 47 FR 9396, Mar. 5, 1982;
50 FR 8996, Mar. 6, 1985; 55 FR 11577, Mar. 29, 1990)
21 CFR 211.176 Subpart J -- Records and Reports
21 CFR 211.180 General requirements.
(a) Any production, control, or distribution record that is required
to be maintained in compliance with this part and is specifically
associated with a batch of a drug product shall be retained for at least
1 year after the expiration date of the batch or, in the case of certain
OTC drug products lacking expiration dating because they meet the
criteria for exemption under 211.137, 3 years after distribution of the
batch.
(b) Records shall be maintained for all components, drug product
containers, closures, and labeling for at least 1 year after the
expiration date or, in the case of certain OTC drug products lacking
expiration dating because they meet the criteria for exemption under
211.137, 3 years after distribution of the last lot of drug product
incorporating the component or using the container, closure, or
labeling.
(c) All records required under this part, or copies of such records,
shall be readily available for authorized inspection during the
retention period at the establishment where the activities described in
such records occurred. These records or copies thereof shall be subject
to photocopying or other means of reproduction as part of such
inspection. Records that can be immediately retrieved from another
location by computer or other electronic means shall be considered as
meeting the requirements of this paragraph.
(d) Records required under this part may be retained either as
original records or as true copies such as photocopies, microfilm,
microfiche, or other accurate reproductions of the original records.
Where reduction techniques, such as microfilming, are used, suitable
reader and photocopying equipment shall be readily available.
(e) Written records required by this part shall be maintained so that
data therein can be used for evaluating, at least annually, the quality
standards of each drug product to determine the need for changes in drug
product specifications or manufacturing or control procedures. Written
procedures shall be established and followed for such evaluations and
shall include provisions for:
(1) A review of every batch, whether approved or rejected, and, where
applicable, records associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug
products, and investigations conducted under 211.192 for each drug
product.
(f) Procedures shall be established to assure that the responsible
officials of the firm, if they are not personally involved in or
immediately aware of such actions, are notified in writing of any
investigations conducted under 211.198, 211.204, or 211.208 of these
regulations, any recalls, reports of inspectional observations issued by
the Food and Drug Administration, or any regulatory actions relating to
good manufacturing practices brought by the Food and Drug
Administration.
21 CFR 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except
routine maintenance such as lubrication and adjustments), and use shall
be included in individual equipment logs that show the date, time,
product, and lot number of each batch processed. If equipment is
dedicated to manufacture of one product, then individual equipment logs
are not required, provided that lots or batches of such product follow
in numerical order and are manufactured in numerical sequence. In cases
where dedicated equipment is employed, the records of cleaning,
maintenance, and use shall be part of the batch record. The persons
performing and double-checking the cleaning and maintenance shall date
and sign or initial the log indicating that the work was performed.
Entries in the log shall be in chronological order.
21 CFR 211.184 Component, drug product container, closure, and labeling
records.
These records shall include the following:
(a) The identity and quantity of each shipment of each lot of
components, drug product containers, closures, and labeling; the name
of the supplier; the supplier's lot number(s) if known; the receiving
code as specified in 211.80; and the date of receipt. The name and
location of the prime manufacturer, if different from the supplier,
shall be listed if known.
(b) The results of any test or examination performed (including those
performed as required by 211.82(a), 211.84(d), or 211.122(a)) and the
conclusions derived therefrom.
(c) An individual inventory record of each component, drug product
container, and closure and, for each component, a reconciliation of the
use of each lot of such component. The inventory record shall contain
sufficient information to allow determination of any batch or lot of
drug product associated with the use of each component, drug product
container, and closure.
(d) Documentation of the examination and review of labels and
labeling for conformity with established specifications in accord with
211.122(c) and 211.130(c).
(e) The disposition of rejected components, drug product containers,
closure, and labeling.
21 CFR 211.186 Master production and control records.
(a) To assure uniformity from batch to batch, master production and
control records for each drug product, including each batch size
thereof, shall be prepared, dated, and signed (full signature,
handwritten) by one person and independently checked, dated, and signed
by a second person. The preparation of master production and control
records shall be described in a written procedure and such written
procedure shall be followed.
(b) Master production and control records shall include:
(1) The name and strength of the product and a description of the
dosage form;
(2) The name and weight or measure of each active ingredient per
dosage unit or per unit of weight or measure of the drug product, and a
statement of the total weight or measure of any dosage unit;
(3) A complete list of components designated by names or codes
sufficiently specific to indicate any special quality characteristic;
(4) An accurate statement of the weight or measure of each component,
using the same weight system (metric, avoirdupois, or apothecary) for
each component. Reasonable variations may be permitted, however, in the
amount of components necessary for the preparation in the dosage form,
provided they are justified in the master production and control
records;
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weight or measure at appropriate
phases of processing;
(7) A statement of theoretical yield, including the maximum and
minimum percentages of theoretical yield beyond which investigation
according to 211.192 is required;
(8) A description of the drug product containers, closures, and
packaging materials, including a specimen or copy of each label and all
other labeling signed and dated by the person or persons responsible for
approval of such labeling;
(9) Complete manufacturing and control instructions, sampling and
testing procedures, specifications, special notations, and precautions
to be followed.
21 CFR 211.188 Batch production and control records.
Batch production and control records shall be prepared for each batch
of drug product produced and shall include complete information relating
to the production and control of each batch. These records shall
include:
(a) An accurate reproduction of the appropriate master production or
control record, checked for accuracy, dated, and signed;
(b) Documentation that each significant step in the manufacture,
processing, packing, or holding of the batch was accomplished,
including:
(1) Dates;
(2) Identity of individual major equipment and lines used;
(3) Specific identification of each batch of component or in-process
material used;
(4) Weights and measures of components used in the course of
processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labeling area before and after
use;
(7) A statement of the actual yield and a statement of the percentage
of theoretical yield at appropriate phases of processing;
(8) Complete labeling control records, including specimens or copies
of all labeling used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;
(11) Identification of the persons performing and directly
supervising or checking each significant step in the operation;
(12) Any investigation made according to 211.192.
(13) Results of examinations made in accordance with 211.134.
21 CFR 211.192 Production record review.
All drug product production and control records, including those for
packaging and labeling, shall be reviewed and approved by the quality
control unit to determine compliance with all established, approved
written procedures before a batch is released or distributed. Any
unexplained discrepancy (including a percentage of theoretical yield
exceeding the maximum or minimum percentages established in master
production and control records) or the failure of a batch or any of its
components to meet any of its specifications shall be thoroughly
investigated, whether or not the batch has already been distributed.
The investigation shall extend to other batches of the same drug product
and other drug products that may have been associated with the specific
failure or discrepancy. A written record of the investigation shall be
made and shall include the conclusions and followup.
21 CFR 211.194 Laboratory records.
(a) Laboratory records shall include complete data derived from all
tests necessary to assure compliance with established specifications and
standards, including examinations and assays, as follows:
(1) A description of the sample received for testing with
identification of source (that is, location from where sample was
obtained), quantity, lot number or other distinctive code, date sample
was taken, and date sample was received for testing.
(2) A statement of each method used in the testing of the sample.
The statement shall indicate the location of data that establish that
the methods used in the testing of the sample meet proper standards of
accuracy and reliability as applied to the product tested. (If the
method employed is in the current revision of the United States
Pharmacopeia, National Formulary, Association of Official Analytical
Chemists, Book of Methods,2 or in other recognized standard references,
or is detailed in an approved new drug application and the referenced
method is not modified, a statement indicating the method and reference
will suffice). The suitability of all testing methods used shall be
verified under actual conditions of use.
(3) A statement of the weight or measure of sample used for each
test, where appropriate.
(4) A complete record of all data secured in the course of each test,
including all graphs, charts, and spectra from laboratory
instrumentation, properly identified to show the specific component,
drug product container, closure, in-process material, or drug product,
and lot tested.
(5) A record of all calculations performed in connection with the
test, including units of measure, conversion factors, and equivalency
factors.
(6) A statement of the results of tests and how the results compare
with established standards of identity, strength, quality, and purity
for the component, drug product container, closure, in-process material,
or drug product tested.
(7) The initials or signature of the person who performs each test
and the date(s) the tests were performed.
(8) The initials or signature of a second person showing that the
original records have been reviewed for accuracy, completeness, and
compliance with established standards.
(b) Complete records shall be maintained of any modification of an
established method employed in testing. Such records shall include the
reason for the modification and data to verify that the modification
produced results that are at least as accurate and reliable for the
material being tested as the established method.
(c) Complete records shall be maintained of any testing and
standardization of laboratory reference standards, reagents, and
standard solutions.
(d) Complete records shall be maintained of the periodic calibration
of laboratory instruments, apparatus, gauges, and recording devices
required by 211.160(b)(4).
(e) Complete records shall be maintained of all stability testing
performed in accordance with 211.166.
(43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar. 29,
1990)
2Copies may be obtained from: Association of Official Analytical
Chemists, 2200 Wilson Blvd., Suite 400, Arlington, VA 22201-3301.
21 CFR 211.196 Distribution records.
Distribution records shall contain the name and strength of the
product and description of the dosage form, name and address of the
consignee, date and quantity shipped, and lot or control number of the
drug product. For compressed medical gas products, distribution records
are not required to contain lot or control numbers.
(Approved by the Office of Management and Budget under control number
0910-0139)
(49 FR 9865, Mar. 16, 1984)
21 CFR 211.198 Complaint files.
(a) Written procedures describing the handling of all written and
oral complaints regarding a drug product shall be established and
followed. Such procedures shall include provisions for review by the
quality control unit, of any complaint involving the possible failure of
a drug product to meet any of its specifications and, for such drug
products, a determination as to the need for an investigation in
accordance with 211.192. Such procedures shall include provisions for
review to determine whether the complaint represents a serious and
unexpected adverse drug experience which is required to be reported to
the Food and Drug Administration in accordance with 310.305 of this
chapter.
(b) A written record of each complaint shall be maintained in a file
designated for drug product complaints. The file regarding such drug
product complaints shall be maintained at the establishment where the
drug product involved was manufactured, processed, or packed, or such
file may be maintained at another facility if the written records in
such files are readily available for inspection at that other facility.
Written records involving a drug product shall be maintained until at
least 1 year after the expiration date of the drug product, or 1 year
after the date that the complaint was received, whichever is longer. In
the case of certain OTC drug products lacking expiration dating because
they meet the criteria for exemption under 211.137, such written
records shall be maintained for 3 years after distribution of the drug
product.
(1) The written record shall include the following information, where
known: the name and strength of the drug product, lot number, name of
complainant, nature of complaint, and reply to complainant.
(2) Where an investigation under 211.192 is conducted, the written
record shall include the findings of the investigation and followup.
The record or copy of the record of the investigation shall be
maintained at the establishment where the investigation occurred in
accordance with 211.180(c).
(3) Where an investigation under 211.192 is not conducted, the
written record shall include the reason that an investigation was found
not to be necessary and the name of the responsible person making such a
determination.
(43 FR 45077, Sept. 29, 1978, as amended at 51 FR 24479, July 3,
1986)
21 CFR 211.198 Subpart K -- Returned and Salvaged Drug Products
21 CFR 211.204 Returned drug products.
Returned drug products shall be identified as such and held. If the
conditions under which returned drug products have been held, stored, or
shipped before or during their return, or if the condition of the drug
product, its container, carton, or labeling, as a result of storage or
shipping, casts doubt on the safety, identity, strength, quality or
purity of the drug product, the returned drug product shall be destroyed
unless examination, testing, or other investigations prove the drug
product meets appropriate standards of safety, identity, strength,
quality, or purity. A drug product may be reprocessed provided the
subsequent drug product meets appropriate standards, specifications, and
characteristics. Records of returned drug products shall be maintained
and shall include the name and label potency of the drug product dosage
form, lot number (or control number or batch number), reason for the
return, quantity returned, date of disposition, and ultimate disposition
of the returned drug product. If the reason for a drug product being
returned implicates associated batches, an appropriate investigation
shall be conducted in accordance with the requirements of 211.192.
Procedures for the holding, testing, and reprocessing of returned drug
products shall be in writing and shall be followed.
21 CFR 211.208 Drug product salvaging.
Drug products that have been subjected to improper storage conditions
including extremes in temperature, humidity, smoke, fumes, pressure,
age, or radiation due to natural disasters, fires, accidents, or
equipment failures shall not be salvaged and returned to the
marketplace. Whenever there is a question whether drug products have
been subjected to such conditions, salvaging operations may be conducted
only if there is (a) evidence from laboratory tests and assays
(including animal feeding studies where applicable) that the drug
products meet all applicable standards of identity, strength, quality,
and purity and (b) evidence from inspection of the premises that the
drug products and their associated packaging were not subjected to
improper storage conditions as a result of the disaster or accident.
Organoleptic examinations shall be acceptable only as supplemental
evidence that the drug products meet appropriate standards of identity,
strength, quality, and purity. Records including name, lot number, and
disposition shall be maintained for drug products subject to this
section.
21 CFR 211.208 Pt. 225
21 CFR 211.208 PART 225 -- CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICATED FEEDS
21 CFR 211.208 Subpart A -- General Provisions
Sec.
225.1 Current good manufacturing practice.
225.10 Personnel.
21 CFR 211.208 Subpart B -- Construction and Maintenance of Facilities
and Equipment
225.20 Buildings.
225.30 Equipment.
225.35 Use of work areas, equipment, and storage areas for other
manufacturing and storage purposes.
21 CFR 211.208 Subpart C -- Product Quality Control
225.42 Components.
225.58 Laboratory controls.
225.65 Equipment cleanout procedures.
21 CFR 211.208 Subpart D -- Packaging and Labeling
225.80 Labeling.
21 CFR 211.208 Subpart E -- Records and Reports
225.102 Master record file and production records.
225.110 Distribution records.
225.115 Complaint files.
21 CFR 211.208 Subpart F -- Facilities and Equipment
225.120 Buildings and grounds.
225.130 Equipment.
225.135 Work and storage areas.
21 CFR 211.208 Subpart G -- Product Quality Assurance
225.142 Components.
225.158 Laboratory assays.
225.165 Equipment cleanout procedures.
21 CFR 211.208 Subpart H -- Labeling
225.180 Labeling.
21 CFR 211.208 Subpart I -- Records
225.202 Formula, production, and distribution records.
Authority: Secs. 501, 502, 512, 701, 704 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 351, 352, 360b, 371, 374).
Source: 41 FR 52618, Nov. 30, 1976, unless otherwise noted.
21 CFR 211.208 Subpart A -- General Provisions
21 CFR 225.1 Current good manufacturing practice.
(a) Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act
provides that a drug (including a drug contained in a medicated feed)
shall be deemed to be adulterated if the methods used in, or the
facilities or controls used for, its manufacture, processing, packing,
or holding do not conform to or are not operated or administered in
conformity with current good manufacturing practice to assure that such
drug meets the requirement of the act as to safety and has the identity
and strength, and meets the quality and purity characteristics, which it
purports or is represented to possess.
(b)(1) The provisions of this part set forth the criteria for
determining whether the manufacture of a medicated feed is in compliance
with current good manufacturing practice. These regulations shall apply
to all types of facilities and equipment used in the production of
medicated feeds, and they shall also govern those instances in which
failure to adhere to the regulations has caused nonmedicated feeds that
are manufactured, processed, packed, or held to be adulterated. In such
cases, the medicated feed shall be deemed to be adulterated within the
meaning of section 501(a)(2)(B) of the act, and the nonmedicated feed
shall be deemed to be adulterated within the meaning of section
402(a)(2)(D) of the act.
(2) The regulations in 225.10 through 225.115 apply to facilities
manufacturing one or more medicated feeds for which an approved
medicated feed application is required. The regulations in 225.120
through 225.202 apply to facilities manufacturing solely medicated feeds
for which approved medicated feed applications are not required.
(41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7389, Mar. 3, 1986)
21 CFR 225.10 Personnel.
(a) Qualified personnel and adequate personnel training and
supervision are essential for the proper formulation, manufacture, and
control of medicated feeds. Training and experience leads to proper use
of equipment, maintenance of accurate records, and detection and
prevention of possible deviations from current good manufacturing
practices.
(b)(1) All employees involved in the manufacture of medicated feeds
shall have an understanding of the manufacturing or control operation(s)
which they perform, including the location and proper use of equipment.
(2) The manufacturer shall provide an on-going program of evaluation
and supervision of employees in the manufacture of medicated feeds.
(41 FR 52618, Nov. 30, 1976, as amended at 42 FR 12426, Mar. 4, 1977)
21 CFR 225.10 Subpart B -- Construction and Maintenance of Facilities and Equipment
21 CFR 225.20 Buildings.
(a) The location, design, construction, and physical size of the
buildings and other production facilities are factors important to the
manufacture of medicated feed. The features of facilities necessary for
the proper manufacture of medicated feed include provision for ease of
access to structures and equipment in need of routine maintenance; ease
of cleaning of equipment and work areas; facilities to promote
personnel hygiene; structural conditions for control and prevention of
vermin and pest infestation; adequate space for the orderly receipt and
storage of drugs and feed ingredients and the controlled flow of these
materials through the processing and manufacturing operations; and the
equipment for the accurate packaging and delivery of a medicated feed of
specified labeling and composition.
(b) The construction and maintenance of buildings in which medicated
feeds are manufactured, processed, packaged, labeled, or held shall
conform to the following:
(1) The building grounds shall be adequately drained and routinely
maintained so that they are reasonably free from litter, waste, refuse,
uncut weeds or grass, standing water, and improperly stored equipment.
(2) The building(s) shall be maintained in a reasonably clean and
orderly manner.
(3) The building(s) shall be of suitable construction to minimize
access by rodents, birds, insects, and other pests.
(4) The buildings shall provide adequate space and lighting for the
proper performance of the following medicated feed manufacturing
operations:
(i) The receipt, control, and storage of components.
(ii) Component processing.
(iii) Medicated feed manufacturing.
(iv) Packaging and labeling.
(v) Storage of containers, packaging materials, labeling and finished
products.
(vi) Routine maintenance of equipment.
21 CFR 225.30 Equipment.
(a) Equipment which is designed to perform its intended function and
is properly installed and used is essential to the manufacture of
medicated feeds. Such equipment permits production of feeds of uniform
quality, facilitates cleaning, and minimizes spillage of drug components
and finished product.
(b)(1) All equipment shall possess the capability to produce a
medicated feed of intended potency, safety, and purity.
(2) All equipment shall be maintained in a reasonably clean and
orderly manner.
(3) All equipment, including scales and liquid metering devices,
shall be of suitable size, design, construction, precision, and accuracy
for its intended purpose.
(4) All scales and metering devices shall be tested for accuracy upon
installation and at least once a year thereafter, or more frequently as
may be necessary to insure their accuracy.
(5) All equipment shall be so constructed and maintained as to
prevent lubricants and coolants from becoming unsafe additives in feed
components or medicated feed.
(6) All equipment shall be designed, constructed, installed and
maintained so as to facilitate inspection and use of cleanout
procedure(s).
21 CFR 225.35 Use of work areas, equipment, and storage areas for other
manufacturing and storage purpose.
(a) Many manufacturers of medicated feeds are also involved in the
manufacture, storage, or handling of products which are not intended for
animal feed use, such as fertilizers, herbicides, insecticides,
fungicides, rodenticides, and other pesticides. Manufacturing, storage,
or handling of nonfeed and feed products in the same facilities may
cause adulteration of feed products with toxic or otherwise unapproved
feed additives.
(b) Work areas and equipment used for the manufacture or storage of
medicated feeds or components thereof shall not be used for, and shall
be physically separated from, work areas and equipment used for the
manufacture of fertilizers, herbicides, insecticides, fungicides,
rodenticides, and other pesticides unless such articles are approved
drugs or approved food additives intended for use in the manufacture of
medicated feed.
21 CFR 225.35 Subpart C -- Product Quality Control
21 CFR 225.42 Components.
(a) A medicated feed, in addition to providing nutrients, is a
vehicle for the administration of a drug, or drugs, to animals. To
ensure proper safety and effectiveness, such medicated feeds must
contain the labeled amounts of drugs. It is necessary that adequate
procedures be established for the receipt, storage, and inventory
control for all such drugs to aid in assuring their identity, strength,
quality, and purity when incorporated into products.
(b) The receipt, storage, and inventory of drugs, including undiluted
drug components, medicated premixes, and semiprocessed (i.e.,
intermediate premixes, inplant premixes and concentrates) intermediate
mixes containing drugs, which are used in the manufacture and processing
of medicated feeds shall conform to the following:
(1) Incoming shipments of drugs shall be visually examined for
identity and damage. Drugs which have been subjected to conditions
which may have adversely affected their identity, strength, quality, or
purity shall not be accepted for use.
(2) Packaged drugs in the storage areas shall be stored in their
original closed containers.
(3) Bulk drugs shall be identified and stored in a manner such that
their identity, strength, quality, and purity will be maintained.
(4) Drugs in the mixing areas shall be properly identified, stored,
handled, and controlled to maintain their integrity and identity.
Sufficient space shall be provided for the location of each drug.
(5) A receipt record shall be prepared and maintained for each lot of
drug received. The receipt record shall accurately indicate the
identity and quantity of the drug, the name of the supplier, the
supplier's lot number or an identifying number assigned by the feed
manufacturer upon receipt which relates to the particular shipment, the
date of receipt, the condition of the drug when received, and the return
of any damaged drugs.
(6) A daily inventory record for each drug used shall be maintained
and shall list by manufacturer's lot number or the feed manufacturer's
shipment identification number at least the following information:
(i) The quantity of drug on hand at the beginning and end of the work
day (the beginning amount being the same as the previous day's closing
inventory if this amount has been established to be correct); the
quantity shall be determined by weighing, counting, or measuring, as
appropriate.
(ii) The amount of each drug used, sold, or otherwise disposed of.
(iii) The batches or production runs of medicated feed in which each
drug was used.
(iv) When the drug is used in the preparation of a semiprocessed
intermediate mix intended for use in the manufacture of medicated feed,
any additional information which may be required for the purpose of
paragraph (b)(7) of this section.
(v) Action taken to reconcile any discrepancies in the daily
inventory record.
(7) Drug inventory shall be maintained of each lot or shipment of
drug by means of a daily comparison of the actual amount of drug used
with the theoretical drug usage in terms of the semiprocessed,
intermediate and finished medicated feeds manufactured. Any significant
discrepancy shall be investigated and corrective action taken. The
medicated feed(s) remaining on the premises which are affected by this
discrepancy shall be detained until the discrepancy is reconciled.
(8) All records required by this section shall be maintained on the
premises for at least one year after complete use of a drug component of
a specific lot number or feed manufacturer's shipment identification
number.
21 CFR 225.58 Laboratory controls.
(a) The periodic assay of medicated feeds for drug components
provides a measure of performance of the manufacturing process in
manufacturing a uniform product of intended potency.
(b) The following assay requirements shall apply to medicated feeds:
(1) For feeds requiring approved Medicated Feed Applications (Form
FDA 1900) for their manufacture and marketing, at least three
representative samples of medicated feed containing each drug or drug
combination used in the establishment shall be collected and assayed by
approved official methods, at periodic intervals during the calendar
year, unless otherwise specified in this chapter. At least one of these
assays shall be performed on the first batch using the drug. If a
medicated feed contains a combination of drugs, only one of the drugs
need be subject to analysis each time, provided the one tested is
different from the one(s) previously tested.
(2) (Reserved)
(c) The originals or copies of all results of assays, including those
from State feed control officials and any other governmental agency,
shall be maintained on the premises for a period of not less than 1 year
after distribution of the medicated feed. The results of assays
performed by State feed control officials may be considered toward
fulfillment of the periodic assay requirements of this section.
(d) Where the results of assays indicate that the medicated feed is
not in accord with label specifications or is not within permissible
assay limits as specified in this chapter, investigation and corrective
action shall be implemented and an original or copy of the record of
such action maintained on the premises.
(e) Corrective action shall include provisions for discontinuing
distribution where the medicated feed fails to meet the labeled drug
potency. Distribution of subsequent production of the particular feed
shall not begin until it has been determined that proper control
procedures have been established.
(41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986;
55 FR 11577, Mar. 29, 1990)
21 CFR 225.65 Equipment cleanout procedures.
(a) Adequate cleanout procedures for all equipment used in the
manufacture and distribution of medicated feeds are essential to
maintain proper drug potency and avoid unsafe contamination of feeds
with drugs. Such procedures may consist of cleaning by physical means,
e.g., vacuuming, sweeping, washing, etc. Alternatively, flushing or
sequencing or other equally effective techniques may be used whereby the
equipment is cleaned either through use of a feed containing the same
drug(s) or through use of drug free feedstuffs.
(b) All equipment, including that used for storage, processing,
mixing, conveying, and distribution that comes in contact with the
active drug component, feeds in process, or finished medicated feed
shall be subject to all reasonable and effective procedures to prevent
unsafe contamination of manufactured feed. The steps used to prevent
unsafe contamination of feeds shall include one or more of the
following, or other equally effective procedures:
(1) Such procedures shall, where appropriate, consist of physical
means (vacuuming, sweeping, or washing), flushing, and/or sequential
production of feeds.
(2) If flushing is utilized, the flush material shall be properly
identified, stored, and used in a manner to prevent unsafe contamination
of other feeds.
(3) If sequential production of medicated feeds is utilized, it shall
be on a predetermined basis designed to prevent unsafe contamination of
feeds with residual drugs.
21 CFR 225.65 Subpart D -- Packaging and Labeling
21 CFR 225.80 Labeling.
(a) Appropriate labeling identifies the medicated feed, and provides
the user with directions for use which, if adhered to, will assure that
the article is safe and effective for its intended purposes.
(b)(1) Labels and labeling, including placards, shall be received,
handled, and stored in a manner that prevents labeling mixups and
assures that correct labeling is employed for the medicated feed.
(2) Labels and labeling, including placards, upon receipt from the
printer shall be proofread against the Master Record File to verify
their suitability and accuracy. The proofread label shall be dated,
initialed by a responsible individual, and kept for 1 year after all the
labels from that batch have been used.
(3) In those instances where medicated feeds are distributed in bulk,
complete labeling shall accompany the shipment and be supplied to the
consignee at the time of delivery. Such labeling may consist of a
placard or other labels attached to the invoice or delivery ticket, or
manufacturer's invoice that identifies the medicated feed and includes
adequate information for the safe and effective use of the medicated
feed.
(4) Label stock shall be reviewed periodically and discontinued
labels shall be discarded.
21 CFR 225.80 Subpart E -- Records and Reports
21 CFR 225.102 Master record file and production records.
(a) The Master Record File provides the complete procedure for
manufacturing a specific product, setting forth the formulation,
theoretical yield, manufacturing procedures, assay requirements, and
labeling of batches or production runs. The production record(s)
includes the complete history of a batch or production run. This record
includes the amounts of drugs used, the amount of medicated feed
manufactured, and provides a check for the daily inventory record of
drug components.
(b) The Master Record File and production records shall comply with
the following provisions:
(1) A Master Record File shall be prepared, checked, dated, and
signed or initialed by a qualified person and shall be retained for not
less than 1 year after production of the last batch or production run of
medicated feed to which it pertains. The Master Record File or card
shall include at least the following:
(i) The name of the medicated feed.
(ii) The name and weight percentage or measure of each drug or drug
combination and each nondrug ingredient to be used in manufacturing a
stated weight of the medicated feed.
(iii) A copy or description of the label or labeling that will
accompany the medicated feed.
(iv) Manufacturing instructions or reference thereto that have been
determined to yield a properly mixed medicated feed of the specified
formula for each medicated feed produced on a batch or continuous
operation basis, including mixing steps, mixing times and, in the case
of medicated feeds produced by continuous production run, any additional
manufacturing directions including, when indicated, the settings of
equipment.
(v) Appropriate control directions or reference thereto, including
the manner and frequency of collecting the required number of samples
for specified laboratory assay.
(2) The original production record or copy thereof shall be prepared
by qualified personnel for each batch or run of medicated feed produced
and shall be retained on the premises for not less than 1 year. The
production record shall include at least the following:
(i) Product identification, date of production, and a written
endorsement in the form of a signature or initials by a responsible
individual.
(ii) The quantity and name of drug components used.
(iii) The theoretical quantity of medicated feed to be produced.
(iv) The actual quantity of medicated feed produced. In those
instances where the finished feed is stored in bulk and actual yield
cannot be accurately determined, the firm shall estimate the quantity
produced and provide the basis for such estimate in the Master Record
File.
(3) In the case of a custom formula feed made to the specifications
of a customer, the Master Record File and production records required by
this section shall consist either of such records or of copies of the
customer's purchase orders and the manufacturer's invoices bearing the
information required by this section. When a custom order is received
by telephone, the manufacturer shall prepare the required production
records.
(4) Batch production records shall be checked by a responsible
individual at the end of the working day in which the product was
manufactured to determine whether all required production steps have
been performed. If significant discrepancies are noted, an
investigation shall be instituted immediately, and the production record
shall describe the corrective action taken.
(5) Each batch or production run of medicated feed shall be
identified with its own individual batch or production run number, code,
date, or other suitable identification applied to the label, package,
invoice or shipping document. This identification shall permit the
tracing of the complete and accurate manufacturing history of the
product by the manufacturer.
21 CFR 225.110 Distribution records.
(a) Distribution records permit the manufacturer to relate complaints
to specific batches and/or production runs of medicated feed. This
information may be helpful in instituting a recall.
(b) Distribution records for each shipment of a medicated feed shall
comply with the following provisions:
(1) Each distribution record shall include the date of shipment, the
name and address of purchaser, the quantity shipped, and the name of the
medicated feed. A lot or control number, or date of manufacture or
other suitable identification shall appear on the distribution record or
the label issued with each shipment.
(2) The originals or copies of the distribution records shall be
retained on the premises for not less than one year after the date of
shipment of the medicated feed.
21 CFR 225.115 Complaint files.
(a) Complaints and reports of experiences of product defects relative
to the drug's efficacy or safety may provide an indicator as to whether
or not medicated feeds have been manufactured in conformity with current
good manufacturing practices. These complaints and experiences may
reveal the existence of manufacturing problems not otherwise detected
through the normal quality control procedures. Timely and appropriate
follow-up action can serve to correct a problem and minimize future
problems.
(b) The medicated feed manufacturer shall maintain on the premises a
file which contains the following information:
(1) The original or copy of a record of each oral and written
complaint received relating to the safety and effectiveness of the
product produced. The record shall include the date of the complaint,
the complainant's name and address, name and lot or control number or
date of manufacture of the medicated feed involved, and the specific
details of the complaint. This record shall also include all
correspondence from the complainant and/or memoranda of conversations
with the complainant, and a description of all investigations made by
the manufacturer and of the method of disposition of the complaint.
(2) For medicated feeds requiring an approved Medicated Feed
Application (Form FDA 1900), records and reports of clinical and other
experience with the drug shall be maintained and reported, appropriately
identified with the number(s) of the Form FDA 1900 to which they relate,
to the Center for Veterinary Medicine, 7500 Standish Pl., Rockville, MD
20855, in duplicate, pursuant to 510.301 of this chapter.
(41 FR 52618, Nov. 30, 1976, as amended at 51 FR 7390, Mar. 3, 1986;
57 FR 6475, Feb. 25, 1992)
21 CFR 225.115 Subpart F -- Facilities and Equipment
Source: 51 FR 7390, Mar. 3, 1986, unless otherwise noted.
21 CFR 225.120 Buildings and grounds.
Buildings used for production of medicated feed shall provide
adequate space for equipment, processing, and orderly receipt and
storage of medicated feed. Areas shall include access for routine
maintenance and cleaning of equipment. Buildings and grounds shall be
constructed and maintained in a manner to minimize vermin and pest
infestation.
21 CFR 225.130 Equipment.
Equipment shall be capable of producing a medicated feed of intended
potency and purity, and shall be maintained in a reasonably clean and
orderly manner. Scales and liquid metering devices shall be accurate
and of suitable size, design, construction, precision, and accuracy for
their intended purposes. All equipment shall be designed, constructed,
installed, and maintained so as to facilitate inspection and use of
cleanout procedure(s).
21 CFR 225.135 Work and storage areas.
Work areas and equipment used for the production or storage of
medicated feeds or components thereof shall not be used for, and shall
be physically separated from, work areas and equipment used for the
manufacture and storage of fertilizers, herbicides, insecticides,
fungicides, rodenticides, and other pesticides unless such articles are
approved for use in the manufacture of animal feed.
21 CFR 225.135 Subpart G -- Product Quality Assurance
Source: 51 FR 7390, Mar. 3, 1986, unless otherwise noted.
21 CFR 225.142 Components.
Adequate procedures shall be established and maintained for the
identification, storage, and inventory control (receipt and use) of all
Type A medicated articles and Type B medicated feeds intended for use in
the manufacture of medicated feeds to aid in assuring the identity,
strength, quality, and purity of these drug sources. Packaged Type A
medicated articles and Type B medicated feeds shall be stored in
designated areas in their original closed containers. Bulk Type A
medicated articles and bulk Type B medicated feeds shall be identified
and stored in a manner such that their identity, strength, quality, and
purity will be maintained. All Type A medicated articles and Type B
medicated feeds shall be used in accordance with their labeled mixing
directions.
21 CFR 225.158 Laboratory assays.
Where the results of laboratory assays of drug components, including
assays by State feed control officials, indicate that the medicated feed
is not in accord with the permissible limits specified in this chapter,
investigation and corrective action shall be implemented immediately by
the firm and such records shall be maintained on the premises for a
period of 1 year.
21 CFR 225.165 Equipment cleanout procedures.
Adequate procedures shall be established and used for all equipment
used in the production and distribution of medicated feeds to avoid
unsafe contamination of medicated and nonmedicated feeds.
21 CFR 225.165 Subpart H -- Labeling
21 CFR 225.180 Labeling.
Labels shall be received, handled, and stored in a manner that
prevents label mixups and assures that the correct labels are used for
the medicated feed. All deliveries of medicated feeds, whether bagged
or in bulk, shall be adequately labeled to assure that the feed can be
properly used.
(51 FR 7390, Mar. 3, 1986)
21 CFR 225.180 Subpart I -- Records
21 CFR 225.202 Formula, production, and distribution records.
Records shall be maintained identifying the formulation, date of
mixing, and if not for own use, date of shipment. The records shall be
adequate to facilitate the recall of specific batches of medicated feed
that have been distributed. Such records shall be retained on the
premises for 1 year following the date of last distribution.
(Approved by the Office of Management and Budget under control number
0910-0152)
(51 FR 7390, Mar. 3, 1986)
21 CFR 225.202 PART 226 -- CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED ARTICLES
21 CFR 225.202 Subpart A -- General Provisions
Sec.
226.1 Current good manufacturing practice.
226.10 Personnel.
21 CFR 225.202 Subpart B -- Construction and Maintenance of Facilities
and Equipment
226.20 Buildings.
226.30 Equipment.
21 CFR 225.202 Subpart C -- Product Quality Control
226.40 Production and control procedures.
226.42 Components.
226.58 Laboratory controls.
21 CFR 225.202 Subpart D -- Packaging and Labeling
226.80 Packaging and labeling.
21 CFR 225.202 Subpart E -- Records and Reports
226.102 Master-formula and batch-production records.
226.110 Distribution records.
226.115 Complaint files.
Authority: Secs. 501, 502, 512, 701, 704 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 351, 352, 360b, 371, 374).
Source: 40 FR 14031, Mar. 27, 1975, unless otherwise noted.
Editorial Note: Nomenclature change to part 226 appears at 51 FR
7390, Mar. 3, 1986.
21 CFR 225.202 Subpart A -- General Provisions
21 CFR 226.1 Current good manufacturing practice.
The criteria in 226.10 through 226.115, inclusive, shall apply in
determining whether the methods used in, or the facilities and controls
used for the manufacture, processing, packing, or holding of a Type A
medicated article(s) conform to or are operated or administered in
conformity with current good manufacturing practice to assure that a
Type A medicated article(s) meets the requirements of the act as to
safety, and has the identity and strength, and meets the quality and
purity characteristics which it purports or is represented to possess,
as required by section 501(a) (2)(B) of the act. The regulations in
this part 226 permit the use of precision, automatic, mechanical, or
electronic equipment in the production of a Type A medicated article(s)
when adequate inspection and checking procedures or other quality
control procedures are used to assure proper performance.
21 CFR 226.10 Personnel.
The key personnel and any consultants involved in the manufacture and
control of the Type A medicated article(s) shall have a background of
appropriate education or appropriate experience or combination thereof
for assuming responsibility to assure that the Type A medicated
article(s) has the proper labeling and the safety, identity, strength,
quality, and purity that it purports to possess.
21 CFR 226.10 Subpart B -- Construction and Maintenance of Facilities and Equipment
21 CFR 226.20 Buildings.
Buildings in which Type A medicated article(s) are manufactured,
processed, packaged, labeled, or held shall be maintained in a clear and
orderly manner and shall be of suitable size, construction and location
in relation to surroundings to facilitate maintenance and operation for
their intended purpose. The building shall:
(a) Provide adequate space for the orderly placement of equipment and
materials used in any of the following operations for which they are
employed to minimize risk of mixups between different Type A medicated
article(s), their components, packaging, or labeling:
(1) The receipt, sampling, control, and storage of components.
(2) Manufacturing and processing operations performed on the Type A
medicated article(s).
(3) Packaging and labeling operations.
(4) Storage of containers, packaging materials, labeling, and
finished products.
(5) Control laboratory operations.
(b) Provide adequate lighting and ventilation, and when necessary for
the intended production or control purposes, adequate screening, dust
and temperature controls, to avoid contamination of Type A medicated
article(s), and to avoid other conditions unfavorable to the safety,
identity, strength, quality, and purity of the raw materials and Type A
medicated article(s) before, during, and after production.
(c) Provide for adequate washing, cleaning, toilet, and locker
facilities.
Work areas and equipment used for the production of Type A medicated
article(s) or for the storage of the components of Type A medicated
article(s) shall not be used for the production, mixing or storage of
finished or unfinished insecticides, fungicides, rodenticides, or other
pesticides or their components unless such materials are recognized as
approved drugs intended for use in animal feeds.
21 CFR 226.30 Equipment.
Equipment used for the manufacture, processing, packaging, bulk
shipment, labeling, holding, or control of Type A medicated article(s)
or their components shall be maintained in a clean and orderly manner
and shall be of suitable design, size, construction, and location to
facilitate maintenance and operation for its intended purpose. The
equipment shall:
(a) Be so constructed that any surfaces that come into contact with
Type A medicated article(s) are suitable, in that they are not reactive,
additive, or absorptive to an extent that significantly affects the
identity, strength, quality, or purity of the Type A medicated
article(s) or its components.
(b) Be so constructed that any substance required for the operation
of the equipment, such as lubricants, coolants, etc., may be employed
without hazard of becoming an unsafe additive to the Type A medicated
article(s).
(c) Be constructed to facilitate adjustment, cleaning, and
maintenance, and to assure uniformity of production and reliability of
control procedures and to assure the exclusion from Type A medicated
article(s) of contamination, including cross-contamination from
manufacturing operations.
(d) Be suitably grounded electrically to prevent lack of uniform
mixing due to electrically charged particles.
(e) Be of suitable size and accuracy for use in any intended
measuring, mixing, or weighing operations.
21 CFR 226.30 Subpart C -- Product Quality Control
21 CFR 226.40 Production and control procedures.
Production and control procedures shall include all reasonable
precautions, including the following, to assure that the Type A
medicated article(s) produced have the identity, strength, quality, and
purity they purport to possess:
(a) Each critical step in the process, such as the selection,
weighing, and measuring of components; the addition of drug components
during the process; weighing and measuring during various stages of the
processing; and the determination of the finished yield, shall be
performed by one or more competent, responsible individuals. If such
steps in the processing are controlled by precision, automatic,
mechanical, or electronic equipment, their proper performance shall be
adequately checked by one or more competent, responsible individuals.
(b) All containers to be used for undiluted drugs, drug components,
intermediate mixtures thereof, and Type A medicated article(s) shall be
received, adequately identified, and properly stored and handled in a
manner adequate to avoid mixups and contamination.
(c) Equipment, including dust-control and other equipment, such as
that used for holding and returning recovered or flush-out materials
back into production, shall be maintained and operated in a manner to
avoid contamination of the Type A medicated article(s) and to insure the
integrity of the finished product.
(d) Competent and responsible personnel shall check actual against
theoretical yield of a batch of Type A medicated article(s), and, in the
event of any significant discrepancies, key personnel shall prevent
distribution of the batch in question and other associated batches of
Type A medicated article(s) that may have been involved in a mixup with
it.
(e) Adequate procedures for cleaning of those parts of storage,
mixing conveying and other equipment coming in contact with the drug
component of the Type A medicated article(s) shall be used to avoid
contamination of Type A medicated article(s).
(f) If there is sequential production of batches of a Type A
medicated article(s) containing the same drug component (or components)
at the same or lower levels, there shall be sufficient safeguards to
avoid any buildup above the specified levels of the drug components in
any of the batches of the Type A medicated article(s).
(g) Production and control procedures shall include provision for
discontinuing distribution of any Type A medicated article(s) found by
the assay procedures, or other controls performed to fail to conform to
appropriate specifications. Distribution of subsequent production of
such Type A medicated article(s) shall not begin until it has been
determined that proper control procedures have been established.
21 CFR 226.42 Components.
(a) Drug components, including undiluted drugs and any intermediate
mixes containing drugs used in the manufacture and processing of Type A
medicated article(s), shall be received, examined or tested, stored,
handled, and otherwise controlled in a manner to maintain the integrity
and identification of such articles. Appropriate receipt and inventory
records shall be maintained for 2 years, and such records shall show the
origin of any drug components, the manufacturer's control number (if
any), the dates and batches in which they were used, and the results of
any testing of them.
(b) Nondrug components shall be stored and otherwise handled in a
manner to avoid contamination, including cross-contamination from
manufacturing operations.
21 CFR 226.58 Laboratory controls.
Laboratory controls shall include the establishment of adequate
specifications and test procedures to assure that the drug components
and the Type A medicated article(s) conform to appropriate standards of
identity, strength, quality, and purity. Laboratory controls shall
include:
(a) The establishment of master records containing appropriate
specifications and a description of the test procedures used to check
them for each kind of drug component used in the manufacture of Type A
medicated article(s). This may consist of the manufacturer's or
supplier's statement of specifications and methods of analyses.
(b) The establishment of specifications for Type A medicated
article(s) and a description of necessary laboratory test procedures to
check such specifications.
(c) Assays which shall be made of representative samples of finished
Type A medicated article(s) in accordance with the following schedule:
(1) Each batch of a Type A medicated article(s) manufactured from an
undiluted drug shall be assayed for its drug component(s).
(2) In the case of Type A medicated article(s) which are manufactured
by dilution of Type A medicated article(s) assayed in accordance with
paragraph (c)(1) of this section, each batch shall be assayed for its
drug component(s) with the first five consecutive batches assaying
within the limitations, followed thereafter by assay of representative
samples of not less than 5 percent of all batches produced. When any
batch does not assay within limitations, each batch should again be
assayed until five consecutive batches are within limitations.
(d) A determination establishing that the drug components remain
uniformly dispersed and stable in the Type A medicated article(s) under
ordinary conditions of shipment, storage, and use. This may consist of
a determination on a Type A medicated article(s) of substantially the
same formula and characteristics. Suitable expiration dates shall
appear on the labels of the Type A medicated article(s) to assure that
the articles meet the appropriate standards of identity, strength,
quality, and purity at the time of use.
(e) Adequate provision to check the reliability, accuracy, and
precision of any laboratory test procedure used. The official methods
in ''Methods of Analysis of the Association of Official Analytical
Chemists,''1002 methods described in an official compendium, and any
method submitted as a part of a food additive petition or new-drug
application that has been accepted by the Food and Drug Administration
shall be regarded as meeting this provision.
(f) Provisions for the maintenance of the results of any assays,
including dates and endorsement of analysts. Such records shall be
retained in the possession of the manufacturer and shall be maintained
for a period of at least 2 years after distribution by the manufacturer
of the Type A medicated article(s) has been completed.
(40 FR 14031, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29,
1990; 55 FR 23703, June 12, 1990)
0021Copies may be obtained from: Association of Official Analytical
Chemists, 2200 Wilson Blvd., Suite 400, Arlington, VA 22201-3301.
21 CFR 226.58 Subpart D -- Packaging and Labeling
21 CFR 226.80 Packaging and labeling.
(a) Packaging and labeling operations shall be adequately controlled:
(1) To assure that only those Type A medicated article(s) that have
met the specifications established in the master-formula records shall
be distributed.
(2) To prevent mixups during the packaging and labeling operations.
(3) To assure that correct labeling is employed for each Type A
medicated article(s).
(4) To identify Type A medicated article(s) with lot or control
numbers that permit determination of the history of the manufacture and
control of the batch of Type A medicated article(s).
(b) Packaging and labeling operations shall provide:
(1) For storage of labeling in a manner to avoid mixups.
(2) For careful checking of labeling for identity and conformity to
the labeling specified in the batch-production records.
(3) For adequate control of the quantities of labeling issued for use
with the Type A medicated article(s).
(c) Type A medicated article(s) shall be distributed in suitable
containers to insure the safety, identity, strength, and quality of the
finished product.
21 CFR 226.80 Subpart E -- Records and Reports
21 CFR 226.102 Master-formula and batch-production records.
(a) For each Type A medicated article(s) master-formula records shall
be prepared, endorsed, and dated by a competent and responsible
individual and shall be independently checked, reconciled, endorsed, and
dated by a second competent and responsible individual. The record
shall include:
(1) The name of the Type A medicated article(s) and a specimen copy
of its label.
(2) The weight or measure of each ingredient, adequately identified,
to be used in manufacturing a stated weight of the Type A medicated
article(s).
(3) A complete formula for each batch size, or of appropriate size in
the case of continuous systems to be produced from the master-formula
record, including a complete list of ingredients designated by names or
codes sufficiently specific to indicate any special quality
characteristics; an accurate statement of the weight or measure of each
ingredient, except that reasonable variations may be permitted in the
amount of ingredients necessary in the preparation of the Type A
medicated article(s), provided that the variations are stated in the
master formula; an appropriate statement concerning any calculated
excess of an ingredient; and a statement of the theoretical yield.
(4) Manufacturing instructions for each type of Type A medicated
article(s) produced on a batch or continuous operation basis, including
mixing steps and mixing times that have been determined to yield an
adequately mixed Type A medicated article(s); and in the case of Type A
medicated article(s) produced by continuous production run, any
additional manufacturing directions including, when indicated, the
settings of equipment that have been determined to yield an adequately
mixed Type A medicated article(s) of the specified formula.
(5) Control instructions, procedures, specifications, special
notations, and precautions to be followed.
(b) A separate batch-production and control record shall be prepared
for each batch or run of Type A medicated article(s) produced and shall
be retained for at least 2 years after distribution by the manufacturer
has been completed. The batch-production and control record shall
include:
(1) Product identification, date of production, and endorsement by a
competent and responsible individual.
(2) Records of each step in the manufacturing, packaging, labeling,
and controlling of the batch, including dates, specific identification
of drug components used, weights or measures of all components,
laboratory-control results, mixing times, and the endorsements of the
individual actively performing or the individual actively supervising or
checking each step in the operation.
(3) A batch number that permits determination of all
laboratory-control procedures and results on the batch and all lot or
control numbers appearing on the labels of the Type A medicated
article(s).
21 CFR 226.110 Distribution records.
Complete records shall be maintained for each shipment of Type A
medicated article(s) in a manner that will facilitate the recall,
diversion, or destruction of the Type A medicated article(s), if
necessary. Such records shall be retained for at least 2 years after
the date of the shipment by the manufacturer and shall include the name
and address of the consignee, the date and quantity shipped, and the
manufacturing dates, control numbers, or marks identifying the Type A
medicated article(s) shipped.
21 CFR 226.115 Complaint files.
Records shall be maintained for a period of 2 years of all written or
verbal complaints concerning the safety or efficacy of each Type A
medicated article(s). Complaints shall be evaluated by competent and
responsible personnel and, where indicated, appropriate action shall be
taken. The record shall indicate the evaluation and the action.
21 CFR 226.115 Pt. 250
21 CFR 226.115 PART 250 -- SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS
21 CFR 226.115 Subpart A -- Drugs Regarded as Misbranded
Sec.
250.10 Oral prenatal drugs containing fluorides intended for human
use.
250.11 Thyroid-containing drug preparations intended for treatment of
obesity in humans.
250.12 Stramonium preparations labeled with directions for use in
self-medication regarded as misbranded.
21 CFR 226.115 Subpart B -- New Drug or Prescription Status of Specific
Drugs
250.100 Amyl nitrite inhalant as a prescription drug for human use.
250.101 Amphetamine and methamphetamine inhalers regarded as
prescription drugs.
250.102 Drug preparations intended for human use containing certain
''coronary vasodilators.''
250.103 Thorium dioxide for drug use.
250.104 Status of salt substitutes under the Federal Food, Drug, and
Cosmetic Act.
250.105 Gelsemium-containing preparations regarded as prescription
drugs.
250.106 Cobalt preparations intended for use by man.
250.107 (Reserved)
250.108 Potassium permanganate preparations as prescription drugs.
21 CFR 226.115 Subpart C -- Requirements for Drugs and Foods
250.201 Preparations for the treatment of pernicious anemia.
250.203 Status of fluoridated water and foods prepared with
fluoridated water.
21 CFR 226.115 Subpart D -- Requirements for Drugs and Cosmetics
250.250 Hexachlorophene, as a component of drug and cosmetic
products.
Authority: Secs. 201, 306, 402, 502, 503, 505, 601(a), 602 (a) and
(c), 701, 705(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321, 336, 342, 352, 353, 355, 361(a), 362 (a) and (c), 371, 375(b)).
Source: 40 FR 14033, Mar. 27, 1975, unless otherwise noted.
21 CFR 226.115 Subpart A -- Drugs Regarded as Misbranded
21 CFR 250.10 Oral prenatal drugs containing fluorides intended for
human use.
(a) The Food and Drug Administration finds that there is neither
substantial evidence of effectiveness nor a general recognition by
qualified experts that prenatal drug preparations containing fluorides
promote tooth development in the fetus, prevent dental caries in the
offspring, or prevent dental caries in pregnant women.
(b) Any such drug preparation that is so labeled, represented, or
advertised will be regarded as misbranded and subject to regulatory
proceedings unless such recommendations are covered by a new-drug
application, including substantial evidence of effectiveness, approved
pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act.
Any such drug preparation that is labeled, represented, or advertised as
containing fluorides as an active ingredient of the drug for prenatal
use will similarly be regarded as misbranded and subject to regulatory
proceedings.
(c) A completed and signed ''Investigational New Drug Application,''
set forth in part 312 of this chapter, must be submitted to cover
clinical investigations designed to obtain evidence that such
preparations are effective for such use.
(d) Regulatory proceedings may be initiated with respect to drug
preparations shipped within the jurisdiction of the act that are
contrary to provisions of this statement after 30 days from the date of
publication of this statement in the Federal Register.
(40 FR 14033, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29,
1990)
21 CFR 250.11 Thyroid-containing drug preparations intended for
treatment of obesity in humans.
(a) Investigation by the Food and Drug Administration has revealed
that a large number of drug preparations containing thyroid or
thyrogenic substances in combination with central nervous system
stimulants, with or without one or more additional drug substances such
as barbiturates or laxatives, are being marketed for or as adjuncts to
the treatment, control, or management of obesity in humans. The
Commissioner of Food and Drugs finds that the administration of such
combinations for said purposes is without medical rationale except
possibly in those relatively uncommon instances where the condition is
directly related to hypothyroidism and there exists a concurrent need
for appetite control (in such instances the safety and effectiveness of
such combinations are not generally recognized). In particular, the
Commissioner of Food and Drugs finds that neither the consensus of
informed medical opinion nor clinical experience justifies any
representation that such combinations are safe and effective in
connection with the treatment, control, or management of obesity in
patients having normal thyroid function.
(b) Combinations of thyroid or other thyrogenic drugs with central
nervous system stimulants with or without other drug substances when
offered for or as adjuncts to the treatment, control, or management of
obesity not related to hypothyroidism are regarded as misbranded. Such
combinations when offered for obesity in humans directly attributable to
established hypothyroidism are regarded as new drugs within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act.
21 CFR 250.12 Stramonium preparations labeled with directions for use
in self-medication regarded as misbranded.
(a) Stramonium products for inhalation have been offered for use in
the therapy of the acute attacks of bronchial asthma for many years
although their reliability and effectiveness are questionable.
Recently, a significantly increased number of reports have come to the
attention of the Food and Drug Administration showing that such products
have been subject to abuse and misuse on a fairly large scale, mostly by
young people, through oral ingestion for the purpose of producing
hallucinations. Reports of such use have been received from physicians
and police and other law enforcement authorities. Reports have also
appeared in the public press and in medical journals.
(b) Labeling these products with a warning that they are not for oral
ingestion has not been effective in protecting the public. Misuse of
stramonium preparations can cause serious toxic effects including toxic
delirium, visual disturbances, fever, and coma. A number of serious
reactions have already occurred from the oral ingestion of such
products.
(c) On the basis of this information, the Commissioner of Food and
Drugs has concluded that such articles have a potentiality for harmful
effect through misuse and are not safe for use except under the
supervision of a physician. In the interest of public health
protection, therefore, the Food and Drug Administration adopts the
following policy:
(1) Preparations containing stramonium supplied from the leaves,
seeds, or any other part of the plant in the form of a powder, pipe
mixture, cigarette, or any other form, with or without admixture of
other ingredients, will be regarded as misbranded if they are labeled
with directions for use in self-medication.
(2) The Food and Drug Administration will, on request, furnish
comment on proposed labeling limiting any such preparation to
prescription sale.
(d) The labeling or dispensing of stramonium preparations contrary to
this statement after 60 days following the date of its publication in
the Federal Register may be made the subject of regulatory proceedings.
21 CFR 250.12 Subpart B -- New Drug or Prescription Status of Specific Drugs
21 CFR 250.100 Amyl nitrite inhalant as a prescription drug for human
use.
(a) Amyl nitrite inhalant has been available over-the-counter for
emergency use by the patient in the management of angina pectoris for a
number of years. As a result of a proposed policy statement published
August 25, 1967 (32 FR 12404), the Commissioner of Food and Drugs
received reports of the abuse of this drug by those who do not require
it for medical purposes. Additionally, comment included a great deal of
concern expressed by individual physicians, medical associations,
pharmaceutical associations, manufacturers, and State and local health
authorities. Based on the information available, it is the opinion of
the Commissioner of Food and Drugs, concurred in by the Food and Drug
Administration Medical Advisory Board, that amyl nitrite inhalant is a
drug with a potentiality for harmful effect and that it should be
removed from over-the-counter status and restricted to sale on the
prescription of a practitioner licensed by law to administer such drug.
(b) Therefore, amyl nitrite inhalant will be regarded as misbranded
unless the labeling on or within the package from which the drug is to
be dispensed bears adequate information for its safe and effective use
by physicians, in accordance with 201.100(c) of this chapter, and its
label bears the legend ''Caution: Federal law prohibits dispensing
without prescription.''
(c) Regulatory proceedings may be initiated with regard to the
interstate shipment of amyl nitrite inhalant that is labeled,
advertised, or dispensed contrary to this statement of policy if such
act occurs after July 1, 1969.
21 CFR 250.101 Amphetamine and methamphetamine inhalers regarded as
prescription drugs.
(a) Recurring reports of abuse and misuse of methamphetamine (also
known as desoxyephedrine) inhalers show that they have a potentiality
for harmful effect and that they should not be freely available to the
public through over-the-counter sale. From complaints by
law-enforcement officials, health officials, individual physicians,
parents, and others as well as from Food and Drug Administration
investigations, it is evident that the wicks from these inhalers are
being removed and the methamphetamine they contain is being used as a
substitute for amphetamine tablets. Amphetamine tablets and amphetamine
inhalers have been restricted to prescription sale because of their
potentiality for harm to the user.
(b) It is the considered opinion of the Food and Drug Administration
that, in order to adequately protect the public health, inhalers
containing methamphetamine or methamphetamine salts (d-desoxyephedrine,
or dl-desoxyephedrine, or their salts), as well as amphetamine inhalers
should be restricted to prescription sale and should be labeled with the
legend ''Caution: Federal law prohibits dispensing without
prescription.''
21 CFR 250.102 Drug preparations intended for human use containing
certain ''coronary vasodilators.''
(a)(1) The Food and Drug Administration finds that the following
''coronary vasodilators'' are extensively regarded by physicians as safe
and useful as employed under medical supervision for the management of
angina pectoris in some patients:
Amyl nitrite.
Erythrityl tetranitrate.
Mannitol hexanitrate.
Nitroglycerin.
Potassium nitrite.
Sodium nitrite.
(2) Additionally, new-drug applications have been approved for
products containing:
Inositol hexanitrate.
Isosorbide dinitrate.
Octyl nitrite.
Pentaerythritol tetranitrate.
Triethanolamine trinitrate biphosphate (trolnitrate phosphate).
(b) The Food and Drug Administration also finds that there is neither
substantial evidence of effectiveness nor a general recognition by
qualified experts that such drugs are effective for any of the other
purposes for which some such drugs are promoted to the medical
profession in labeling and advertising. In particular, neither clinical
investigations nor clinical experience justify any representations that
such drugs are effective in the management of hypertension; in the
management of coronary insufficiency or coronary artery disease, except
for their anginal manifestations; or in the management of the post
coronary state, except angina pectoris present after coronary occlusion
and myocardial infarction.
(c) Any preparation containing such drugs that is labeled or
advertised for any use other than management of angina pectoris, or that
is represented to be efficacious for any other purpose by reason of its
containing such drug, will be regarded by the Food and Drug
Administration as misbranded and subject to regulatory proceedings,
unless such recommendations are covered by the approval of a new-drug
application based on a showing of safety and effectiveness.
(d) Any such drug in long-acting dosage form is regarded as a new
drug that requires an approved new-drug application before marketing.
(e) Any of the drugs listed in paragraph (a) (2) of this section is
regarded as a new drug that requires an approved new-drug application.
Articles for which new-drug approvals are now in effect should be
covered by supplemental new-drug applications as necessary to provide
for labeling revisions consistent with this policy statement.
21 CFR 250.103 Thorium dioxide for drug use.
(a) Thorium dioxide is a source of naturally occurring radioactivity
that has been used over a period of years as a radiopaque medium. When
thorium dioxide is injected, it is permanently stored in the body.
Because of its radioactivity, this storage causes scarring and
carcinogenesis in the area of storage. There are reports in the medical
literature of malignancy and deaths resulting from the injection of
thorium dioxide. Therefore, the use in man of drugs containing thorium
dioxide is justified only when this drug has a unique clinical
usefulness and there is substantial evidence of limited life expectancy
by reason of disease or advanced age. The administration of the drug to
food-producing animals cannot be justified since it may result in
residues of the drug in food.
(b) Drugs containing thorium dioxide are unsafe and are regarded as
misbranded within the meaning of section 502(f) (1), (2), and (j) of the
Federal Food, Drug, and Cosmetic Act when labeled or advertised for
administration to man except when they have a unique clinical usefulness
and there is substantial evidence of limited life expectancy by reason
of disease or advanced age.
(c) Drug preparations containing thorium dioxide may be approved for
marketing on the basis of new-drug applications containing labeling
bearing, in addition to other requirements, information to the following
effect, which differs substantially from the labeling that has been
employed in the past in the marketing of such drugs:
(1) Warning. For use only when this drug has a unique clinical
usefulness and there is substantial evidence of limited life expectancy
by reason of disease or advanced age. Not for administration to
food-producing animals.
(2) Precautions. Special precautions should be taken to prevent soft
tissue extravasation of the injected material. Precautions should be
taken to prevent injection of thorium dioxide into the subarachnoid
space.
(3) Indications for use. For demonstration of primary or secondary
tumors in the liver; for the delineation of the wall of a cystic
malignant brain tumor when such delineation is deemed advantageous for
purposes of progressive monitoring in the course of therapy.
(4) Dosage. Minimum amount necessary for adequate visualization
should be utilized.
(d) A new drug application will be regarded as approvable if it
contains appropriate labeling conforming to the provisions of paragraph
(c) of this section and satisfactory information of the kinds required
by 314.50 of this chapter.
(40 FR 14033, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29,
1990)
21 CFR 250.104 Status of salt substitutes under the Federal Food, Drug,
and Cosmetic Act.
(a) As a result of reported poisonings from salt substitutes
containing lithium chloride, under date of March 8, 1949, the Food and
Drug Administration announced that it would regard each salt substitute
as a new drug within the meaning of section 201(p) of the Federal Food,
Drug, and Cosmetic Act, and that interstate distribution of each salt
substitute should be discontinued until a new-drug application had been
filed and become effective. Substantial information concerning the
safety of many of the ingredients used in salt substitutes has been
developed and published since the announcement was made. It is now
possible to evaluate the safety of many individual salt substitutes and
to determine whether they are new drugs requiring effective applications
prior to distribution in interstate commerce.
(b) The Food and Drug Administration no longer regards all salt
substitutes as new drugs. Upon request, the Administration will express
its opinion whether a new-drug application is necessary for any
particular product if complete information concerning its composition
and proposed labeling is submitted.
21 CFR 250.105 Gelsemium-containing preparations regarded as
prescription drugs.
It is the consensus of informed medical opinion that the margin of
safety between the therapeutic and toxic concentration of gelsemium is
narrow and it is difficult to predict the point at which the dose will
be toxic. Very small doses may cause toxic symptoms. It is therefore
the view of the Food and Drug Administration that gelsemium is not a
proper ingredient in any product that is to be sold without
prescription. Accordingly, any drug containing gelsemium will be
regarded as misbranded under section 503(b)(4) of the Federal Food,
Drug, and Cosmetic Act if its label fails to bear in a prominent and
conspicuous fashion the statement ''Caution: Federal law prohibits
dispensing without prescription.''
21 CFR 250.106 Cobalt preparations intended for use by man.
(a) On January 17, 1967 (21 CFR 3.48; 32 FR 449), the Commissioner
of Food and Drugs issued a revised statement of policy with respect to
the status of cobalt-containing drug preparations intended for use by
man, which revision was to be modified as needed following consideration
of such drugs by a panel of hematologists. A panel consisting of
authorities in the field of hematology met on March 8, 1967, with
representatives of the Medical Advisory Board for the Food and Drug
Administration to consider the status of cobalt-containing drugs and the
following findings and recommendations were made:
(1) Cobalt salts are not suitable for over-the-counter sale to the
public for the treatment of iron-deficiency anemia. They are associated
with toxic effects and offer no advantage over iron alone.
(2) Potential toxic effects of these salts includes liver damage,
claudication, myocardial damage, thyroid hyperplasia, hypothyroidism,
dermatitis, nausea, and anorexia.
(3) Cobalt salts are not generally recognized as safe or effective
therapy for any disease condition.
(b) On the basis of the available evidence and the findings and
recommendations of the representatives of the Medical Advisory Board,
the Commissioner of Food and Drugs finds and determines with respect to
cobalt-containing drug preparations intended for use by man, except
radioactive forms of cobalt and its salts and cobalamin and its
derivatives, that:
(1) Such articles, because of their potential for causing toxic
effects, are not suitable for over-the-counter use in iron-deficiency
anemia; any such article that is labeled, represented, or advertised
for over-the-counter use in the prevention or treatment of
iron-deficiency anemia will be regarded as subject to regulatory
proceedings.
(2) Such articles are not generally recognized by qualified experts
as safe or effective therapeutic agents for iron-deficiency anemia or
for any condition whether for over-the-counter sale or for prescription
dispensing; any such article labeled, represented, or advertised for
any condition will be regarded as subject to regulatory proceedings
unless such recommendations are covered by a new-drug application
approved pursuant to section 505 of the Federal Food, Drug, and Cosmetic
Act and based on a showing of safety and effectiveness.
(3) Cobalt salts added to drugs in small amounts are not effective
for any purpose and should be removed.
(c) A completed and signed ''Investigational New Drug Application,''
set forth in part 312 of this chapter, must be submitted to cover
clinical investigations to obtain evidence that such preparations are
safe and effective for any purpose.
(d) (1) For such preparations for which new-drug approvals are in
effect, supplemental new-drug applications may be submitted if changes
consistent with this policy statement can be effected thereby. If the
composition and labeling of an article are such that the cobalt is not
significant in relation to the labeling claims, it will be permissible
for the applicant to remove the cobalt salt from the formulation, delete
all references to it in the labeling and resume marketing the
reformulated drug, provided that a supplement is submitted within 30
days from the date of publication of this policy statement in the
Federal Register furnishing full information regarding such changes,
including the date on which such changes are being effected.
(2) Applicants holding other approved new-drug applications for such
preparations should submit, within 30 days, a written statement waiving
opportunity for a hearing preliminary to withdrawing approval of the
application unless the applicant wishes to avail himself of the
opportunity for a hearing.
(e) Regulatory proceedings may be initiated with respect to any drug
within the jurisdiction of the act that is contrary to the provisions
of:
(1) Paragraph (b) of this section and shipped after the date of
publication of this policy statement in the Federal Register.
(2) Paragraphs (c) and (d) of this section and shipped after 30 days
from the date of publication of this policy statement in the Federal
Register.
(40 FR 14033, Mar. 27, 1975, as amended at 55 FR 11577, Mar. 29,
1990)
250.107 (Reserved)
21 CFR 250.108 Potassium permanganate preparations as prescription
drugs.
(a) There have been a number of reports in the medical literature of
serious injuries to women resulting from the misuse of potassium
permanganate in an effort to induce abortion. Reports from physicians
who have treated such cases show that the injuries are commonly caused
by introducing tablets or crystals of potassium permanganate into the
vagina. Experience with these cases shows that such use of potassium
permanganate is not effective in producing abortion, but that instead
the drug produces serious and painful injury to the walls of the vagina,
causing ulcers, massive hemorrhage, and infection. Such dangerous and
useless employment of potassium permanganate is apparently encouraged
among the misinformed by the mistaken idea that the vaginal bleeding
caused by the corrosive action of the drug indicates a termination of
pregnancy, which it does not.
(b) Potassium permanganate is a strong oxidizing agent, a highly
caustic, tissue-destroying chemical, and a poison. There are no
circumstances under which crystals and tablets of potassium permanganate
constitute safe dosage forms for use in self-medication. It is the
consensus of informed medical opinion that the only dosage forms of
potassium permanganate known to be safe for use in self-medication are
aqueous solutions containing not more than 0.04 percent potassium
permanganate. Such solutions are safe for use in self-medication only
by external application to the skin.
(c) In view of the very real potentiality for harmful effect, and the
actual injuries caused by the misuse of potassium permanganate, the Food
and Drug Administration believes that in order adequately to protect the
public health:
(1) Potassium permanganate and potassium permanganate tablets
intended for human use are drugs subject to section 503(b)(1) of the
Federal Food, Drug, and Cosmetic Act and should be restricted to
prescription sale. Such drugs will be regarded as misbranded if at any
time prior to dispensing the label fails to bear the legend, ''Caution:
Federal law prohibits dispensing without prescription.''
(2) Potassium permanganate labeled for use as a prescription
component in human drugs under the exemption provided in 201.120 of
this chapter or labeled for manufacturing use under the exemption
provided in 201.122 of this chapter will be regarded as misbranded
unless the label bears the statement, ''Caution: Federal law prohibits
dispensing without prescription.''
(3) These drugs will be regarded as misbranded when intended for
veterinary use unless the label bears the legend, ''Caution: Federal
law restricts this drug to sale by or on the order of a licensed
veterinarian''; Provided, however, That this shall not apply to a drug
labeled and marketed for veterinary use if such drug contains not more
than 50 percent of potassium permanganate and includes other ingredients
which make it unsuitable for human use and unlikely that the article
would be used in an attempt to induce abortion.
(4) Any preparation of potassium permanganate intended for
over-the-counter sale for human use internally or by application to any
mucous membranes or for use in the vagina will be regarded as misbranded
under the provisions of section 502(f) (1) and (2) and section 502(j) of
the act.
(5) Any other preparation of potassium permanganate intended for
over-the-counter sale for human use will be regarded as misbranded under
section 502(f) (1) and (2) and section 502(j) of the act unless, among
other things, all of the following conditions are met:
(i) It is an aqueous solution containing not more than 0.04 percent
potassium permanganate.
(ii) The label and labeling bear, in juxtaposition with adequate
directions for use, clear warning statements designated as ''Warning,''
and to the effect: ''Warning -- For external use on the skin only.
Severe injury may result from use internally or as a douche. Avoid
contact with mucous membranes.''
(d) The labeling or dispensing of any potassium permanganate
preparations intended for drug use within the jurisdiction of the
Federal Food, Drug, and Cosmetic Act contrary to this statement after 60
days from the date of its publication in the Federal Register may be
made the subject of regulatory proceedings.
21 CFR 250.108 Subpart C -- Requirements for Drugs and Foods
21 CFR 250.201 Preparations for the treatment of pernicious anemia.
(a) The ninth announcement of the Anti-anemia Preparations Advisory
Board of the United States Pharmacopeia is concerned with the status of
the treatment of pernicious anemia. It clearly presents the following
facts:
(1) The Sixteenth Revision of the Pharmacopeia of the United States,
which became official on October 1, 1960, does not include preparations
intended for the treatment of pernicious anemia by oral administration.
(2) The U.S.P. unit for anti-anemia preparations no longer has any
significance.
(3) The U.S.P. Anti-anemia Preparations Advisory Board was disbanded.
(b) On the basis of the scientific evidence and conclusions
summarized in the statement of the U.S.P. Anti-anemia Preparations
Advisory Board as well as pertinent information from other sources, the
Commissioner of Food and Drugs finds it is the consensus of well
informed medical opinion that:
(1) The parenteral administration of cyanocobalamin or vitamin B12 is
generally recognized as a fully effective treatment of pernicious
anemia. Parenteral cyanocobalamin preparations have not been and are
not authorized for use except by or on the prescription of a duly
licensed medical practitioner.
(2) Some patients afflicted with pernicious anemia do not respond to
orally ingested products. There is no known way to predict which
patients will fail to respond or will cease to respond to the treatment
of pernicious anemia with orally ingested preparations.
(3) The substitution of a possibly inadequate treatment, such as the
ingestion of oral preparations of vitamin B12 with intrinsic factor
concentrate, in place of parenteral vitamin B12 products for a disease
condition as serious as pernicious anemia cannot be regarded as safe in
all cases.
(4) The development of the classical symptoms of pernicious anemia
that would cause a person to seek medical attention may in some cases be
delayed by oral ingestion of intrinsic factor. Pernicious anemia is a
disease that is associated, among other things, with a higher than
normal incidence of cancer of the stomach and that for the safety of the
patient, requires continuous expert medical supervision.
(5) With inadequate treatment there may be markedly deleterious
effects on the nervous system. It is well established that whereas the
development of anemia is completely reversible with adequate treatment,
the involvement of the nervous system may not be completely reversible
and thus may result in permanent damage.
(6) Some hematologists prescribe oral preparations of vitamin B12 in
the treatment of pernicious-anemia patients.
(7) Intrinsic factor and intrinsic factor concentrate serve no known
useful therapeutic or nutritive purpose except to the extent that they
do increase the gastrointestinal absorption of vitamin B12 in patients
with a deficiency or absence of intrinsic factor, which may eventually
lead to pernicious anemia. This conclusion does not apply to diagnostic
procedures using radioactive cyanocobalamin.
(8) Medical expertise is required for the diagnosis as well as the
management of pernicious anemia.
(c) The Eleventh Edition of The National Formulary and its first
Interim Revision include monographs for oral preparations of vitamin B12
with intrinsic factor concentrate, establish a unit of vitamin B12 with
intrinsic factor concentrate, and provide for a National Formulary
Anti-anemia Preparations Advisory Board to assign the potency of such
preparations. This provides for the availability of such oral
preparations, standardized within the meaning of the broad limits
characteristic of the evaluation of such preparations.
(d) Any drug that is offered for or purports to contain intrinsic
factor or intrinsic factor concentrate will be regarded as misbranded
within the meaning of section 503(b) of the Federal Food, Drug, and
Cosmetic Act unless it is labeled with the legend ''Caution -- Federal
law prohibits dispensing without prescription.''
(e) Any drug for oral ingestion intended, represented, or advertised
for the prevention or treatment of pernicious anemia or which purports
to contain any substance or mixture of substances described in paragraph
(d) of this section (other than diagnostic drugs containing radioactive
cyanocobalamin) will be regarded as misbranded under sections 502(f)(2)
and (j) of the act unless its labeling bears a statement to the effect
that some patients afflicted with pernicious anemia may not respond to
the orally ingested product and that there is no known way to predict
which patients will respond or which patients may cease to respond to
the orally ingested products. The labeling shall also bear a statement
that periodic examinations and laboratory studies of pernicious anemia
patients are essential and recommended.
(f) Under section 409 of the Federal Food, Drug, and Cosmetic Act,
intrinsic factor and intrinsic factor concentrate are regarded as food
additives. No food additive regulation nor existing extension of the
effective date of section 409 of the act authorizes these additives in
foods, including foods for special dietary uses. Any food containing
added intrinsic factor or intrinsic factor concentrate will be regarded
as adulterated within the meaning of section 402(a)(2)(C) of the act.
(g) Regulatory action may be initiated with respect to any article
shipped within the jurisdiction of the act contrary to the provisions of
this policy statement after the 180th day following publication of this
statement in the Federal Register.
21 CFR 250.203 Status of fluoridated water and foods prepared with
fluoridated water.
(a) The program for fluoridation of public water supplies recommended
by the Department of Health and Human Services, through the Public
Health Service (Centers for Disease Control), contemplates the
controlled addition of fluorine at a level optimum for the prevention of
dental caries.
(b) Public water supplies do not ordinarily come under the provisions
of the Federal Food, Drug, and Cosmetic Act. Nevertheless, a
substantial number of inquiries have been received concerning the status
of such water under the provisions of the act and the status, in
interstate commerce, of commercially prepared foods in which fluoridated
water has been used.
(c) The Department of Health and Human Services will regard water
supplies containing fluorine, within the limitations recommended by the
Environmental Protection Agency, as not actionable under the Federal
Food, Drug, and Cosmetic Act. Similarly, commercially prepared foods
within the jurisdiction of the act, in which a fluoridated water supply
has been used in the processing operation, will not be regarded as
actionable under the Federal law because of the fluorine content of the
water so used, unless the process involves a significant concentration
of fluorine from the water. In the latter instance the facts with
respect to the particular case will be controlling.
(40 FR 14033, Mar. 27, 1975, as amended at 48 FR 11426, Mar. 18,
1983)
21 CFR 250.203 Subpart D -- Requirements for Drugs and Cosmetics
21 CFR 250.250 Hexachlorophene, as a component of drug and cosmetic
products.
(a) Antibacterial component. The use of hexachlorophene as an
antibacterial component in drug and cosmetic products has expanded
widely in recent years. It is used in such products because of its
bacteriostatic action against gram-positive organisms, especially
against strains of staphylococcus; however, hexachlorophene offers no
protection against gram-negative infections. In addition the
antibacterial activity depends largely on repeated use. A notice
published in the Federal Register of April 4, 1972 (37 FR 6775), invited
data on OTC antimicrobial ingredients, including hexachlorophene, for
review by an OTC Drug Advisory Review Panel to be convened under the
procedures set forth in the Federal Register of May 11, 1972 (37 FR
9464). This statement of policy will remain in effect unless and until
replaced by a monograph resulting from the OTC Drug Advisory Review
Panel.
(b) Adverse effects. Though considered safe for many years, recent
information has become available associating hexachlorophene with toxic
effects, including deaths. Studies have shown that toxic amounts of
hexachlorophene can be absorbed through the skin of humans, especially
the skin of premature babies or damaged skin. Human toxicity reports
include data on symptomatology, blood and tissue levels of
hexachlorophene, and descriptions of neuropathologic lesions. Recent
infant deaths due to use of baby powder accidentally contaminated with 6
percent hexachlorophene have occurred. The accumulated evidence of
toxicity is sufficient to require that continued marketing of
hexachlorophene containing products be carefully defined in order to
protect consumers.
(c) Prescription drugs. (1) Because of their potential for harmful
effect, drugs containing hexachlorophene, other than as a preservative
as described below, are not considered to have been shown to be safe and
effective, are regarded as new drugs requiring approved new drug
applications, and would be misbranded for over-the-counter distribution.
In the interest of public health protection, hexachlorophene containing
drugs will be regarded as misbranded and subject to regulatory
proceedings unless the label bears the legend ''Caution: Federal law
prohibits dispensing without a prescription,'' and the labeling on or
within the package from which the drug is to be dispensed bears adequate
information for its safe and effective use by practitioners, in accord
with 201.100(c) of this chapter.
(2) The Food and Drug Administration recognizes that hexachlorophene
is useful as a bacteriostatic skin cleanser. It further concludes that
the margin of safety is such that products containing hexachlorophene
may appropriately be used within clearly delineated conditions of use.
(3) In order for such drugs to bear adequate information for safe and
effective use the following statements are representative of the type of
labeling for products shown to be effective bacteriostatic skin
cleansers. Labeling for products other than bacteriostatic skin
cleansers will be determined through the new drug procedures based on
the available data.
(i) In the labeling other than on the immediate container label.
1. Bacteriostatic skin cleanser for surgical scrubbing or handwashing
as part of patient care.
2. For topical application to control an outbreak of gram-positive
infection where other infection control procedures have been
unsuccessful. Use only as long as necessary for infection control.
1. Not for use on burned or denuded skin or on mucous membranes.
2. Not for routine prophylactic total body bathing.
Rinse thoroughly after use. Patients should be closely monitored and
use should be immediately discontinued at the first sign of any of the
symptoms described below.
Hexachlorophene is rapidly absorbed and may produce toxic blood
levels when applied to skin lesions such as ichthyosis congenita or the
dermatitis of Letterer-Siwe's syndrome or other generalized dermatologic
conditions. Application to burns has also produced neurotoxicity and
death.
Infants have developed dermatitis, irritability, generalized clonic
muscular contractions and decerebrate rigidity following application of
a 6 percent hexachlorophene powder. Examination of brainstems of those
infants revealed vacuolization like that which can be produced in
newborn experimental animals following repeated topical application of 3
percent hexachlorophene. Moreover, a study of histologic sections of
premature infants who died of unrelated causes has shown a positive
correlation between hexachlorophene baths and lesions in white matter of
brains.
(ii) On the immediate container label prominently displayed and in
bold print:
''Special Warning: This compound may be toxic if used other than as
directed. Rinse thoroughly after use. Monitor patients closely for
toxicity symptoms.''
(4) Marketing of products for the indications listed in paragraph (c)
(3) of this section may be continued without an approved new drug
application (or required supplement thereto) either until a notice of
opportunity for hearing is issued on a proposal by the Director of the
Center for Drug Evaluation and Research to refuse to approve such new
drug application (or required supplement) or until January 31, 1978,
whichever comes first, if all the following conditions were met after
September 27, 1972:
(i) The product is labeled with the prescription legend and adequate
information for safe and effective use as set forth in paragraph (c) (3)
of this section.
(ii) Within 30 days, or by (10-27-72) the holder of an approved new
drug application submits a supplement to provide for the revised label
and full disclosure labeling. As the label and labeling will have been
put into use, the supplement should be submitted under the provision of
314.70(c)(2) of this chapter.
(iii) Within 30 days, or by (10-27-72) the holder of an approved new
drug application submits a supplement to provide for a revised
formulation where appropriate to comply with this order.
(iv) Within 90 days, or by (12-26-72) the holder of an approved new
drug application submits a supplement containing blood level data
obtained from use of the drug as recommended, unless such information is
a part of the new drug application file.
(v) Within 90 days, or by (12-26-72), the manufacturer or distributor
of such a drug for which a new drug approval is not in effect submits a
new drug application in accord with 314.50 of the new drug regulations
(21 CFR 314.50), including blood level data obtained from use of the
drug as recommended.
(5) Prescription drug products may contain hexachlorophene as part of
an effective preservative system only under the conditions and
limitations provided for under paragraph (d) of this section.
(d) Over-the-counter (OTC) drugs. Over-the-counter drug products,
other than those which in normal use may be applied to mucous membranes
or which are intended to be used on mucous membranes, may contain
hexachlorophene only as part of an effective preservative system, at a
level that is no higher than necessary to achieve the intended
preservative function, and in no event higher than 0.1 percent. Such use
of hexachlorophene shall be limited to situations where an alternative
preservative has not yet been shown to be as effective or where adequate
integrity and stability data for the reformulated product are not yet
available. This use of hexachlorophene will not, by itself, require an
approved new drug application. Use of hexachlorophene as a preservative
at a level higher than 0.1 percent is regarded as a new drug use
requiring an approved new drug application, which must be submitted
within the time set out in paragraph (c) (4) of this section.
(e) Cosmetics. Hexachlorophene may be used as a preservative in
cosmetic products other than those which in normal use may be applied to
mucous membranes or which are intended to be used on mucous membranes,
at a level that is no higher than necessary to achieve the intended
preservative function, and in no event higher than 0.1 percent. Such use
of hexachlorophene shall be limited to situations where an alternative
preservative has not yet been shown to be as effective or where adequate
integrity and stability data for the reformulated product are not yet
available. The component of a preservative system whether
hexachlorophene or other antimicrobial agent, should be selected on the
basis of the effect on the total microbial ecology of the product, not
merely on gram-positive bacteria.
(1) Adequate safety data do not presently exist to justify wider use
of hexachlorophene in cosmetics.
(2) Antibacterial ingredients used as substitutes for hexachlorophene
in cosmetic products, and finished cosmetic products containing such
ingredients, shall be adequately tested for safety prior to marketing.
Any such ingredient or product whose safety is not adequately
substantiated prior to marketing may be adulterated and will in any
event be deemed misbranded unless it contains a conspicuous front panel
statement that the product has not been adequately tested for safety and
may be hazardous.
(f) Content statement. All reference to hexachlorophene limit in
this order is on a weight-in-weight (w/w) basis. Quantitative
declaration of hexachlorophene content on the labeling of the products,
where required, shall be on a w/w basis.
(g) Shipments of products. Shipments of products falling within the
scope of paragraphs (c), (d), or (e) of this section which are not in
compliance with the guidelines stated herein shall be the subject of
regulatory proceedings after the effective date of the final order.
(h) Prior notices. This order preempts any conditions for marketing
products set forth in the following prior notices.
1. DESI No. 4749 (34 FR 15389, October 2, 1969), ''Certain OTC Drugs
for Topical Use.''
2. DESI No. 2855 (35 FR 12423, August 4, 1970), ''Certain Mouthwash
and Gargle Preparations.''
3. DESI No. 8940 (36 FR 14510, August 6, 1971), ''Topical Cream
Containing Pyrilamine Maleate, Benzocaine, Hexachlorophene, and
Cetrimonium Bromide.''
4. DESI No. 6615 (36 FR 18022, September 8, 1971),
''Deodorant/Antiperspirant.''
5. DESI No. 6270 (36 FR 23330, December 8, 1971), ''Certain
Preparations Containing Hexachlorophene''.
(40 FR 14033, Mar. 27, 1975, as amended at 42 FR 63773, Dec. 20,
1977; 55 FR 11577, Mar. 29, 1990)
21 CFR 250.250 Pt. 290
21 CFR 250.250 PART 290 -- CONTROLLED DRUGS
21 CFR 250.250 Subpart A -- General Provisions
Sec.
290.5 Drugs; statement of required warning.
290.6 Spanish-language version of required warning.
290.10 Definition of emergency situation.
21 CFR 250.250 Subpart B -- (Reserved)
21 CFR 250.250 Subpart C -- Requirements for Specific Controlled Drugs
-- (Reserved)
Authority: Secs. 502, 503, 505, 701 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 352, 353, 355, 371).
Source: 40 FR 14040, Mar. 27, 1975, unless otherwise noted.
21 CFR 250.250 Subpart A -- General Provisions
21 CFR 290.5 Drugs; statement of required warning.
The label of any drug listed as a ''controlled substance'' in
schedule II, III, or IV of the Federal Controlled Substances Act shall,
when dispensed to or for a patient, contain the following warning:
''Caution: Federal law prohibits the transfer of this drug to any
person other than the patient for whom it was prescribed.'' This
statement is not required to appear on the label of a controlled
substance dispensed for use in clinical investigations which are
''blind.''
21 CFR 290.6 Spanish-language version of required warning.
By direction of section 305(c) of the Federal Controlled Substances
Act, 290.5, promulgated under section 503(b) of the Federal Food, Drug,
and Cosmetic Act, requires the following warning on the label of certain
drugs when dispensed to or for a patient: ''Caution: Federal law
prohibits the transfer of this drug to any person other than the patient
for whom it was prescribed.'' The Spanish version of this is:
''Precaucion: La ley Federal prohibe el transferir de esta droga a otra
persona que no sea el paciente para quien fue recetada.''
21 CFR 290.10 Definition of emergency situation.
For the purposes of authorizing an oral prescription of a controlled
substance listed in schedule II of the Federal Controlled Substances
Act, the term ''emergency situation'' means those situations in which
the prescribing practitioner determines:
(a) That immediate administration of the controlled substance is
necessary, for proper treatment of the intended ultimate user; and
(b) That no appropriate alternative treatment is available, including
administration of a drug which is not a controlled substance under
schedule II of the Act, and
(c) That it is not reasonably possible for the prescribing
practitioner to provide a written prescription to be presented to the
person dispensing the substance, prior to the dispensing.
21 CFR 290.10 Subpart B -- (Reserved)
21 CFR 290.10 Subpart C -- Requirements for Specific Controlled Drugs -- (Reserved)
21 CFR 290.10 Pt. 291
21 CFR 290.10 PART 291 -- DRUGS USED FOR TREATMENT OF NARCOTIC ADDICTS
Secs.
291.501 Methadone in the maintenance treatment of narcotic addicts.
291.505 Conditions for the use of narcotic drugs; appropriate
methods of professional practice for medical treatment of the narcotic
addiction of various classes of narcotic addicts under section 4 of the
Comprehensive Drug Abuse Prevention and Control Act of 1970.
Authority: Secs. 505, 701 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 355, 371); 21 U.S.C. 823; secs. 301(d), 548 of the
Public Health Service Act (42 U.S.C. 241(d), 290ee-3); 42 U.S.C. 257a.
21 CFR 291.501 Methadone in the maintenance treatment of narcotic
addicts.
(a) The Food and Drug Administration and the Drug Enforcement
Administration recognize that the investigational use of methadone
requiring the prolonged maintenance of narcotic dependence as part of a
total treatment effort has shown promise in the management and
rehabilitation of selected narcotic addicts. It is also recognized that
a number of dangers and possible abuses may arise from such efforts if
professional services and controls are inadequately applied. It is
further felt that additional research is urgently needed so that data
may be accumulated which will permit sound determinations of safety,
efficacy, and necessary procedural safeguards.
(b) Therefore, the Commissioner of Food and Drugs and the Director of
the Drug Enforcement Administration, Department of Justice, agree that
interested professionals, municipalities, and organizations should be
allowed to conduct further research in this area within a framework of
adequate controls designed to protect the individual patients and the
community. To facilitate this purpose, the Food and Drug Administration
and the Drug Enforcement Administration, Department of Justice, have
jointly agreed upon acceptable criteria and guidelines which are set
forth in 291.505. In addition, such other provisions of the Federal
narcotic laws and regulations as are applicable must also be observed.
(42 FR 46698, Sept. 16, 1977)
21 CFR 291.505 Conditions for the use of narcotic drugs; appropriate
methods of professional practice for medical treatment of the narcotic
addiction of various classes of narcotic addicts under section 4 of the
Comprehensive Drug Abuse Prevention and Control Act of 1970.
(a) Definitions. As used in this part:
(1) Detoxification treatment means the dispensing of a narcotic drug
in decreasing doses to an individual to alleviate adverse physiological
or psychological effects incident to withdrawal from the continuous or
sustained use of a narcotic drug and as a method of bringing the
individual to a narcotic drug-free state within such period. There are
two types of detoxification treatment: short-term detoxification
treatment and long-term detoxification treatment.
(i) Short-term detoxification treatment is for a period not in excess
of 30 days.
(ii) Long-term detoxification treatment is for a period more than 30
days but not in excess of 180 days.
(2) Maintenance treatment means the dispensing of a narcotic drug in
the treatment of an individual for dependence on heroin or other
morphine-like drug.
(3) A medical director is a physician, licensed to practice medicine
in the jurisdiction in which the program is located, who assumes
responsibility for the administration of all medical services performed
by the narcotic treatment program including ensuring that the program is
in compliance with all Federal, State, and local laws and regulations
regarding the medical treatment of narcotic addiction with a narcotic
drug.
(4) A medication unit is a facility established as part of, but
geographically dispersed, i.e., separate from a narcotic treatment
program from which licensed private practitioners and community
pharmacists --
(i) Are permitted to administer and dispense a narcotic drug, and
(ii) Are authorized to collect samples for drug testing or analysis
for narcotic drugs.
(5) Narcotic dependent means an individual who physiologically needs
heroin or a morphine-like drug to prevent the onset of signs of
withdrawal.
(6) A narcotic treatment program is an organization (or a person,
including a private physician) that administers or dispenses a narcotic
drug to a narcotic addict for maintenance or detoxification treatment,
provides, when appropriate or necessary, a comprehensive range of
medical and rehabilitative services, is approved by the State authority
and the Food and Drug Administration, and that is registered with the
Drug Enforcement Administration to use a narcotic drug for the treatment
of narcotic addiction.
(7) A program sponsor is a person (or representative of an
organization) who is responsible for the operation of a narcotic
treatment program and who assumes responsibility for all its employees
including any practitioners, agents, or other persons providing services
at the program (including its medication units).
(8) The term services, as used in this part, includes medical
evaluations, counseling, rehabilitative and other social programs (e.g.,
vocational and educational guidance, employment placement), which will
help the patient become a productive member of society.
(9) A State authority is the agency designated by the Governor or
other appropriate official to exercise the responsibility and authority
within the State or Territory for governing the treatment of narcotic
addiction with a narcotic drug.
(b) Organizational structure and approval requirements --
(1) Organizational structure. (i) A narcotic treatment program may
be an independent organization or part of a centralized organization.
For example, if a centralized organizational structure consists of a
primary facility and other outpatient facilities, all of which conduct
initial evaluation of patients and administer or dispense medication,
the primary facility and each outpatient facility are separate programs,
even though some services (e.g., the same hospital or rehabilitative
services) are shared.
(ii) The program sponsor shall submit to the Food and Drug
Administration and the State authority a description of the
organizational structure of the program, the name of the persons
responsible for the program, the address of the program, and the
responsibilities of each facility or medication unit. The sources of
funding for each program shall be listed and the name and address of
each governmental agency providing funding shall be stated.
(iii) Where two or more programs share a central administration
(e.g., a city or State-wide organization), the person responsible for
the organization (administrator or program sponsor) is required to be
listed as the program sponsor for each separate participating program.
An individual program shall indicate its participation in the central
organization at the time of its application. The administrator or
sponsor may fulfill all recordkeeping and reporting requirements for
these programs, but each program must continue to receive separate
approval.
(iv) One physician may assume primary medical responsibility for more
than one program and be listed as medical director. If a physician
assumes medical responsibility for more than one program, a statement
documenting the feasibility of the arrangement is required to be
attached to the application.
(v) (Reserved)
(2)(i) Program approval. Before a narcotic treatment program may be
lawfully operated, the program, whether an outpatient facility or a
private practitioner, shall submit the applications specified in this
section simultaneously to the Food and Drug Administration and the State
authority and must receive the approval of both, except as provided for
in paragraph (h)(5) of this section. Before granting approval, the Food
and Drug Administration will consult with the Drug Enforcement
Administration, Department of Justice, to ascertain if the program is in
compliance with Federal controlled substances laws. Each physical
location within any program is required to be identified and listed in
the approval application. At the time of application for approval, the
program sponsor shall indicate whether medication will be administered
or dispensed at the facility. Before medication may be administered or
dispensed at a location not previously approved for this purpose, the
program is required to obtain approval from FDA and the State agency.
However, no approval is necessary, but notification is required when a
facility in which medication is administered or dispensed is deleted by
a program. In that event, the program shall notify the Food and Drug
Administration and the State authority within three weeks of the
deletion. Similarly, addition or deletion of facilities which provide
services other than administering or dispensing medication is also
permitted without approval, but notification must be made within 3 weeks
to the Food and Drug Administration and the State authority about the
addition and/or deletion.
(ii) Exemption of Federal programs. The provisions of this section
requiring approval (or permitting disapproval or revocation of approval)
by the State authority, compliance with requirements imposed by State
law, or the submission of applications or reports required by the State
authority do not apply to programs operated directly by the Veterans'
Administration or any other department or agency of the United States.
Federal agencies operating narcotic treatment programs have agreed to
cooperate voluntarily with State agencies by granting permission on an
informal basis for designated State representatives to visit Federal
narcotic treatment programs and by furnishing a copy of Federal reports
to the State authority, including the reports required under this
section.
(iii) Services. Each narcotic treatment program shall provide
medical and rehabilitative services and programs. (See paragraph (d)(4)
of this section.) These services should normally be made available at
the primary facility, but the program sponsor may enter into a formal
documented agreement with private or public agencies, organizations, or
institutions for these services if they are available elsewhere. The
program sponsor, in any event, must be able to document that medical and
rehabilitative services are fully available to patients.
(iv) Prohibition against unapproved use of narcotic drugs. No
prescribing, administering, or dispensing of a narcotic drug for the
treatment of narcotic addiction may occur without prior approval by the
Food and Drug Administration and the State authority, except as provided
for in paragraph (h)(5) of this section, unless specifically exempted by
this section.
(v) Approved narcotic drugs for use in treatment programs. The
following narcotic drug has been approved for use in the treatment of
narcotic addiction: Methadone.
(3)(i) Medication unit. A program may establish a medication unit to
facilitate the needs of patients who are stabilized on an optimal dosage
level. To lawfully operate a medication unit, the program shall, for
each separate unit, obtain approval from the Food and Drug
Administration, the Drug Enforcement Administration, and the State
authority, except as provided for in paragraph (h)(5) of this section.
The Food and Drug Administration, in determining whether to approve a
medication unit, will consider the distribution of units within a
particular geographic area. Any new medication unit is required to
receive approval before it may lawfully commence operation.
(ii) Revocation of approval. If the Food and Drug Administration
revokes the primary program's approval, the approval for any medication
unit associated with the program is deemed to be automatically revoked.
The Food and Drug Administration's revocation of the approval of a
particular medication unit, will not, in and of itself, affect the
approval of the primary program.
(iii) Narcotic drug supply. A medication unit must receive its
supply of the narcotic drug directly from the stocks of the primary
facility. Only persons permitted to administer or dispense the drug or
security personnel licensed or otherwise authorized by State law to do
so may deliver the drug to a medication unit.
(iv) Referral. (A) The patient shall be stabilized at his or her
optimal dosage level before he or she may be referred to a medication
unit.
(B) Since the medication unit does not provide a range of services,
the program sponsor shall determine that the patient to be referred is
not in need of frequent counseling, rehabilitative, and other services
which are only available at the primary program facility.
(v) Services. A medication unit is limited to administering or
dispensing a narcotic drug and collecting samples for drug testing or
analysis for narcotic drugs in accordance with paragraph (d)(2) of this
section. If a private practitioner wishes to provide other services
besides administering or dispensing a narcotic drug and collecting
samples for drug testing or analysis for narcotic drugs, he or she must
submit an application for separate approval.
(vi) Responsibility for patient. After a patient is referred to a
medication unit, the program sponsor retains continuing responsibility
for the patient's care. The program sponsor shall ensure that the
patient receives needed medical and rehabilitative services at the
primary facility.
(c) Conditions for approval of the use of a narcotic drug in a
treatment program -- (1) Applicants. An individual listed as program
sponsor for a treatment program using a narcotic drug need not
personally be a licensed practitioner but shall employ a licensed
physician for the position of medical director. Persons responsible for
administering or dispensing the narcotic drug shall be practitioners as
defined by section 102(21) of the Controlled Substances Act (21 U.S.C.
802(21)) and licensed to practice by the State in which the program is
to be established.
(2)(i) Assent to regulation. A person who sponsors a narcotic
treatment program, and any persons responsible for a particular program,
shall agree to adhere to all the rules, directives, and procedures, set
forth in this section, and any regulation regarding the use of narcotic
drugs in the treatment of narcotic addiction which may be promulgated in
the future. The program sponsor has responsibility for all personnel
and individuals providing services, who work in the program at the
primary facility or at other facilities or medication units. The
program sponsors shall agree to inform all personnel and individuals
providing services of the provisions of this section and to monitor
their activities to assure compliance with the provisions.
(ii) The Food and Drug Administration and the State authority are
required to be notified within 3 weeks of any replacement of the program
sponsor or medical director. Activities in violation of this regulation
may give rise to the sanctions set forth in paragraph (i) of this
section.
(3) Description of facilities. Only program site(s) approved by
Federal, State, and local authorities may treat narcotic addicts with a
narcotic drug. To obtain program approval, the applicant shall
demonstrate that he or she will have access to adequate physical
facilities to provide all necessary services. A program must have ready
access to a comprehensive range of medical and rehabilitative services
so that the services may be provided when necessary. The name, address,
and description of each hospital, institution, clinical laboratory, or
other facility available to provide the necessary services are required
to be included in the application submitted to the Food and Drug
Administration and the State authority. The application is also
required to include the name and address of each medication unit.
(4) Submission of proper applications. The following applications
shall be filed simultaneously with both the Food and Drug Administration
and the State authority:
(i) Form FDA-2632 ''Application for Approval of Use of Methadone in a
Treatment Program.'' This form, required by paragraph (k) of this
section, shall be completed and signed by the program sponsor and
submitted in duplicate to the Food and Drug Administration and the State
authority.
(ii) Form FDA-2633 ''Medical Responsibility Statement for Use of
Methadone in a Treatment Program.'' This form, required by paragraph (k)
of this section, shall be completed and signed by each licensed
physician authorized to administer or dispense narcotic drugs and
submitted in duplicate to the Food and Drug Administration and the State
authority. The names of any other persons licensed by law to administer
or dispense narcotic drugs working in the program shall be listed even
if they are not responsible for administering or dispensing the drug at
the time the application is submitted.
(5) State and Federal approval, denial, and revocation of approval of
narcotic treatment programs. (i) The Food and Drug Administration may
grant approval to a program only after FDA has received notification
from both the State authority and the Drug Enforcement Administration
that the program conforms to all pertinent State and Federal
requirements.
(ii) The Food and Drug Administration will revoke the approval of a
narcotic treatment program if so requested by the State authority or the
Drug Enforcement Administration. If approval of a program is denied or
revoked, the program shall have a right to appeal to the Commissioner,
as provided for in paragraph (h)(5) of this section.
(iii) No shipment of a narcotic drug may lawfully be made to any
program which does not have current approval from the Food and Drug
Administration. Within 60 days after receipt of the application from
the program sponsor for approval, the Food and Drug Administration will
notify the sponsor whether the application is approved or denied.
(d)(1) Minimum standards for admission -- (i) History of addiction
and current physiologic dependence. (A) A person may be admitted as a
patient for a maintenance program only if a program physician determines
that the person is currently physiologically dependent upon a narcotic
drug and became physiologically dependent at least 1 year before
admission for maintenance treatment. A 1-year history of addiction
means that an applicant for admission to a maintenance program was
physiologically addicted to a narcotic at a time at least 1 year before
admission to a program and was addicted, continuously or episodically,
for most of the year immediately before admission to a program. In the
case of a person for whom the exact date on which physiological
addiction began cannot be ascertained, the admitting program physician
may, in his or her reasonable clinical judgment, admit the person to
maintenance treatment, if from the evidence presented, observed, and
recorded in the patient's record, it is reasonable to conclude that
there was physiologic dependence at a time approximately 1 year before
admission.
(B) Although daily use of a narcotic for an entire year could satisfy
the regulatory definition of a 1-year history of addiction,
operationally one might be physiologically dependent without daily use
during the entire 1-year period and still satisfy the definition. The
following, although not exhaustive, are examples of applicants who would
meet the minimum standard of a 1-year history of addiction and who, if
currently physiologically dependent on the date of application for
admission, would be eligible for admission to a maintenance program:
(1) Physiologic addiction began in August 1987 and continued to the
date of application for admission in August 1988.
(2) Physiologic addiction began in January 1988 and continued until
April 1988. Physiologic addiction began again in July 1988 and
continued until the application for admission in January 1989.
(3) Physiologic addiction began in January 1987 and continued until
October 1987. The date of application for admission was January 1988,
at which time the patient had been readdicted for 1 month preceding his
or her admission.
(4) Physiologic addiction consisted of four episodes in the last
year, each episode lasting 2 1/2 months.
(C) The program physician or an appropriately trained staff member
designated and supervised by the physician shall record in the patient's
record the criteria used to determine the patient's current physiologic
dependence and history of addiction. In the latter circumstance, the
program physician shall review, date, and countersign the supervised
staff member's evaluation to demonstrate his or her agreement with the
evaluation. The program physician shall make the final determination
concerning a patient's physiologic dependence and history of addiction.
The program physician shall sign, date, and record a statement that he
or she has reviewed all the documented evidence to support a 1-year
history of addiction and the current physiologic dependence and that in
his or her reasonable clinical judgment the patient fulfills the
requirements for admission to maintenance treatment. The program
physician shall complete and record the statement before the program
administers any methadone to the patient.
(ii) Voluntary participation, informed consent. The person
responsible for the program shall ensure that: A patient voluntarily
chooses to participate in a program; all relevant facts concerning the
use of the narcotic drug used by the program are clearly and adequately
explained to the patient; all patients, with full knowledge and
understanding of its contents, sign the ''Consent to Methadone
Treatment'' Form FDA-2635 (see paragraph (k) of this section); a
parent, legal guardian, or responsible adult designated by the State
authority (e.g., ''emancipated minor'' laws) sign for patients under the
age of 18 the second part of Form FDA-2635 ''Consent to Methadone
Treatment.''
(iii) Exceptions to minimum admission criteria -- (A) Penal or
chronic care. A person who has resided in a penal or chronic care
institution for 1 month or longer may be admitted to maintenance
treatment within 14 days before release or discharge, or within 6 months
after release from such an institution without documented evidence to
support findings of physiological dependence, provided the person would
have been eligible for admission before he or she was incarcerated or
institutionalized and, in the reasonable clinical judgment of a program
physician, treatment is medically justified. Documented evidence of the
prior residence in a penal or chronic care institution and evidence of
all other findings and the criteria used to determine the findings are
required to be recorded in the patient's record by the admitting program
physician, or by program personnel supervised by the admitting program
physician. The admitting program physician shall date and sign these
recordings or review the health-care professional's recordings before
the initial dose is administered to the patient. In the latter case,
the admitting program physician shall date and sign the recordings in
the patient's record made by the health-care professional within 72
hours of administration of the initial dose to the patient.
(B) Pregnant patients. (1) Pregnant patients, regardless of age, who
have had a documented narcotic dependency in the past and who may return
to narcotic dependency, with all its attendant dangers during pregnancy,
may be placed on a maintenance regimen. For such patients, evidence of
current physiological dependence on narcotic drugs is not needed if a
program physician certifies the pregnancy and, in his or her reasonable
clinical judgment, finds treatment to be medically justified. Evidence
of all findings and the criteria used to determine the findings are
required to be recorded in the patient's record by the admitting program
physician, or by program personnel supervised by the admitting program
physician. The admitting program physician shall date and sign these
recordings or review the health-care professional's recordings before
the initial methadone dose is administered to the patient. In the
latter case, the admitting program physician shall date and sign the
recordings in the patient's record made by the health-care professional
within 72 hours of administration of the initial methadone dose to the
patient. Pregnant patients are required to be given the opportunity for
prenatal care either by the program or by referral to appropriate
health-care providers.
(2) If a program cannot provide direct prenatal care for pregnant
patients in treatment, the program shall establish a system for
informing the patients of the publicly or privately funded prenatal care
opportunities available. If there are no publicly funded prenatal
referral opportunities and the program cannot provide such services or
the patient cannot afford them or refuses them, then the treatment
program shall, at a minimum, offer her basic prenatal instruction on
maternal, physical, and dietary care as part of its counseling service.
(3) Counseling records and/or other appropriate patient records are
required to reflect the nature of prenatal support provided by the
program. If the patient is referred for prenatal services, the
physician to whom she is referred is required to be notified that she is
in maintenance treatment, provided that notification is in accordance
with the Department of Health and Human Services' confidentiality
regulations (42 CFR part 2). If a pregnant patient refuses direct
treatment or appropriate referral for treatment, the treating program
physician should consider using informed consent procedures; e.g., to
have the patient acknowledge in writing that she had the opportunity for
this treatment but refuses it. The program physician, consistent with
the confidentiality regulations, shall request the physician or the
hospital to which a patient is referred to provide, following birth, a
summary of the delivery and treatment outcome for the patient and
offspring. If the program physician does not receive a response to the
request, he or she shall document in the record that such a request was
made.
(4) Within 3 months after termination of pregnancy, the program
physician shall enter an evaluation of the patient's treatment state
into her record and state whether she should remain in the maintenance
program or be detoxified.
(5) Caution should be taken in the maintenance treatment of pregnant
patients. Dosage levels should be maintained at the lowest effective
dose if treatment is deemed necessary. The program sponsor shall ensure
that each female patient is fully informed of the possible risks to her
or to her unborn child from continued use of illicit drugs and from the
use of, or withdrawal from, a narcotic drug administered or dispensed by
the program in maintenance or detoxification treatment.
(C) Previously treated patients. Under certain circumstances a
patient who has been treated and later voluntarily detoxified from
maintenance treatment may be readmitted to maintenance treatment,
without evidence to support findings of current physiologic dependence,
up to 2 years after discharge, if the program attended is able to
document prior narcotic drug maintenance treatment of 6 months or more,
and the admitting program physician, in his or her reasonable clinical
judgment, finds readmission to maintenance treatment to be medically
justified. For patients meeting these criteria, the quantity of
take-home medication will be determined in the reasonable clinical
judgment of the program physician, but in no case may the quantity of
take-home medication be greater than would have been allowed at the time
the patient voluntarily terminated previous treatment. The admitting
program physician or a program employee under supervision of the
admitting program physician must enter in the patient's record
documented evidence of the patient's prior treatment and evidence of all
decisions and criteria used relating to the admission of the patient and
the quantity of take-home medication permitted. The admitting program
physician shall date and sign these entries in the patient's record or
review the health-care professional's entries therein before the program
administers any medication to the patient. In the latter case, the
admitting program physician shall date and sign the entries in the
patient's record made by the health-care professional within 72 hours of
administration of the initial dose to the patient.
(iv) Special limitation; treatment of patients under 18 years of
age. A person under 18 is required to have had two documented attempts
at short-term detoxification or drug-free treatment to be eligible for
maintenance treatment. A 1-week waiting period is required after such a
detoxification attempt, however, before an attempt is repeated. The
program physician shall document in the patient's record that the
patient continues to be or is again physiologically dependent on
narcotic drugs. No person under 18 years of age may be admitted to a
maintenance treatment program unless a parent, legal guardian, or
responsible adult designated by the State authority (e.g., ''emancipated
minor'' laws) completes and signs consent form, Form FDA-2635 ''Consent
to Methadone Treatment.''
(v) Denial of admission. If in the reasonable clinical judgment of
the medical director a particular patient would not benefit from
treatment with a narcotic drug, the patient may be refused such
treatment even if the patient meets the admission standards.
(2) Minimum testing or analysis for drugs: Uses and frequency. (i)
The person(s) responsible for a program shall ensure that: An initial
drug-screening test or analysis is completed for each prospective
patient; at least eight additional random tests or analyses are
performed on each patient during the first year in maintenance
treatment; and at least quarterly random tests or analyses are
performed on each patient in maintenance treatment for each subsequent
year, except that a random test or analysis is performed monthly on each
patient who receives a 6-day supply of take-home medication. When a
sample is collected from each patient for such test or analysis, it must
be done in a manner that minimizes opportunity for falsification. Each
test or analysis must be analyzed for opiates, methadone, amphetamines,
cocaine, and barbiturates. In addition, if any other drug or drugs have
been determined by a program to be abused in that program's locality, or
as otherwise indicated, each test or analysis must be analyzed for any
of those drugs as well. Any laboratory that performs the testing
required under this regulation shall be in compliance with all
applicable Federal proficiency testing and licensing standards and all
applicable State standards. If a program proposes to change a
laboratory used for such testing or analysis, the program shall have the
change approved by the Food and Drug Administration.
(ii) The person responsible for a program shall ensure that test
results are not used as the sole criterion to force a patient out of
treatment but are used as a guide to change treatment approaches. The
person responsible for a program shall also ensure that when test
results are used, presumptive laboratory results are distinguished from
results that are definitive.
(3) Patient evaluation; minimum admission and periodic requirements
-- (i) Minimum contents of medical evaluation. Each patient is required
to have a medical evaluation by a program physician or an authorized
health-care professional under the supervision of a program physician on
admission to a program. At a minimum, this evaluation is required to
consist of a medical history which includes the required history of
narcotic dependence, evidence of current physiologic dependence unless
excepted by the regulations, and a physical examination, and includes
the following laboratory examinations: serological test for syphilis, a
tuberculin skin test, and a test or analysis for drug determination. If
in the reasonable clinical judgment of the program physician, a
patient's subcutaneous veins are severely damaged to the extent that a
blood specimen cannot be obtained, the serological test for syphilis may
be omitted. The physical examination is required to consist of an
investigation of the organ systems for possibilities of infectious
disease, pulmonary, liver, and cardiac abnormalities, and dermatologic
sequelae of addiction. In addition, the physical examination is
required to include a determination of the patient's vital signs
(temperature, pulse, and blood pressure and respiratory rate); an
examination of the patient's general appearance, head, ears, eyes, nose,
throat (thyroid), chest (including heart, lungs, and breasts), abdomen,
extremities, skin, and neurological assessment; and the program
physician's overall impression of the patient.
(ii) Recordings of findings. The admitting program physician or an
appropriately trained health care professional supervised by the
admitting program physician shall record in the patient's record all
findings from the admission medical evaluation. In each case the
admitting program physician shall date and sign these entries, or date,
review, and countersign these recordings in the patient's record to
signify his or her review of and concurrence with the history and
physical findings.
(iii) Admission evaluation. (A) Each patient seeking admission or
readmission for treatment services is required to be interviewed by a
well-trained program counselor, qualified by virtue of education,
training, or experience to assess the psychological and sociological
background of drug abusers, to determine the appropriate treatment plan
for the patient. To determine the most appropriate treatment plan for a
patient, the interviewer shall obtain and document in the patient's
record the patient's history.
(B) A patient's history includes information relating to his or her
educational and vocational achievements. If a patient has no such
history; i.e., he or she has no formal education or has never had an
occupation, this requirement is met by writing this information in the
patient's history.
(iv) Initial treatment plan. (A)(1) The initial treatment plan is
required to contain a statement that outlines realistic short-term
treatment goals which are mutually acceptable to the patient and the
program. The initial treatment plan is also required to spell out the
behavioral tasks a patient must perform to complete each short-term
goal; the patient's requirements for education, vocational
rehabilitation, and employment; and the medical, psychosocial,
economic, legal, or other supportive services that a patient needs. The
plan is also required to identify the frequency with which these
services are likely to be provided. Prior to developing a treatment
plan, the patient's needs for medical, social, and psychological
services; education; vocational rehabilitation; and employment must
be assessed, and the needs reflected, when clinically appropriate, in
the treatment plan.
(2) A primary counselor is one who is assigned by the program to
develop, implement, and evaluate the patient's initial and periodic
treatment plan and to monitor a patient's progress in treatment. The
primary counselor shall enter in the patient's record the counselor's
name, the contents of a patient's initial assessment, and the initial
treatment plan. The primary counselor shall make these entries
immediately after the patient is stabilized on a dose or within 4 weeks
after admission, whichever is sooner.
(B) It is recognized that patients need varying degrees of treatment
and rehabilitative services which are often dependent on or limited by a
number of variables; e.g., patient resources, available program, and
community services. It is not the intent of this regulation to
prescribe a particular treatment and rehabilitative service or the
frequency at which a service should be offered.
(C) The program supervisory counselor or other appropriate program
personnel so designated by the program physician shall review and
countersign all the information and findings required to be recorded in
each patient's record under paragraph (d)(3)(iv) of this section.
(v) Periodic treatment plan evaluation. (A) The program physician or
the primary counselor shall review, reevaluate, and alter where
necessary each patient's treatment plan at least once each 90 days
during the first year of treatment, and then at least twice a year after
the first year of continuous treatment.
(B) The program physician shall ensure that the periodic treatment
plan becomes part of each patient's record and that it is signed and
dated in the patient's record by the primary counselor and is
countersigned and dated by the supervisory counselor.
(C) At least once a year, the program physician shall date, review,
and countersign the treatment plan recorded in each patient's record and
ensure that each patient's progress or lack of progress in achieving the
treatment goals is entered in the patient's record by the primary
counselor. When appropriate, the treatment plan and progress notes
should deal with the patient's mental and physical problems, apart from
drug abuse. The treatment plan is required to include the name of and
the reasons for prescribing any medication for emotional or physical
problems.
(D) The requirement for annual physician review and signature by the
program physician in paragraph (d)(3)(v)(C) of this section is
discretionary, however, as it applies to a patient who has
satisfactorily adhered to program rules for at least 3 consecutive years
from his or her entrance into the maintenance treatment program and who
has made substantial progress in rehabilitation.
(4) Minimum program services -- (i)(A) Access to a range of services.
A treatment program shall provide a comprehensive range of medical and
rehabilitative services to its patients especially during the first 3
years of treatment.
(B) Pregnant patients. (1) For pregnant patients in a treatment
program who were not admitted under paragraph (d)(1)(iii)(B) of this
section, a treatment program shall give them the opportunity for
prenatal care either by the narcotic treatment program or by referral to
appropriate health care providers. If a program cannot provide direct
prenatal care for pregnant patients in treatment, it shall establish a
system of referring them for prenatal care which may be either publicly
or privately funded. If there is no publicly funded prenatal care
available to which a patient may be referred, and the program cannot
provide such services, or the patient cannot afford or refuses prenatal
care services, then the treatment program shall, at a minimum, offer her
basic prenatal instruction on maternal, physical, and dietary care as a
part of its counseling service.
(2) Counseling records and other appropriate patient records are
required to reflect the nature of prenatal support provided by the
program. If the program refers a patient for prenatal services, it
shall inform the physician to whom she is referred that the patient is
in maintenance treatment, provided such notification is in accordance
with the Department of Health and Human Services' confidentiality
regulations (42 CFR part 2). If a pregnant patient refuses direct
prenatal services or appropriate referral for prenatal services, the
treating program physician should consider using informed consent
procedures; i.e., to have the patient acknowledge in writing that she
has the opportunity for this treatment but refuses it. The program
physician shall request the physician or the hospital to which a patient
is referred to provide, following birth, a summary of the delivery and
treatment outcome for the patient and offspring. The information should
be obtained in accordance with the Department of Health and Human
Services' confidentiality regulations (42 CFR part 2). If no response
is received, the program physician shall document in the record that
such a request was made and no response was received.
(3) Caution should be taken in the maintenance treatment of pregnant
patients. Dosage levels should be maintained at the lowest effective
dose if continued treatment is deemed necessary. It is the
responsibility of the program sponsor to ensure that each female patient
is fully informed of the possible risks to a pregnant woman and her
unborn child from continued use of illicit drugs and from the use of, or
withdrawal from, a narcotic drug administered or dispensed by the
program in maintenance or detoxification treatment.
(C) (Reserved)
(D) Off-site services. Any service not furnished at the primary
facility is required to be listed in any application for approval
submitted to the Food and Drug Administration or to the State authority.
The addition, modification, or deletion of any program service is
required to be reported immediately to the Food and Drug Administration.
(ii) Minimum medical services; designation of medical director and
responsibilities. Each program shall have a designated medical director
who assumes responsibility for administering all medical services
performed by the program. The medical director and other authorized
program physicians are required to be licensed to practice medicine in
the jurisdiction in which the program is located. The medical director
is responsible for ensuring that the program is in compliance with all
Federal, State, and local laws and regulations regarding medical
treatment of narcotic addiction. In addition, the medical director or
other authorized physicians shall:
(A) Ensure that evidence of current physiologic dependence, length of
history of addiction, or exceptions to criteria for admission are
documented in the patient's record before the patient receives the
initial dose.
(B) Ensure that a medical evaluation including a medical history has
been taken, and physical examination has been done before the patient
receives the initial dose (except that in an emergency situation, the
initial dose may be given before the physical examination).
(C) Ensure that appropriate laboratory studies have been performed
and reviewed.
(D) Sign or countersign all medical orders as required by Federal or
State law. (Such medical orders include but are not limited to the
initial medication orders and all subsequent medication order changes,
all changes in the frequency of take-home medication, and prescribing
additional take-home medication for an emergency situation.)
(E) Review and countersign treatment plans at least annually as
qualified by paragraph (d)(3)(v)(D) of this section.
(F) Ensure that justification is recorded in the patient's record for
reducing the frequency of clinic visits for observed drug ingesting,
providing additional take-home medication under exceptional
circumstances or when there is physicial disability, or prescribing any
medication for physical or emotional problems.
(iii) Use of health-care professionals. Although the final decision
to accept a patient for treatment may be made only by the medical
director or other designated program physician, it is recognized that
physicians can train program personnel to detect and document narcotic
abstinence symptons and that some jurisdictions allow State-licensed or
certified health-care professionals; e.g., physician's assistants,
nurse practitioners, to perform certain functions -- record medical
histories, perform physicial examinations, and prescribe, administer, or
dispense certain medications -- that are ordinarily performed by a
licensed physician. These regulations do not prohibit licensed or
certified health-care professionals from performing those functions in
narcotic treatment programs if it is authorized by Federal, State, and
local laws and regulations, and if those functions are delegated to them
by the medical director, and records are properly countersigned by the
medical director or a licensed physician.
(iv) Vocational rehabilitation, education, and employment. Each
program shall provide opportunities directly, or through referral to
community resources, for patients who either desire or have been deemed
by the program staff to be ready to participate in educational job
training programs or to obtain gainful employment as soon as possible.
(5) Staffing patterns -- (i) Program personnel. The person(s)
responsible for a program shall determine program personnel requirements
after considering the number of patients who are vocationally and
educationally impaired; the number of patients with significant
psychopathology; the number of patients who are also nonnarcotic drug
or alcohol abusers; the number of patients with behavioral problems in
the program; and the number of patients with serious medical problems.
(ii) Supportive services. The person(s) responsible for the program
shall take notice, when considering the staffing pattern, that
maintenance treatment programs need to establish supportive services in
accordance with the varying characteristics and needs of their patient
populations. The person(s) responsible for a program shall also take
notice of the availability of existing community resources which may
complement or enhance the program's delivery of supportive services and
then establish a staffing pattern based on a combination of patient
needs and available, accessible community resources.
(6) Frequency of attendance; quantity of take-home medication;
dosage of methadone; initial and stabilization -- (i) Dosage and
responsibility for administration. (A) The person(s) responsible for
the program shall ensure that the initial dose of methadone does not
exceed 30 milligrams and that the total dose for the first day does not
exceed 40 milligrams, unless the program medical director documents in
the patient's record that 40 milligrams did not suppress opiate
abstinence symptoms.
(B) A licensed physician shall assume responsibility for the amount
of the narcotic drug administered or dispensed and shall record, date,
and sign in each patient's record each change in the dosage schedule.
(C) The administering licensed physician shall ensure that a daily
dose greater than 100 milligrams is justified in the patient's record.
(ii) Authorized dispensers of narcotic drugs; responsibility. A
narcotic drug may be administered or dispensed only by a practitioner
licensed under the apporpriate State law and registered under the
appropriate State and Federal laws to order narcotic drugs for patients,
or by an agent of such a practitioner, supervised by and under the order
of the practitioner. This agent is required to be a pharmacist,
registered nurse, or licensed practical nurse, or any other health care
professional authorized by federal and State law to administer or
dispense narcotic drugs. The licensed practitioner assumes
responsibility for the amounts of narcotic drugs administered or
dispensed and shall record and countersign all changes in dosage
schedule.
(iii) Form. Methadone may be administered or dispensed in oral form
only when used in a treatment program. Hospitalized patients under care
for a medical or surgical condition are permitted to receive methadone
in parenteral form when the attending physician judges it advisable.
Although tablet, syrup concentrate, or other formulations may be
distributed to the program, all oral medication is required to be
administered or dispensed in a liquid formulation. The oral dosage form
is required to be formulated in such a way as to reduce its potential
for parenteral abuse. Take-home medication is required to be labeled
with the treatment center's name, address, and telephone number and must
be packaged in special packaging as required by 16 CFR 1700.14 in
accordance with the Poison Prevention Packaging Act (Pub. L. 91-601, 15
U.S.C. 1471 et seq.) to reduce the chances of accidental ingestion.
Exceptions may be granted when these provisions conflict with State law
with regard to the administering or dispensing of drugs.
(iv) Take-home medication. (A) Take-home medication may be given
only to a patient who, in the reasonable clinical judgment of the
program physician, is responsible in handling narcotic drugs. Before
the program physician reduces the frequency of a patient's clinical
visits, she or he or a designated staff member shall record the
rationale for the decision in the patient's clinical record. If this is
done by a designated staff member, a program physician shall review,
countersign, and date the patient's record where this information is
recorded.
(B) The program physician shall consider the following in determining
whether, in his or her reasonable clinical judgment, a patient is
responsible in handling narcotic drugs:
(1) Absence of recent abuse of drugs (narcotic or nonnarcotic),
including alcohol;
(2) Regularity of clinic attendance;
(3) Absence of serious behavioral problems at the clinic;
(4) Absence of known recent criminal activity, e.g., drug dealing;
(5) Stability of the patient's home environment and social
relationships;
(6) Length of time in maintenance treatment;
(7) Assurance that take-home medication can be safely stored within
the patient's home; and
(8) Whether the rehabilitative benefit to the patient derived from
decreasing the frequency of clinic attendance outweighs the potential
risks of diversion.
(v) Take-home requirements. The requirement of time in treatment is
a minimum reference point after which a patient may be eligible for
take-home privileges. The time reference is not intended to mean that a
patient in treatment for a particular time has a specific right to
take-home medication. Thus, regardless of time in treatment, a program
physician may, in his or her reasonable judgment, deny or rescind the
take-home medication privileges of a patient.
(A)(1) In maintenance treatment it is required that a patient come to
the clinic for observation daily or at least 6 days a week. If, in the
reasonable clinical judgment of the program physician, a patient
demonstrates that he or she has satisfactorily adhered to program rules
for at least 3 months, has made substantial progress in rehabilitation
and responsibility in handling narcotic drugs (see paragraphs
(d)(6)(iv)(B) (1) through (8) of this section, and would improve his or
her rehabilitative progress by decreasing the frequency of attendance at
the clinic for observation, the patient may be permitted to reduce his
or her attendance at the clinic for observation to three times weekly.
The patient may receive no more than a 2-day take-home supply of
medication.
(2) If, in the reasonable clinical judgment of the program physician,
a patient demonstrates that he or she has satisfactorily ahered to
program rules for at least 2 years from his or her entrance into the
program, has made substantial progress in rehabilitation and
responsibility in handling narcotic drugs (see paragraphs (d)(6)(iv)(B)
(1) through (8) of this section), and would improve his or her
rehabilitative progress by decreasing the frequency of attendance at the
clinic for observation, the patient may be permitted to reduce his or
her clinic attendance at the clinic for observation to twice weekly.
Such a patient may receive no more than a 3-day take-home supply of
medication.
(3) If, in the reasonable clinical judgment of the program physician,
a patient demonstrates that he or she has satisfactorily adhered to
program rules for at least 3 consecutive years from his or her entrance
into the maintenance treatment program, has made substantial progress in
rehabilitation, has no major behavioral problems, is responsible in
handling narcotic drugs (see paragraphs (d)(6)(iv)(B) (1) through (8) of
this section), and would improve his or her rehabilitative progress by
decreasing the frequency of his or her clinic attendance for
observation, the patient may be permitted to reduce clinic attendance
for observation to once weekly, provided that the following additional
criteria are met: The program physician has written into the patient's
record an evaluation that the patient is responsible in handling
narcotic drugs (paragraphs (d)(6)(iv)(B)(1) through (8) of this
section); the patient is employed (or actively seeking employment),
attends school, is a homemaker, or is considered unemployable for mental
or physical reasons by a program physician; the patient is not known to
have abused drugs including alcohol in the last year; and the patient
is not known to have engaged in criminal activity; e.g., drug dealing,
in the last year. A patient permitted to reduce clinic attendance for
observation to once weekly may receive no more than a 6-day take-home
supply of medication.
(B)(1) If a patient, after receiving a supply of take-home
medication, is inexcusably absent from or misses a scheduled appointment
with a treatment program without authorization from the program staff,
the program physician shall increase the frequency of the patient's
clinic attendance for drug ingestion under observation. For such a
patient, the program physician shall not reduce the frequency of the
patient's clinic attendance for drug ingestion under observation until
she or he has had at least three consecutive monthly tests or analyses
that are neither positive for morphine-like drugs (except from the
narcotic drug administered or dispensed by the program) or other drugs
of abuse, nor negative for the narcotic drug administered or dispensed
by the program, and until she or he is again determined by a program
physician to be responsible in handling narcotic drugs (see paragraphs
(d)(6)(iv)(B) (1) through (8) of this section) and to meet criteria in
paragraph (d)(6)(v)(A) of this section.
(2) If a patient, after receiving a 6-day supply of take-home
medication, has a test or analysis which is confirmed to be positive for
morphine-like drugs (except for the narcotic drug administered or
dispensed by the program) or other drugs of abuse, or negative for the
narcotic drug administered or dispensed by the program, the program
physician shall place the patient on probation for 3 months. If, during
this probation, the patient has a test or analysis either positive for
morphine-like drugs (except for the narcotic drug administered or
dispensed by the program) or other drugs of abuse, or negative for the
narcotic drug administered or dispensed by the program, the program
physician shall increase the frequency of the patient's clinic
attendance for observation to at least twice weekly. Such a patient may
receive no more than a 3-day take-home supply of medication until she or
he has had at least three consecutive monthly tests or analyses which
are neither positive for morphine-like drugs (except for the narcotic
drug administered or dispensed by the program) or other drugs of abuse,
nor negative for the narcotic drug administered or dispensed by the
program, and the program physician again determines that the patient is
responsible in handling narcotic drugs (see paragraphs (d)(6)(iv)(B)(1)
through (8) of this section) and meets the criteria contained in
paragraph (d)(6)(v)(A) of this section.
(C) In calculating the number of years of maintenance treatment, the
period is considered to begin on the first day the medication is
administered, or on readmission if a patient has had a continuous
absence of 90 days or more. Cumulative time spent by the patient in
more than one program is counted toward the number of years of
treatment, provided there has not been a continuous absence of 90 days
or more.
(D) Each patient whose daily dose is above 100 milligrams is required
to be under observation while ingesting the drug at least 6 days per
week irrespective of the length of time in treatment, unless the program
has received prior approval from the Food and Drug Administration with
the concurrence of the State authority.
(vi) Exceptions to take-home requirements. If, in the reasonable
clinical judgment of the program physician:
(A) A patient is found to have a physical disability which interferes
with his or her ability to conform to the applicable mandatory schedule,
she or he may be permitted a temporarily or permanently reduced
schedule, provided she or he is also found to be responsible in handling
narcotic drugs.
(B) A patient, because of exceptional circumstances such as illness,
personal or family crises, travel, or other hardship, is unable to
conform to the applicable mandatory schedule, she or he may be permitted
a temporarily reduced schedule, provided she or he is also found to be
responsible in handling narcotic drugs. The rationale for an exception
to a mandatory schedule is to be based on the reasonable clinical
judgment of the program physician and shall be recorded in the patient's
record by the program physician or by program personnel supervised by
the program physician. In the latter situation, the physician shall
review, countersign, and date the patient's record where this rationale
is recorded. In any event, a patient may not be given more than a
2-week supply of narcotic drugs at one time.
(vii) Official State holidays. If a treatment center program is not
in operation due to the observance of an official State holiday,
patients may be permitted one extra take-home dose per visit and one
fewer clinic visit per week to allow patients not to have to attend the
clinic on an official State holiday. An official State holiday is a
holiday on which most State offices are usually closed and routine State
government business is not conducted.
(7) (Reserved)
(8) Minimum standards for short-term detoxification treatment. (i)
For short-term detoxification from narcotic drugs, the narcotic drug is
required to be administered by the program physician or by an authorized
agent of the physician, supervised by and under the order of the
physician. The narcotic drug is required to be administered daily,
under close observation, in reducing dosages over a period not to exceed
30 days. All requirements for maintenance treatment apply to short-term
detoxification treatment with the following exceptions:
(A) Take-home medication is not allowed during short-term
detoxification.
(B) A history of 1 year physiologic dependence is not required for
admission to short-term detoxification.
(C) Patients who have been determined by the program physician to be
currently physiologically narcotic dependent may be placed in short-term
detoxification treatment, regardless of age.
(D) No test or analysis is required except for the initial drug
screening test or analysis.
(E) The initial treatment plan and periodic treatment plan evaluation
required for maintenance patients are not necessary for short-term
detoxification patients. However, a primary counselor must be assigned
by the program to monitor a patient's progress toward the goal of
short-term detoxification and possible drug-free treatment referral.
(F) The requirements of paragraph (d)(4) of this section, except
paragraphs (d)(4)(ii) (A) through (D) and (d)(4)(iii) of this section,
do not apply to short-term detoxification treatment.
(ii) A patient is required to wait at least 7 days between concluding
a short-term detoxification treatment episode and beginning another.
Before a short-term detoxification attempt is repeated, the program
physician shall document in the patient's record that the patient
continues to be, or is again, physiologically dependent on narcotic
drugs. The provisions of these requirements, except as noted in
paragraph (d)(8)(i) of this section, apply to both inpatient and
ambulatory short-term detoxification treatment.
(iii) Short-term detoxification treatment is not recommended for a
pregnant patient.
(9) Minimum standards for long-term detoxification treatment. (i)
For long-term detoxification from narcotic drugs, the narcotic drug is
required to be administered by the program physician or by an authorized
agent of the physician, supervised by and under the order of the
physician. The narcotic drug is required to be administered on a
regimen designed to reach a drug-free state and to make progress in
rehabilitation in 180 days or less. All requirements for maintenance
treatment apply to long-term detoxification treatment with the following
exceptions.
(A) In long-term detoxification treatment it is required that the
patient be under observation while ingesting the drug daily or at least
6 days a week, for the duration of the long-term detoxification
treatment.
(B) A history of 1 year physiologic dependence is not required for
admission to long-term detoxification.
(C) The program physician shall document in the patient's record that
short-term detoxification is not a sufficiently long enough treatment
course to provide the patient with the additional program services he or
she deems necessary for the patient's rehabilitation. The program
physician shall document this information in the patient's record before
long-term detoxification may begin.
(D) Patients who have been determined by the program physician to be
currently physiologically dependent on narcotics may be placed in
long-term detoxification treatment, regardless of age.
(E) An initial drug screening test or analysis is required for each
patient. And at least one additional random test or analysis must be
performed monthly on each patient during long-term detoxification.
(F) The initial treatment plan and periodic treatment plan evaluation
required for maintenance patients are also required for long-term
detoxification patients, except that the required periodic treatment
plan evaluation is required to occur monthly.
(ii) A patient is required to wait at least 7 days between concluding
a long-term treatment episode and beginning another. Before a long-term
detoxification attempt is repeated, the program physician shall document
in the patient's record that the patient continues to be or is again
physicologically dependent on narcotic drugs. The provisions of these
requirements apply to both inpatient and ambulatory long-term
detoxification treatment.
(iii) Long-term detoxification is not recommended for a pregnant
patient.
(10) Inspections of programs; patient confidentiality. A program
shall allow inspections by duly authorized employees of the State
authority, and in accordance with Federal controlled substances laws and
Federal confidentiality laws, by duly authorized employees of the Food
and Drug Administration, the Drug Enforcement Administration of the
Department of Justice, and the National Institute on Drug Abuse.
(11) Exemptions from specific program standards. (i) A program is
permitted, at the time of application or any time thereafter, to request
exemption from specific program standards. The rationale for an
exemption shall be thoroughly documented in an appendix to be submitted
with the application or at some later time. The Food and Drug
Administration will approve such exemptions of program standards at the
time of application, or any time thereafter, with the concurrence of the
State authority. An example of a case in which an exemption might be
granted would be for a private practitioner who wishes to treat a
limited number of patients in a nonmetropolitan area with few physicians
and no rehabilitative services geographically accessible and requests
exemption from some of the staffing and service standards.
(ii) The Food and Drug Administration has the right to withhold the
granting of an exemption requested at the time of application until a
program is in actual operation in order to assess if the exemption is
necessary. If periodic inspections of the progam reveal that
discrepancies or adverse conditions exist, the Food and Drug
Administration shall reserve the right to revoke any or all exemptions
previously granted.
(12) Research. When a program conducts research on human subjects or
provides subjects for research, there must be written policies and
written review to assure the rights of the patients involved.
Appropriate informed consent forms are required to be signed by the
patient and to be retained in his or her patient record at the program.
All research, development, and related activities which involve human
subjects and which are funded by grants from or contracts with the
Department of Health and Human Services are required to comply with the
Department of Health and Human Services' regulations on the protection
of human subjects, 45 CFR part 46, and confidentiality of information,
42 CFR part 2. All investigational research involving human subjects
conducted for submission to the Food and Drug Administration must be
conducted in compliance with part 312 of this chapter.
(13) Patient record system -- (i) Patient care. The person(s)
responsible for a program shall establish a record system to document
and monitor patient care. This system is required to comply with all
Federal and State reporting requirements relevant to methadone. All
records are required to be kept confidential and in accordance with all
applicable Federal and State regulations regarding confidentiality.
(ii) Drug dispensing. The person(s) responsible for a program shall
ensure that accurate records traceable to specific patients are
maintained showing dates, quantity, and batch or code marks of the drug
dispensed. These records must be retained for a period of 3 years from
the date of dispensing.
(iii) Patient's record. An adequate record must be maintained for
each patient. The record is required to contain a copy of the signed
consent form(s), the date of each visit, the amount of drug administered
or dispensed, the results of each test or analysis for drugs, any
significant physical or psychological disability, the type of
rehabilitative and counseling efforts employed, an account of the
patient's progress, and other relevant aspects of the treatment program.
For recordkeeping purposes, if a patient misses appointments for 2
weeks or more without notifying the program, the episode of care is
considered terminated and is to be so noted in the patient's record.
This does not mean that the patient cannot return for care. If the
patient does return for care and is accepted into the program, this is
considered a readmission and is to be so noted in the patient's record.
This method of recordkeeping helps assure the easy detection of sporadic
attendance and decreases the possibility of administering inappropriate
doses of narcotic drugs (e.g., the patient who has received no
medication for several days or more and upon return receives the usual
stabilization dose). An annual evaluation of the patient's progress
must be entered in the patient's record.
(14) Security of drug stocks. adequate security is required to be
maintained over drug stocks, over the manner in which it is administered
or dispensed, over the manner in which it is distributed to medication
units, and over the manner in which it is stored to guard against theft
and diversion of the drug. The program is required to meet the security
standards for the distribution and storage of controlled substances as
required by the Drug Enforcement Administration, Department of Justice
(21 CFR 1301.72-1301.76).
(e) Multiple enrollments -- (1) Administering or dispensing to
patients enrolled in other programs. There is a danger of drug
dependent persons attempting to enroll in more than one narcotic
treatment program to obtain quantities of drugs for the purpose of
self-administration or illicit marketing. Therefore, except in an
emergency situation, drugs shall not be provided to a patient who is
known to be currently receiving drugs from another treatment program
(2) Patient attendance requirements. The patient shall always report
to the same treatment facility unless prior approval is obtained from
the program sponsor for treatment at another program. Permission to
report for treatment at the facility of another program shall be granted
only in exceptional circumstances and shall be noted on the patient's
clinical record.
(f) Conditions for use of narcotic drugs in hospitals for
detoxification treatment -- (1) Form. The drug may be administered or
dispensed in either oral or parenteral form. (See paragraph (d)(6)(iii)
of this section.)
(2) Use of narcotic drugs in hospitals -- (1) Approved uses. For
hospitalized patients, the use of a narcotic drug for narcotic addict
treatment may be administered or dispensed only for detoxification
treatment. If a narcotic drug is administered for treatment of narcotic
dependence for more than 180 days, the procedure is no longer considered
detoxification but is, rather, considered maintenance treatment. Only
approved narcotic treatment programs may undertake maintenance
treatment. This does not preclude the maintenance treatment of a
patient who is hospitalized for treatment of medical conditions other
than addiction and who requires temporary maintenance treatment during
the critical period of his or her stay or whose enrollment in a program
which has approval for maintenance treatment using narcotic drugs has
been verified. (See 21 CFR 1306.07(c).) Any hospital which already has
received approval under this paragraph (f) may serve as a temporary
narcotic treatment program when an approved treatment program has been
terminated and there is no other facility immediately available in the
area to provide narcotic drug treatment for the patients. The Food and
Drug Administration may give this approval upon the request of the State
authority or the hospital, When no State authority has been established.
(ii) Individuals responsible for supplies. Hospitals shall submit to
the Food and Drug Administration and the State authority the name of the
individual (e.g., pharmacist) responsible for receiving and securing
supplies of narcotic drugs for the treatment of narcotic addicts. The
individual responsible for supplies shall ensure that the only persons
who receive supplies of narcotic drugs are those who are authorized to
do so by Federal or State law.
(iii) General description. The hospital shall submit to the Food and
Drug Administration and the State authority a general description of the
hospital including the number of beds, specialized treatment facilities
for drug dependence, and nature of patient care undertaken.
(iv) Anticipated quantity of drug needed. The hospital shall submit
to the Food and Drug Administration and the State authority the
anticipated quantity of narcotic drugs for narcotic addict treatment
needed per year.
(v) Records. The hospital shall maintain accurate records showing
dates, quantity, and batch or code marks of the drug used for inpatient
treatment. The hospital shall retain the records for at least a period
of 3 years.
(vi) Inspection. The hospital shall permit the Food and Drug
Administration and the State authority to inspect supplies of the drug
at the hospital and evaluate the uses to which the drug is being put.
The Food and Drug Administration and the State authority will keep the
identity of the patients confidential in accordance with confidentiality
requirements of 42 CFR part 2. Records on the receipt, storage, and
distribution of narcotic medication are subject to inspection under
Federal controlled substances laws; but use or disclosure of records
identifying patients will, in any case, be limited to actions involving
the program or its personnel.
(vii) Approval of hospital pharmacy. Application for a hospital
pharmacy to provide narcotic drugs for detoxification treatment must be
submitted to the Food and Drug Administration and the State authority
and approval from both is required, except as provided for in paragraph
(h)(5) of this section. Within 60 days after the Food and Drug
Administration receives the application, it will notify the applicant of
approval or denial or will request additional information, when
necessary.
(viii) Approval of shipments to hospital pharmacies. Before a
hospital pharmacy may lawfully receive shipments of narcotic drugs for
detoxification treatment, a responsible official shall complete, sign,
and file in duplicate with the Food and Drug Administration and the
State authority Form FDA-2636 ''Hospital Request for Methadone
Detoxification Treatment'' (see paragraph (k) of this section) and must
have received from the Food and Drug Administration a notice that the
request has been approved.
(ix) Sanctions. Failure to abide by the requirements described in
this section may result in revocation of approval to receive shipments
of narcotic drugs for narcotic addict treatment, seizure of the drug
supply on hand, injunction, and criminal prosecution.
(g) Confidentiality of patient records. (1) Except as provided in
paragraph (g)(2) of this section, disclosure of patient records
maintained by any program is governed by the provisions of 42 CFR part
2, and every program must comply with that part. Records on the
receipt, storage, and distribution of narcotic medication are also
subject to inspection under Federal controlled substances laws: But use
or disclosure of records identifying patients will, in any case, be
limited to actions involving the program or its personnel.
(2) A treatment program or medication unit or any part thereof,
including any facility or any individual, shall permit a duly authorized
employee of the Food and Drug Administration to have access to and to
copy all records on the use of narcotic drugs in accordance with the
provisions of 42 CFR part 2. A treatment program may reveal such
records only when necessary in a related administrative or court
proceeding.
(h) Denial or revocation of approval. (1) Complete or partial denial
or revocation of approval of an application to receive shipments of
narcotic drugs (Forms FDA-2632 ''Application for Approval of Use of
Methadone in a Treatment Program'' and FDA-2636 ''Hospital Request for
Methadone Detoxification Treatment'') may be proposed to the
Commissioner of Food and Drugs by the Director of the Food and Drug
Administration's Center for Drug Evaluation and Research, on his or her
own initiative or at the request of representatives of the Drug
Enforcement Administration, Department of Justice, National Institute of
Drug Abuse, the State authority, or any other interested person.
(2) Before presenting such a proposal to the Commissioner, the
Director of the Center for Drug Evaluation and Research, or his or her
representative, will notify the applicant in writing of the proposed
action and the reasons therefor and will offer the applicant an
opportunity to explain the matters in question in an informal conference
and/or in writing within 10 days after receipt of such notification.
The applicant shall have the right to hear and to question the
information on which the proposal to deny or revoke approval is based,
and may present any oral or written information and views.
(3) If the explanation offered by the applicant is not accepted by
the Center for Drug Evaluation and Research as sufficient to justify
approval of the application, and denial or revocation of approval is
therefore proposed, the Commissioner will evaluate information obtained
in the informal conference and/or in writing before the Director of the
Center for Drug Evaluation and Research. If the Commissioner finds that
the applicant has failed to submit adequate assurance justifying
approval of the application, the Commissioner shall issue a notice of
opportunity for hearing with respect to the matter pursuant to 314.200
of this chapter and the matter shall thereafter be handled in accordance
with established procedures for denial or revocation of approval of a
new drug application. If the Secretary determines that there is an
imminent hazard to health, revocation of approval will become effective
immediately and any administrative procedure will be expedited. Upon
revocation of approval of an application, the Commissioner will notify
the applicant, the State authority, the Drug Enforcement Administration,
Department of Justice, and all other appropriate persons that the
applicant may no longer receive shipments of narcotic drugs, and will
require the recall of all of the drugs from the applicant. Revocation
of approval may also result in criminal prosecution.
(4) Denial or revocation of approval may be reversed when the
Commissioner determines that the applicant has justified approval of the
application.
(5) A treatment program or medication unit or any part thereof,
including any facility or any individual, may appeal to the Food and
Drug Administration a complete or partial denial or revocation of
approval by the State authority unless the denial or revocation is based
upon a State law or regulation. The appeal shall first be made to the
Director of the Center for Drug Evaluation and Research, who shall hold
an informal conference on the matter in accordance with paragraph (h)(2)
of this section. The State authority may participate in the conference.
The appellant or the State authority may appeal the Director's decision
to the Commissioner, who shall decide the matter in accordance with
paragraph (h)(3) of this section. If the Commissioner denies or revokes
approval, such action shall be handled in accordance with paragraph
(h)(3) of this section. The Commissioner may not grant or retain Food
and Drug Administration approval if the Commissioner finds that the
appellant is not in compliance with all applicable State laws and
regulations and with this section.
(i) Sanctions -- (1) Program sponsor or individual responsible for a
particular program. If the program sponsor or the person responsible
for a particular program fails to abide by all the requirements set
forth in this regulation, or fails to adequately monitor the activities
of those employed in the program, he or she may have the approval of his
or her application revoked, his or her narcotic drug supply seized, an
injunction granted precluding operation of his or her program, and
criminal prosecution instituted against him or her.
(2) Persons responsible for administering or dispensing narcotic
drugs. If a person responsible for administering or dispensing narcotic
drugs for narcotic addict treatment fails to abide by all the
requirements set forth in this regulation, criminal prosecution may be
instituted against him or her, his or her drug supply may be seized, the
approval of the program may be revoked, and an injunction may be granted
precluding operation of the program.
(j) Requirements for distribution by manufacturers of narcotic drugs
for narcotic addict treatment -- (1) Distribution requirements.
Shipments of narcotic drugs for narcotic addict treatment are restricted
to direct shipments by manufacturers of the drugs to approved treatment
programs using the narcotic drugs and to approved hospital pharmacies.
If requested by a manufacturer or State authority, wholesale pharmacy
outlets in some regions or States may be authorized to stock narcotic
drugs for narcotic addict treatment for that area and then transship the
drug to approved narcotic treatment programs and approved hospital
pharmacies. Alternative methods of distribution will be permitted if
they are approved by the Food and Drug Administration and the State
authority. Prior to any approval of an alternative method of
distribution there will be consultation with the Drug Enforcement
Administration, Department of Justice, to assure compliance with its
regulations regarding controlled substance distribution.
(2) Information regarding approved programs and hospitals. The Food
and Drug Administration will provide manufacturers and the public with
names and locations of programs and hospitals that have been approved to
receive shipments of narcotic drugs for narcotic addiction treatment.
All information contained in the forms required by paragraph (k) of this
section is available for public disclosure, except the names or other
identifying information with respect to patients.
(3) Acceptance of delivery. Delivery shall only be made to a
licensed practitioner or a licensed pharmacist employed at the facility.
At the time of delivery the licensed practitioner or licensed
pharmacist shall sign for the drugs and place his or her specific title
and identification number on any invoice. Copies of these signed
invoices shall be kept by the manufacturer.
(k) Program forms. The program sponsor must ensure that the
following forms are completed by the proper program staff and submitted
to the appropriate State authority and the Division of Scientific
Investigations, Regulatory Management Branch (HFD-342), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857. Forms are
available upon request from the Regulatory Management Branch (HFD-342),
at the same address.
FDA2632 -- Application for Approval of Use of Methadone in a
Treatment Program.
FDA-2633 -- Medical Responsibility Statement for Use of Methadone in
a Treatment Program.
FDA-2635 -- Consent to Methadone Treatment.
FDA-2636 -- Hospital Request for Methadone Detoxification Treatment.
(Approved by the Office of Management and Budget under number
0910-0140)
(54 FR 8960, Mar. 2, 1989; 54 FR 12531, Mar. 27, 1989)
21 CFR 291.505 Pt. 299
21 CFR 291.505 PART 299 -- DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES
21 CFR 291.505 Subpart A -- General Provisions
Sec.
299.3 Definitions and interpretations.
299.4 Established names for drugs.
299.5 Drugs; compendial name.
Authority: Secs. 301, 501, 502, 505, 508, 512, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 331, 351, 352, 355, 358, 360b,
371).
Source: 40 FR 14041, Mar. 27, 1975, unless otherwise noted.
21 CFR 291.505 Subpart A -- General Provisions
21 CFR 299.3 Definitions and interpretations.
(a) As used in this part 299, act means the Federal Food, Drug, and
Cosmetic Act, sections 201-902, 52 Stat. 1040 (21 U.S.C. 321-392),
with all amendments thereto.
(b) The definitions and interpretations contained in section 201 of
the act shall be applicable to such terms when used in this part 299.
(c) The term official name means, with respect to a drug or
ingredient thereof, the name designated in this part 299 under section
508 of the act as the official name.
21 CFR 299.4 Established names for drugs.
(a) Section 508 of the Federal Food, Drug, and Cosmetic Act (added by
the Kefauver-Harris Drug Amendments of 1962; Pub. L. 87-781) authorizes
the Commissioner of Food and Drugs to designate an official name for any
drug if he determines that such action is necessary or desirable in the
interest of usefulness and simplicity. Section 502(e) of the act (as
amended by said Drug Amendments) prescribes that the labeling of a drug
must bear its established name, if there is one, to the exclusion of any
other nonproprietary name (except the applicable systematic chemical
name or the chemical formula) and, if the drug is fabricated from two or
more ingredients, the established name of each active ingredient.
(b) The term ''established name'' is defined in section 502(e)(3) of
the act as (1) an official name designated pursuant to section 508 of
the act; (2) if no such official name has been designated for the drug
and the drug is an article recognized in an official compendium, then
the official title thereof in such compendium; and (3) if neither
paragraphs (b) (1) or (2) of this section applies, then the common or
usual name of the drug.
(c) The Food and Drug Administration recognizes the skill and
experience of the U.S. Adopted Names Council (USAN) in deriving names
for drugs. The U.S. Adopted Names Council is a private organization
sponsored by the American Medical Association, the United States
Pharmacopeia, and the American Pharmaceutical Association, and has been
engaged in the assignment of names to drugs since January 1964. The
Council negotiates with manufacturing firms in the selection of
nonproprietary names for drugs.
(d) The Food and Drug Administration cooperates with and is
represented on the USAN Council. In addition, the Food and Drug
Administration agrees with ''Guiding Principles for Coining U.S.
Adopted Names for Drugs,'' published in USAN and the USP Dictionary of
Drug Names (USAN 1985 ed., 1961-1984 cumulative list), which is
incorporated by reference. Copies are available from: U.S.
Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway, Rockville, MD
20852, or are available for inspection at the Office of the Federal
Register, 1100 L St. NW., Washington, DC 20408. All applicants for
new-drug applications and sponsors for ''Investigational New Drug
Applications'' (IND's) are encouraged to contact the USAN Council for
assistance in selection of a simple and useful name for a new chemical
entity. Approval of a new-drug application providing for the use of a
new drug substance or a new antibiotic drug may be delayed if a simple
and useful nonproprietary name does not exist for the substance and if
one is not proposed in the application that meets the above-cited
guidelines. Prior use of a name in the medical literature or otherwise
will not commit the Food and Drug Administration to adopting such
terminology as official.
(e) The Food and Drug Administration will not routinely designate
official names under section 508 of the act. As a result, the
established name under section 502(e) of the act will ordinarily be
either the compendial name of the drug or, if there is no compendial
name, the common and usual name of the drug. Interested persons, in the
absence of the designation by the food and Drug Administration of an
official name, may rely on as the established name for any drug the
current compendial name or the USAN adopted name listed in USAN and the
USP Dictionary of Drug Names. The Food and Drug Administration,
however, will continue to publish official names under the provisions of
section 508 of the act when the agency determines that:
(1) The USAN or other official or common or usual name is unduly
complex or is not useful for any other reason;
(2) Two or more official names have been applied to a single drug, or
to two or more drugs that are identical in chemical structure and
pharmacological action and that are substantially identical in strength,
quality, and purity; or
(3) No USAN or other official or common or usual name has been
applied to a medically useful drug. Any official name published under
section 508 of the act will be the established name of the drug.
(f) A cumulative list of U.S. adopted names selected and released
since June 15, 1961, is published yearly by the U.S. Pharmacopeial
Convention, Inc., in USAN and the USP Dictionary of Drug Names. Copies
may be purchased from the U.S. Pharmacopeial Convention, Inc., 12601
Twinbrook Parkway, Rockville, MD 20852.
(40 FR 14041, Mar. 27, 1975, as amended at 49 FR 37575, Sept. 25,
1984; 53 FR 5369, Feb. 24, 1988; 55 FR 11577, Mar. 29, 1990)
21 CFR 299.5 Drugs; compendial name.
(a) The name by which a drug is designated shall be clearly
distinguishing and differentiating from any name recognized in an
official compendium unless such drug complies in identity with the
identity prescribed in an official compendium under such recognized
name.
(b) The term ''drug defined in an official compendium'' means a drug
having the identity prescribed for a drug in an official compendium.
(c) A statement that a drug defined in an official compendium differs
in strength, quality, or purity from the standard of strength, quality,
or purity set forth for such drug in an official compendium shall show
all the respects in which such drug so differs, and the extent of each
such difference.
21 CFR 299.5 FINDING AIDS
A list of CFR titles, subtitles, chapters, subchapters and parts and
an alphabetical list of agencies publishing in the CFR are included in
the CFR Index and Finding Aids volume to the Code of Federal Regulations
which is published separately and revised annually.
Material Approved for Incorporation by Reference
Table of CFR Titles and Chapters
Alphabetical List of Agencies Appearing in the CFR
List of CFR Sections Affected
Title 21 -- Food and Drugs
Material Approved for Incorporation by Reference
Material Approved for Incorporation by Reference
The Director of the Federal Register has approved under 5 U.S.C.
552(a) and 1 CFR Part 51 the incorporation by reference of the following
publications. This list contains only those incorporations by reference
effective as of the revision date of this volume. Incorporations by
reference found within a regulation are effective upon the effective
date of that regulation. For more information on incorporation by
reference, see the preliminary pages of this volume.
21 CFR 299.5 21 CFR CHAPTER I (PARTS 200 TO 299)
FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR
American Plywood Association
P.O. Box 11700, Tacoma, WA 98411-0770
APA PRP-108, ''Performance Standards and Policies for Structural-Use
Panels,'' June 1988 200.944
Form No. E30K, ''APA Design/Construction Guide-Residential and
Commercial,'' January 1989 200.944
American Society for Testing and Materials
1916 Race Street, Philadelphia, PA 19103
ASTM D-3043-87, ''Standard Methods of Testing Structural Panels in
Flexure,'' August 28, 1987 200.944
U.S. Department of Commerce
National Institute for Standards and Technology, Office of Product
Standards, Gaithersburg, MD 20899
Voluntary Product Standard, PS 1-83, ''Construction and Industrial
Plywood,'' May 1984 200.944
U.S. Pharmacopeial Convention, Inc.
12601 Twinbrook Parkway, Rockville, MD 20852
USAN and the USP Dictionary of Drug Names: ''Guiding Principles for
Coining U.S. Adopted Names for Drugs'' (USAN 1985) 299.4
NOTE: The following materials are available through the Food and
Drug Administration at the addresses indicated.
Center for Food Safety and Applied Nutrition (HFD-430), Food and Drug
Administration
200 C St. SW., Washington, DC 20204
''Procedures for Detecting and Measuring Penicillin Contamination in
Drugs'' 211.176
Chap.
21 CFR 299.5 Table of CFR Titles and Chapters
21 CFR 299.5 Title 1 -- General Provisions
I Administrative Committee of the Federal Register (Parts 1 -- 49)
II Office of the Federal Register (Parts 50 -- 299)
III Administrative Conference of the United States (Parts 300 -- 399)
IV Miscellaneous Agencies (Parts 400 -- 500)
21 CFR 299.5 Title 2 -- (Reserved)
21 CFR 299.5 Title 3 -- The President
I Executive Office of the President (Parts 100 -- 199)
21 CFR 299.5 Title 4 -- Accounts
I General Accounting Office (Parts 1 -- 99)
II Federal Claims Collection Standards (General Accounting Office --
Department of Justice) (Parts 100 -- 299)
III General Accounting Office (CASB) (Parts 300 -- 499)
21 CFR 299.5 Title 5 -- Administrative Personnel
I Office of Personnel Management (Parts 1 -- 1199)
II Merit Systems Protection Board (Parts 1200 -- 1299)
III Office of Management and Budget (Parts 1300 -- 1399)
IV Advisory Committee on Federal Pay (Parts 1400 -- 1499)
V The International Organizations Employees Loyalty Board (Parts 1500
-- 1599)
VI Federal Retirement Thrift Investment Board (Parts 1600 -- 1699)
VII Advisory Commission on Intergovernmental Relations (Parts 1700 --
1799)
VIII Office of Special Council (Parts 1800 -- 1899)
IX Appalachian Regional Commission (Parts 1900 -- 1999)
XI United States Soldiers' and Airmen's Home (Parts 2100 -- 2199)
XIV Federal Labor Relations Authority, General Counsel of the Federal
Labor Relations Authority and Federal Service Impasses Panel (Parts 2400
-- 2499)
XV Office of Administration, Executive Office of the President (Parts
2500 -- 2599)
XVI Office of Government Ethics (Parts 2600 -- 2699)
21 CFR 299.5 Title 6 -- Economic Stabilization (Reserved)
21 CFR 299.5 Title 7 -- Agriculture
Subtitle A -- Office of the Secretary of Agriculture (Parts 0 -- 26)
Subtitle B -- Regulations of the Department of Agriculture
I Agricultural Marketing Service (Standards, Inspections, Marketing
Practices), Department of Agriculture (Parts 27 -- 209)
II Food and Nutrition Service, Department of Agriculture (Parts 210
-- 299)
III Animal and Plant Health Inspection Service, Department of
Agriculture (Parts 300 -- 399)
IV Federal Crop Insurance Corporation, Department of Agriculture
(Parts 400 -- 499)
V Agricultural Research Service, Department of Agriculture (Parts 500
-- 599)
VI Soil Conservation Service, Department of Agriculture (Parts 600 --
699)
VII Agricultural Stabilization and Conservation Service (Agricultural
Adjustment), Department of Agriculture (Parts 700 -- 799)
VIII Federal Grain Inspection Service, Department of Agriculture
(Parts 800 -- 899)
IX Agricultural Marketing Service (Marketing Agreements and Orders;
Fruits, Vegetables, Nuts), Department of Agriculture (Parts 900 -- 999)
X Agricultural Marketing Service (Marketing Agreements and Orders;
Milk), Department of Agriculture (Parts 1000 -- 1199)
XI Agricultural Marketing Service (Marketing Agreements and Orders;
Miscellaneous Commodities), Department of Agriculture (Parts 1200 --
1299)
XIV Commodity Credit Corporation, Department of Agriculture (Parts
1400 -- 1499)
XV Foreign Agricultural Service, Department of Agriculture (Parts
1500 -- 1599)
XVI Rural Telephone Bank, Department of Agriculture (Parts 1600 --
1699)
XVII Rural Electrification Administration, Department of Agriculture
(Parts 1700 -- 1799)
XVIII Farmers Home Administration, Department of Agriculture (Parts
1800 -- 2099)
XXI Foreign Economic Development Service, Department of Agriculture
(Parts 2100 -- 2199)
XXII Office of International Cooperation and Development, Department
of Agriculture (Parts 2200 -- 2299)
XXV Office of the General Sales Manager, Department of Agriculture
(Parts 2500 -- 2599)
XXVI Office of Inspector General, Department of Agriculture (Parts
2600 -- 2699)
XXVII Office of Information Resources Management, Department of
Agriculture (Parts 2700 -- 2799)
XXVIII Office of Operations, Department of Agriculture (Parts 2800 --
2899)
XXIX Office of Energy, Department of Agriculture (Parts 2900 -- 2999)
XXX Office of Finance and Management, Department of Agriculture
(Parts 3000 -- 3099)
XXXI Office of Environmental Quality, Department of Agriculture
(Parts 3100 -- 3199)
XXXII Office of Grants and Program Systems, Department of Agriculture
(Parts 3200 -- 3299)
XXXIII Office of Transportation, Department of Agriculture (Parts
3300 -- 3399)
XXXIV Cooperative State Research Service, Department of Agriculture
(Parts 3400 -- 3499)
XXXVI National Agricultural Statistics Service, Department of
Agriculture (Parts 3600 -- 3699)
XXXVII Economic Research Service, Department of Agriculture (Parts
3700 -- 3799)
XXXVIII World Agricultural Outlook Board, Department of Agriculture
(Parts 3800 -- 3899)
XXXIX Economic Analysis Staff, Department of Agriculture (Parts 3900
-- 3999)
XL Economics Management Staff, Department of Agriculture (Parts 4000
-- 4099)
XLI National Agricultural Library, Department of Agriculture (Part
4100)
21 CFR 299.5 Title 8 -- Aliens and Nationality
I Immigration and Naturalization Service, Department of Justice
(Parts 1 -- 499)
21 CFR 299.5 Title 9 -- Animals and Animal Products
I Animal and Plant Health Inspection Service, Department of
Agriculture (Parts 1 -- 199)
II Packers and Stockyards Administration, Department of Agriculture
(Parts 200 -- 299)
III Food Safety and Inspection Service, Meat and Poultry Inspection,
Department of Agriculture (Parts 300 -- 399)
21 CFR 299.5 Title 10 -- Energy
I Nuclear Regulatory Commission (Parts 0 -- 199)
II Department of Energy (Parts 200 -- 699)
III Department of Energy (Parts 700 -- 999)
X Department of Energy (General Provisions) (Parts 1000 -- 1099)
XV Office of the Federal Inspector for the Alaska Natural Gas
Transportation System (Parts 1500 -- 1599)
XVII Defense Nuclear Facilities Safety Board (Parts 1700 -- 1799)
21 CFR 299.5 Title 11 -- Federal Elections
I Federal Election Commission (Parts 1 -- 9099)
21 CFR 299.5 Title 12 -- Banks and Banking
I Comptroller of the Currency, Department of the Treasury (Parts 1 --
199)
II Federal Reserve System (Parts 200 -- 299)
III Federal Deposit Insurance Corporation (Parts 300 -- 399)
IV Export-Import Bank of the United States (Parts 400 -- 499)
V Office of Thrift Supervision, Department of The Treasury (Parts 500
-- 599)
VI Farm Credit Administration (Parts 600 -- 699)
VII National Credit Union Administration (Parts 700 -- 799)
VIII Federal Financing Bank (Parts 800 -- 899)
IX Federal Housing Finance Board (Parts 900 -- 999)
XI Federal Financial Institutions Examination Council (Parts 1100 --
1199)
XIII Farm Credit System Assistance Board (Parts 1300 -- 1399)
XIV Farm Credit System Insurance Corporation (Parts 1400 -- 1499)
XV Thrift Depositor Protection Oversight Board (Parts 1500 -- 1599)
XVI Resolution Trust Corporation (Parts 1600 -- 1699)
21 CFR 299.5 Title 13 -- Business Credit and Assistance
I Small Business Administration (Parts 1 -- 199)
III Economic Development Administration, Department of Commerce
(Parts 300 -- 399)
21 CFR 299.5 Title 14 -- Aeronautics and Space
I Federal Aviation Administration, Department of Transportation
(Parts 1 -- 199)
II Office of the Secretary, Department of Transportation (Aviation
Proceedings) (Parts 200 -- 399)
III Office of Commercial Space Transportation, Department of
Transportation (Parts 400 -- 499)
V National Aeronautics and Space Administration (Parts 1200 -- 1299)
21 CFR 299.5 Title 15 -- Commerce and Foreign Trade
Subtitle A -- Office of the Secretary of Commerce (Parts 0 -- 29)
Subtitle B -- Regulations Relating to Commerce and Foreign Trade
I Bureau of the Census, Department of Commerce (Parts 30 -- 199)
II National Institute of Standards and Technology, Department of
Commerce (Parts 200 -- 299)
III International Trade Administration, Department of Commerce (Parts
300 -- 399)
IV Foreign-Trade Zones Board (Parts 400 -- 499)
VII Bureau of Export Administration, Department of Commerce (Parts
700 -- 799)
VIII Bureau of Economic Analysis, Department of Commerce (Parts 800
-- 899)
IX National Oceanic and Atmospheric Administration, Department of
Commerce (Parts 900 -- 999)
XI Technology Administration, Department of Commerce (Parts 1100 --
1199)
XII United States Travel and Tourism Administration, Department of
Commerce (Parts 1200 -- 1299)
XIII East-West Foreign Trade Board (Parts 1300 -- 1399)
XIV Minority Business Development Agency (Parts 1400 -- 1499)
Subtitle C -- Regulations Relating to Foreign Trade Agreements
XX Office of the United States Trade Representative (Parts 2000 --
2099)
Subtitle D -- Regulations Relating to Telecommunications and
Information
XXIII National Telecommunications and Information Administration,
Department of Commerce (Parts 2300 -- 2399)
21 CFR 299.5 Title 16 -- Commercial Practices
I Federal Trade Commission (Parts 0 -- 999)
II Consumer Product Safety Commission (Parts 1000 -- 1799)
21 CFR 299.5 Title 17 -- Commodity and Securities Exchanges
I Commodity Futures Trading Commission (Parts 1 -- 199)
II Securities and Exchange Commission (Parts 200 -- 399)
IV Department of the Treasury (Parts 400 -- 499)
21 CFR 299.5 Title 18 -- Conservation of Power and Water Resources
I Federal Energy Regulatory Commission, Department of Energy (Parts 1
-- 399)
III Delaware River Basin Commission (Parts 400 -- 499)
VI Water Resources Council (Parts 700 -- 799)
VIII Susquehanna River Basin Commission (Parts 800 -- 899)
XIII Tennessee Valley Authority (Parts 1300 -- 1399)
21 CFR 299.5 Title 19 -- Customs Duties
I United States Customs Service, Department of the Treasury (Parts 1
-- 199)
II United States International Trade Commission (Parts 200 -- 299)
III International Trade Administration, Department of Commerce (Parts
300 -- 399)
21 CFR 299.5 Title 20 -- Employees' Benefits
I Office of Workers' Compensation Programs, Department of Labor
(Parts 1 -- 199)
II Railroad Retirement Board (Parts 200 -- 399)
III Social Security Administration, Department of Health and Human
Services (Parts 400 -- 499)
IV Employees' Compensation Appeals Board, Department of Labor (Parts
500 -- 599)
V Employment and Training Administration, Department of Labor (Parts
600 -- 699)
VI Employment Standards Administration, Department of Labor (Parts
700 -- 799)
VII Benefits Review Board, Department of Labor (Parts 800 -- 899)
VIII Joint Board for the Enrollment of Actuaries (Parts 900 -- 999)
IX Office of the Assistant Secretary for Veterans' Employment and
Training, Department of Labor (Parts 1000 -- 1099)
21 CFR 299.5 Title 21 -- Food and Drugs
I Food and Drug Administration, Department of Health and Human
Services (Parts 1 -- 1299)
II Drug Enforcement Administration, Department of Justice (Parts 1300
-- 1399)
21 CFR 299.5 Title 22 -- Foreign Relations
I Department of State (Parts 1 -- 199)
II Agency for International Development, International Development
Cooperation Agency (Parts 200 -- 299)
III Peace Corps (Parts 300 -- 399)
IV International Joint Commission, United States and Canada (Parts
400 -- 499)
V United States Information Agency (Parts 500 -- 599)
VI United States Arms Control and Disarmament Agency (Parts 600 --
699)
VII Overseas Private Investment Corporation, International
Development Cooperation Agency (Parts 700 -- 799)
IX Foreign Service Grievance Board Regulations (Parts 900 -- 999)
X Inter-American Foundation (Parts 1000 -- 1099)
XI International Boundary and Water Commission, United States and
Mexico, United States Section (Parts 1100 -- 1199)
XII United States International Development Cooperation Agency (Parts
1200 -- 1299)
XIII Board for International Broadcasting (Parts 1300 -- 1399)
XIV Foreign Service Labor Relations Board; Federal Labor Relations
Authority; General Counsel of the Federal Labor Relations Authority;
and the Foreign Service Impasse Disputes Panel (Parts 1400 -- 1499)
XV African Development Foundation (Parts 1500 -- 1599)
XVI Japan-United States Friendship Commission (Parts 1600 -- 1699)
21 CFR 299.5 Title 23 -- Highways
I Federal Highway Administration, Department of Transportation (Parts
1 -- 999)
II National Highway Traffic Safety Administration and Federal Highway
Administration, Department of Transportation (Parts 1200 -- 1299)
III National Highway Traffic Safety Administration, Department of
Transportation (Parts 1300 -- 1399)
21 CFR 299.5 Title 24 -- Housing and Urban Development
Subtitle A -- Office of the Secretary, Department of Housing and
Urban Development (Parts 0 -- 99)
Subtitle B -- Regulations Relating to Housing and Urban Development
I Office of Assistant Secretary for Equal Opportunity, Department of
Housing and Urban Development (Parts 100 -- 199)
II Office of Assistant Secretary for Housing-Federal Housing
Commissioner, Department of Housing and Urban Development (Parts 200 --
299)
III Government National Mortgage Association, Department of Housing
and Urban Development (Parts 300 -- 399)
V Office of Assistant Secretary for Community Planning and
Development, Department of Housing and Urban Development (Parts 500 --
599)
VI Office of Assistant Secretary for Community Planning and
Development, Department of Housing and Urban Development (Parts 600 --
699)
VII Office of the Secretary, Department of Housing and Urban
Development (Section 8 Housing Assistance Programs and Public and Indian
Housing Programs) (Parts 700 -- 799)
VIII Office of the Assistant Secretary for Housing -- Federal Housing
Commissioner, Department of Housing and Urban Development (Section 8
Housing Assistance Programs and Section 202 Direct Loan Program) (Parts
800 -- 899)
IX Office of Assistant Secretary for Public and Indian Housing,
Department of Housing and Urban Development (Parts 900 -- 999)
X Office of Assistant Secretary for Housing -- Federal Housing
Commissioner, Department of Housing and Urban Development (Interstate
Land Sales Registration Program) (Parts 1700 -- 1799)
XI Solar Energy and Energy Conservation Bank, Department of Housing
and Urban Development (Parts 1800 -- 1899)
XII Office of Inspector General, Department of Housing and Urban
Development (Parts 2000 -- 2099)
XV Mortgage Insurance and Loan Programs under the Emergency
Homeowners' Relief Act, Department of Housing and Urban Development
(Parts 2700 -- 2799)
XX Office of Assistant Secretary for Housing -- Federal Housing
Commissioner, Department of Housing and Urban Development (Parts 3200 --
3699)
XXV Neighborhood Reinvestment Corporation (Parts 4100 -- 4199)
21 CFR 299.5 Title 25 -- Indians
I Bureau of Indian Affairs, Department of the Interior (Parts 1 --
299)
II Indian Arts and Crafts Board, Department of the Interior (Parts
300 -- 399)
III National Indian Gaming Commission (Parts 500 -- 599)
IV Office of Navajo and Hopi Indian Relocation (Parts 700 -- 799)
21 CFR 299.5 Title 26 -- Internal Revenue
I Internal Revenue Service, Department of the Treasury (Parts 1 --
799)
21 CFR 299.5 Title 27 -- Alcohol, Tobacco Products and Firearms
I Bureau of Alcohol, Tobacco and Firearms, Department of the Treasury
(Parts 1 -- 299)
21 CFR 299.5 Title 28 -- Judicial Administration
I Department of Justice (Parts 0 -- 199)
III Federal Prison Industries, Inc., Department of Justice (Parts 300
-- 399)
V Bureau of Prisons, Department of Justice (Parts 500 -- 599)
VI Offices of Independent Counsel, Department of Justice (Parts 600
-- 699)
VII Office of Independent Counsel (Parts 700 -- 799)
21 CFR 299.5 Title 29 -- Labor
Subtitle A -- Office of the Secretary of Labor (Parts 0 -- 99)
Subtitle B -- Regulations Relating to Labor
I National Labor Relations Board (Parts 100 -- 199)
II Bureau of Labor-Management Relations and Cooperative Programs,
Department of Labor (Parts 200 -- 299)
III National Railroad Adjustment Board (Parts 300 -- 399)
IV Office of Labor-Management Standards, Department of Labor (Parts
400 -- 499)
V Wage and Hour Division, Department of Labor (Parts 500 -- 899)
IX Construction Industry Collective Bargaining Commission (Parts 900
-- 999)
X National Mediation Board (Parts 1200 -- 1299)
XII Federal Mediation and Conciliation Service (Parts 1400 -- 1499)
XIV Equal Employment Opportunity Commission (Parts 1600 -- 1699)
XVII Occupational Safety and Health Administration, Department of
Labor (Parts 1900 -- 1999)
XX Occupational Safety and Health Review Commission (Parts 2200 --
2499)
XXV Pension and Welfare Benefits Administration, Department of Labor
(Parts 2500 -- 2599)
XXVI Pension Benefit Guaranty Corporation (Parts 2600 -- 2699)
XXVII Federal Mine Safety and Health Review Commission (Parts 2700 --
2799)
21 CFR 299.5 Title 30 -- Mineral Resources
I Mine Safety and Health Administration, Department of Labor (Parts 1
-- 199)
II Minerals Management Service, Department of the Interior (Parts 200
-- 299)
III Board of Surface Mining and Reclamation Appeals, Department of
the Interior (Parts 300 -- 399)
IV Geological Survey, Department of the Interior (Parts 400 -- 499)
VI Bureau of Mines, Department of the Interior (Parts 600 -- 699)
VII Office of Surface Mining Reclamation and Enforcement, Department
of the Interior (Parts 700 -- 999)
21 CFR 299.5 Title 31 -- Money and Finance: Treasury
Subtitle A -- Office of the Secretary of the Treasury (Parts 0 -- 50)
Subtitle B -- Regulations Relating to Money and Finance
I Monetary Offices, Department of the Treasury (Parts 51 -- 199)
II Fiscal Service, Department of the Treasury (Parts 200 -- 399)
IV Secret Service, Department of the Treasury (Parts 400 -- 499)
V Office of Foreign Assets Control, Department of the Treasury (Parts
500 -- 599)
VI Bureau of Engraving and Printing, Department of the Treasury
(Parts 600 -- 699)
VII Federal Law Enforcement Training Center, Department of the
Treasury (Parts 700 -- 799)
VIII Office of International Investment, Department of the Treasury
(Parts 800 -- 899)
21 CFR 299.5 Title 32 -- National Defense
Subtitle A -- Department of Defense
I Office of the Secretary of Defense (Parts 1 -- 399)
V Department of the Army (Parts 400 -- 699)
VI Department of the Navy (Parts 700 -- 799)
VII Department of the Air Force (Parts 800 -- 1099)
Subtitle B -- Other Regulations Relating to National Defense
XII Defense Logistics Agency (Parts 1200 -- 1299)
XVI Selective Service System (Parts 1600 -- 1699)
XIX Central Intelligence Agency (Parts 1900 -- 1999)
XX Information Security Oversight Office (Parts 2000 -- 2099)
XXI National Security Council (Parts 2100 -- 2199)
XXIV Office of Science and Technology Policy (Parts 2400 -- 2499)
XXVII Office for Micronesian Status Negotiations (Parts 2700 -- 2799)
XXVIII Office of the Vice President of the United States (Parts 2800
-- 2899)
21 CFR 299.5 Title 33 -- Navigation and Navigable Waters
I Coast Guard, Department of Transportation (Parts 1 -- 199)
II Corps of Engineers, Department of the Army (Parts 200 -- 399)
IV Saint Lawrence Seaway Development Corporation, Department of
Transportation (Parts 400 -- 499)
21 CFR 299.5 Title 34 -- Education
Subtitle A -- Office of the Secretary, Department of Education (Parts
1 -- 99)
Subtitle B -- Regulations of the Offices of the Department of
Education
I Office for Civil Rights, Department of Education (Parts 100 -- 199)
II Office of Elementary and Secondary Education, Department of
Education (Parts 200 -- 299)
III Office of Special Education and Rehabilitative Services,
Department of Education (Parts 300 -- 399)
IV Office of Vocational and Adult Education, Department of Education
(Parts 400 -- 499)
V Office of Bilingual Education and Minority Languages Affairs,
Department of Education (Parts 500 -- 599)
VI Office of Postsecondary Education, Department of Education (Parts
600 -- 699)
VII Office of Educational Research and Improvement, Department of
Education (Parts 700 -- 799)
21 CFR 299.5 Title 35 -- Panama Canal
I Panama Canal Regulations (Parts 1 -- 299)
21 CFR 299.5 Title 36 -- Parks, Forests, and Public Property
I National Park Service, Department of the Interior (Parts 1 -- 199)
II Forest Service, Department of Agriculture (Parts 200 -- 299)
III Corps of Engineers, Department of the Army (Parts 300 -- 399)
IV American Battle Monuments Commission (Parts 400 -- 499)
V Smithsonian Institution (Parts 500 -- 599)
VII Library of Congress (Parts 700 -- 799)
VIII Advisory Council on Historic Preservation (Parts 800 -- 899)
IX Pennsylvania Avenue Development Corporation (Parts 900 -- 999)
XI Architectural and Transportation Barriers Compliance Board (Parts
1100 -- 1199)
XII National Archives and Records Administration (Parts 1200 -- 1299)
21 CFR 299.5 Title 37 -- Patents, Trademarks, and Copyrights
I Patent and Trademark Office, Department of Commerce (Parts 1 --
199)
II Copyright Office, Library of Congress (Parts 200 -- 299)
III Copyright Royalty Tribunal (Parts 300 -- 399)
IV Assistant Secretary for Technology Policy, Department of Commerce
(Parts 400 -- 499)
V Under Secretary for Technology, Department of Commerce (Parts 500
-- 599)
21 CFR 299.5 Title 38 -- Pensions, Bonuses, and Veterans' Relief
I Department of Veterans Affairs (Parts 0 -- 99)
21 CFR 299.5 Title 39 -- Postal Service
I United States Postal Service (Parts 1 -- 999)
III Postal Rate Commission (Parts 3000 -- 3099)
21 CFR 299.5 Title 40 -- Protection of Environment
I Environmental Protection Agency (Parts 1 -- 799)
V Council on Environmental Quality (Parts 1500 -- 1599)
21 CFR 299.5 Title 41 -- Public Contracts and Property Management
Subtitle B -- Other Provisions Relating to Public Contracts
50 Public Contracts, Department of Labor (Parts 50-1 -- 50-999)
51 Committee for Purchase from the Blind and Other Severely
Handicapped (Parts 51-1 -- 51-99)
60 Office of Federal Contract Compliance Programs, Equal Employment
Opportunity, Department of Labor (Parts 60-1 -- 60-999)
61 Office of the Assistant Secretary for Veterans Employment and
Training, Department of Labor (Parts 61-1 -- 61-999)
Subtitle C -- Federal Property Management Regulations System
101 Federal Property Management Regulations (Parts 101-1 -- 101-99)
105 General Services Administration (Parts 105-1 -- 105-999)
109 Department of Energy Property Management Regulations (Parts 109-1
-- 109-99)
114 Department of the Interior (Parts 114-1 -- 114-99)
115 Environmental Protection Agency (Parts 115-1 -- 115-99)
128 Department of Justice (Parts 128-1 -- 128-99)
132 Department of the Air Force (Parts 132-1 -- 132-99)
Subtitle D -- Other Provisions Relating to Property Management
(Reserved)
Subtitle E -- Federal Information Resources Management Regulations
System
201 Federal Information Resources Management Regulation (Parts 201-1
-- 201-99)
Subtitle F -- Federal Travel Regulation System
301 Travel Allowances (Parts 301-1 -- 301-99)
302 Relocation Allowances (Parts 302-1 -- 302-99)
303 Payment of Expenses Connected with the Death of Certain Employees
(Parts 303-1 -- 303-2)
304 Payment from a non-Federal source for travel expenses (Parts
304-1 -- 304-99)
21 CFR 299.5 Title 42 -- Public Health
I Public Health Service, Department of Health and Human Services
(Parts 1 -- 199)
IV Health Care Financing Administration, Department of Health and
Human Services (Parts 400 -- 499)
V Office of Inspector General-Health Care, Department of Health and
Human Services (Parts 1000 -- 1999)
21 CFR 299.5 Title 43 -- Public Lands: Interior
Subtitle A -- Office of the Secretary of the Interior (Parts 1 --
199)
Subtitle B -- Regulations Relating to Public Lands
I Bureau of Reclamation, Department of the Interior (Parts 200 --
499)
II Bureau of Land Management, Department of the Interior (Parts 1000
-- 9999)
21 CFR 299.5 Title 44 -- Emergency Management and Assistance
I Federal Emergency Management Agency (Parts 0 -- 399)
IV Department of Commerce and Department of Transportation (Parts 400
-- 499)
21 CFR 299.5 Title 45 -- Public Welfare
Subtitle A -- Department of Health and Human Services, General
Administration (Parts 1 -- 199)
Subtitle B -- Regulations Relating to Public Welfare
II Office of Family Assistance (Assistance Programs), Family Support
Administration, Department of Health and Human Services (Parts 200 --
299)
III Office of Child Support Enforcement (Child Support Enforcement
Program), Family Support Administration, Department of Health and Human
Services (Parts 300 -- 399)
IV Office of Refugee Resettlement, Administration for Children and
Families Department of Health and Human Services (Parts 400 -- 499)
V Foreign Claims Settlement Commission of the United States,
Department of Justice (Parts 500 -- 599)
VI National Science Foundation (Parts 600 -- 699)
VII Commission on Civil Rights (Parts 700 -- 799)
VIII Office of Personnel Management (Parts 800 -- 899)
X Office of Community Services, Family Support Administration,
Department of Health and Human Services (Parts 1000 -- 1099)
XI National Foundation on the Arts and the Humanities (Parts 1100 --
1199)
XII ACTION (Parts 1200 -- 1299)
XIII Office of Human Development Services, Department of Health and
Human Services (Parts 1300 -- 1399)
XVI Legal Services Corporation (Parts 1600 -- 1699)
XVII National Commission on Libraries and Information Science (Parts
1700 -- 1799)
XVIII Harry S. Truman Scholarship Foundation (Parts 1800 -- 1899)
XX Commission on the Bicentennial of the United States Constitution
(Parts 2000 -- 2099)
XXI Commission on Fine Arts (Parts 2100 -- 2199)
XXII Christopher Columbus Quincentenary Jubilee Commission (Parts
2200 -- 2299)
XXIV James Madison Memorial Fellowship Foundation (Parts 2400 --
2499)
21 CFR 299.5 Title 46 -- Shipping
I Coast Guard, Department of Transportation (Parts 1 -- 199)
II Maritime Administration, Department of Transportation (Parts 200
-- 399)
III Coast Guard (Great Lakes Pilotage), Department of Transportation
(Parts 400 -- 499)
IV Federal Maritime Commission (Parts 500 -- 599)
21 CFR 299.5 Title 47 -- Telecommunication
I Federal Communications Commission (Parts 0 -- 199)
II Office of Science and Technology Policy and National Security
Council (Parts 200 -- 299)
III National Telecommunications and Information Administration,
Department of Commerce (Parts 300 -- 399)
21 CFR 299.5 Title 48 -- Federal Acquisition Regulations System
1 Federal Acquisition Regulation (Parts 1 -- 99)
2 Department of Defense (Parts 200 -- 299)
3 Department of Health and Human Services (Parts 300 -- 399)
4 Department of Agriculture (Parts 400 -- 499)
5 General Services Administration (Parts 500 -- 599)
6 Department of State (Parts 600 -- 699)
7 Agency for International Development (Parts 700 -- 799)
8 Department of Veterans Affairs (Parts 800 -- 899)
9 Department of Energy (Parts 900 -- 999)
10 Department of the Treasury (Parts 1000 -- 1099)
12 Department of Transportation (Parts 1200 -- 1299)
13 Department of Commerce (Parts 1300 -- 1399)
14 Department of the Interior (Parts 1400 -- 1499)
15 Environmental Protection Agency (Parts 1500 -- 1599)
16 Office of Personnel Management Federal Employees Health Benefits
Acquisition Regulation (Parts 1600 -- 1699)
17 Office of Personnel Management (Parts 1700 -- 1799)
18 National Aeronautics and Space Administration (Parts 1800 -- 1899)
19 United States Information Agency (Parts 1900 -- 1999)
22 Small Business Administration (Parts 2200 -- 2299)
24 Department of Housing and Urban Development (Parts 2400 -- 2499)
25 National Science Foundation (Parts 2500 -- 2599)
28 Department of Justice (Parts 2800 -- 2899)
29 Department of Labor (Parts 2900 -- 2999)
34 Department of Education Acquisition Regulation (Parts 3400 --
3499)
35 Panama Canal Commission (Parts 3500 -- 3599)
44 Federal Emergency Management Agency (Parts 4400 -- 4499)
51 Department of the Army Acquisition Regulations (Parts 5100 --
5199)
52 Department of the Navy Acquisition Regulations (Parts 5200 --
5299)
53 Department of the Air Force Federal Acquisition Regulation
Supplement (Parts 5300 -- 5399)
57 African Development Foundation (Parts 5700 -- 5799)
61 General Services Administration Board of Contract Appeals (Parts
6100 -- 6199)
63 Department of Transportation Board of Contract Appeals (Parts 6300
-- 6399)
99 Cost Accounting Standards Board, Office of Federal Procurement
Policy, Office of Management and Budget (Parts 9900 -- 9999)
21 CFR 299.5 Title 49 -- Transportation
Subtitle A -- Office of the Secretary of Transportation (Parts 1 --
99)
Subtitle B -- Other Regulations Relating to Transportation
I Research and Special Programs Administration, Department of
Transportation (Parts 100 -- 199)
II Federal Railroad Administration, Department of Transportation
(Parts 200 -- 299)
III Federal Highway Administration, Department of Transportation
(Parts 300 -- 399)
IV Coast Guard, Department of Transportation (Parts 400 -- 499)
V National Highway Traffic Safety Administration, Department of
Transportation (Parts 500 -- 599)
VI Urban Mass Transportation Administration, Department of
Transportation (Parts 600 -- 699)
VII National Railroad Passenger Corporation (AMTRAK) (Parts 700 --
799)
VIII National Transportation Safety Board (Parts 800 -- 899)
X Interstate Commerce Commission (Parts 1000 -- 1399)
21 CFR 299.5 Title 50 -- Wildlife and Fisheries
I United States Fish and Wildlife Service, Department of the Interior
(Parts 1 -- 199)
II National Marine Fisheries Service, National Oceanic and
Atmospheric Administration, Department of Commerce (Parts 200 -- 299)
III International Regulatory Agencies (Fishing and Whaling) (Parts
300 -- 399)
IV Joint Regulations (United States Fish and Wildlife Service,
Department of the Interior and National Marine Fisheries Service,
National Oceanic and Atmospheric Administration, Department of
Commerce); Endangered Species Committee Regulations (Parts 400 -- 499)
V Marine Mammal Commission (Parts 500 -- 599)
VI Fishery Conservation and Management, National Oceanic and
Atmospheric Administration, Department of Commerce (Parts 600 -- 699)
21 CFR 299.5 CFR Index and Finding Aids Subject/Agency Index List
of Agency Prepared Indexes Parallel Table of Statutory Authorities and
Rules Acts Requiring Publication in the Federal Register List of CFR
Titles, Chapters, Subchapters, and Parts
21 CFR 299.5 Alphabetical List of Agencies Appearing in the CFR
CFR Title, Subtitle or
Agency
Chapter
ACTION 45, XII
Administrative Committee of the Federal Register 1, I
Administrative Conference of the United States 1, III
Advisory Commission on Intergovernmental Relations 5, VII
Advisory Committee on Federal Pay 5, IV
Advisory Council on Historic Preservation 36, VIII
African Development Foundation 22, XV; 48, 57
Agency for International Development 22, II; 48, 7
Agricultural Marketing Service 7, I, IX, X, XI
Agricultural Research Service 7, V
Agricultural Stabilization and Conservation Service 7, VII
Agriculture Department
Agricultural Marketing Service 7, I, IX, X, XI
Agricultural Research Service 7, V
Agricultural Stabilization and Conservation Service 7, VII
Animal and Plant Health Inspection Service 7, III; 9, I
Commodity Credit Corporation 7, XIV
Cooperative State Research Service 7, XXXIV
Economic Analysis Staff 7, XXXIX
Economic Research Service 7, XXXVII
Economics Management Staff 7, XL
Energy, Office of 7, XXIX
Environmental Quality, Office of 7, XXXI
Farmers Home Administration 7, XVIII
Federal Acquisition Regulation 48, 4
Federal Crop Insurance Corporation 7, IV
Federal Grain Inspection Service 7, VIII
Finance and Management, Office of 7, XXX
Food and Nutrition Service 7, II
Food Safety and Inspection Service 9, III
Foreign Agricultural Service 7, XV
Foreign Economic Development Service 7, XXI
Forest Service 36, II
General Sales Manager, Office of 7, XXV
Grants and Program Systems, Office of 7, XXXII
Information Resources Management, Office of 7, XXVII
Inspector General, Office of 7, XXVI
International Cooperation and Development Office 7, XXII
National Agricultural Library 7, XLI
National Agricultural Statistics Service 7, XXXVI
Operations Office 7, XXVIII
Packers and Stockyards Administration 9, II
Rural Electrification Administration 7, XVII
Rural Telephone Bank 7, XVI
Secretary of Agriculture, Office of 7, Subtitle A
Soil Conservation Service 7, VI
Transportation, Office of 7, XXXIII
World Agriculture Outlook Board 7, XXXVIII
Air Force Department 32, VII; 41, Subtitle C, Ch. 132
Federal Acquisition Regulation Supplement 48, 53
Alaska Natural Gas Transportation System, Office of the Federal
Inspector 10, XV
Alcohol, Tobacco and Firearms, Bureau of 27, I
AMTRAK 49, VII
American Battle Monuments Commission 36, IV
Animal and Plant Health Inspection Service 7, III; 9, I
Appalachian Regional Commission 5, IX
Architectural and Transportation Barriers Compliance Board 36, XI
Arms Control and Disarmament Agency, U.S. 22, VI
Army Department 32, V
Engineers, Corps of 33, II; 36, III
Federal Acquisition Regulation 48, 51
Assistant Secretary for Technology Policy, Department of Commerce 37,
IV
Benefits Review Board 20, VII
Bicentennial of the United States Constitution, Commission on the 45,
XX
Bilingual Education and Minority Languages Affairs, Office of 34, V
Blind and Other Severely Handicapped, Committee for Purchase from 41,
51
Board for International Broadcasting 22, XIII
Budget, Office of Management and 5, III
Census Bureau 15, I
Central Intelligence Agency 32, XIX
Child Support Enforcement, Office of 45, III
Christopher Columbus Quincentenary Jubilee Commission 45, XXII
Civil Rights Commission 45, VII
Civil Rights, Office for (Education Department) 34, I
Claims Collection Standards, Federal 4, II
Coast Guard 33, I; 46, I, III; 49, IV
Commerce Department 44, IV
Census Bureau 15, I
Assistant Secretary for Technology Policy 37, IV
Economic Affairs, Under Secretary 37, V
Economic Analysis, Bureau of 15, VIII
Economic Development Administration 13, III
Endangered Species Committee 50, IV
Export Administration Bureau 15, VII
Federal Acquisition Regulation 48, 13
Fishery Conservation and Management 50, VI
International Trade Administration 15, III; 19, III
National Institute of Standards and Technology 15, II
National Marine Fisheries Service 50, II, IV
National Oceanic and Atmospheric Administration 15, IX; 50, II, III,
IV, VI
National Telecommunications and Information Administration 15, XXIII;
47, III
Patent and Trademark Office 37, I
Productivity, Technology and Innovation, Assistant Secretary for 37,
IV
Secretary of Commerce, Office of 15, Subtitle A
Technology Administration 15, XI
Under Secretary for Technology 37, V
United States Travel and Tourism Administration 15, XII
Commercial Space Transportation, Office of, Department of
Transportation 14, III
Commission on the Bicentennial of the United States Constitution 45,
XX
Committee for Purchase from the Blind and Other Severely Handicapped
41, 51
Commodity Credit Corporation 7, XIV
Commodity Futures Trading Commission 17, I
Community Planning and Development, Office of Assistant Secretary for
24, V, VI
Community Services, Office of 45, X
Comptroller of the Currency 12, I
Construction Industry Collective Bargaining Commission 29, IX
Consumer Product Safety Commission 16, II
Cooperative State Research Service 7, XXXIV
Copyright Office 37, II
Copyright Royalty Tribunal 37, III
Cost Accounting Standards Board, Office of Federal Procurement Policy
48, 99
Council on Environmental Quality 40, V
Customs Service, United States 19, I
Defense Department 32, Subtitle A
Air Force Department 32, VII; 41, Subtitle C, Ch. 132
Army Department 32, V; 33, II; 36, III, 48, 51
Engineers, Corps of 33, II; 36, III
Federal Acquisition Regulation 48, 2
Navy Department 32, VI; 48, 52
Secretary of Defense, Office of 32, I
Defense Logistics Agency 32, XII
Defense Nuclear Facilities Safety Board 10, XVII
Delaware River Basin Commission 18, III
Drug Enforcement Administration 21, II
East-West Foreign Trade Board 15, XIII
Economic Affairs, Under Secretary (Commerce) 37, V
Economic Analysis, Bureau of 15, VIII
Economic Analysis Staff, Department of Agriculture 7, XXXIX
Economic Development Administration 13, III
Economics Management Staff 7, XL
Economic Research Service 7, XXXVII
Education, Department of
Bilingual Education and Minority Languages Affairs, Office of 34, V
Civil Rights, Office for 34, I
Educational Research and Improvement, Office of 34, VII
Elementary and Secondary Education, Office of 34, II
Federal Acquisition Regulation 48, 34
Postsecondary Education, Office of 34, VI
Secretary of Education, Office of 34, Subtitle A
Special Education and Rehabilitative Services, Office of 34, III
Vocational and Adult Education, Office of 34, IV
Educational Research and Improvement, Office of 34, VII
Elementary and Secondary Education, Office of 34, II
Employees' Compensation Appeals Board 20, IV
Employees Loyalty Board, International Organizations 5, V
Employment and Training Administration 20, V
Employment Standards Administration 20, VI
Endangered Species Committee 50, IV
Energy, Department of 10, II, III, X; 41, 109
Federal Acquisition Regulation 48, 9
Federal Energy Regulatory Commission 18, I
Energy, Office of, Department of Agriculture 7, XXIX
Engineers, Corps of 33, II; 36, III
Engraving and Printing, Bureau of 31, VI
Environmental Protection Agency 40, I; 41, 115; 48, 15
Environmental Quality, Office of (Agriculture Department) 7, XXXI
Equal Employment Opportunity Commission 29, XIV
Equal Opportunity, Office of Assistant Secretary for 24, I
Executive Office of the President 3, I
Administration, Office of 5, XV
Export Administration Bureau 15, VII
Export-Import Bank of the United States 12, IV
Family Assistance, Office of 45, II
Family Support Administration 45, II, III, IV, X
Farm Credit Administration 12, VI
Farm Credit System Assistance Board 12, XIII
Farm Credit System Insurance Corporation 12, XIV
Farmers Home Administration 7, XVIII
Federal Acquisition Regulation 48, 1
Federal Aviation Administration 14, I
Federal Claims Collection Standards 4, II
Federal Communications Commission 47, I
Federal Contract Compliance Programs, Office of 41, 60
Federal Crop Insurance Corporation 7, IV
Federal Deposit Insurance Corporation 12, III
Federal Election Commission 11, I
Federal Emergency Management Agency 44, I; 48, 44
Federal Energy Regulatory Commission 18, I
Federal Financial Institutions Examination Council 12, XI
Federal Financing Bank 12, VIII
Federal Grain Inspection Service 7, VIII
Federal Highway Administration 23, I, II; 49, III
Federal Home Loan Mortgage Corporation 1, IV
Federal Housing Finance Board 12, IX
Federal Information Resources Management Regulations 41, Subtitle E,
Ch. 201
Federal Inspector for the Alaska Natural Gas Transportation System,
Office of 10, XV
Federal Labor Relations Authority, and General Counsel of the Federal
Labor Relations Authority 5, XIV; 22, XIV
Federal Law Enforcement Training Center 31, VII
Federal Maritime Commission 46, IV
Federal Mediation and Conciliation Service 29, XII
Federal Mine Safety and Health Review Commission 29, XXVII
Federal Pay, Advisory Committee on 5, IV
Federal Prison Industries, Inc. 28, III
Federal Procurement Policy Office 48, 99
Federal Property Management Regulations 41, 101
Federal Property Management Regulations System 41, Subtitle C
Federal Railroad Administration 49, II
Federal Register, Administrative Committee of 1, I
Federal Register, Office of 1, II
Federal Reserve System 12, II
Federal Retirement Thrift Investment Board 5, VI
Federal Service Impasses Panel 5, XIV
Federal Trade Commission 16, I
Federal Travel Regulation System 41, Subtitle F
Finance and Management, Department of Agriculture 7, XXX
Fine Arts Commission 45, XXI
Fiscal Service 31, II
Fish and Wildlife Service, United States 50, I, IV
Fishery Conservation and Management 50, VI
Fishing and Whaling, International Regulatory Agencies 50, III
Food and Drug Administration 21, I
Food and Nutrition Service 7, II
Food Safety and Inspection Service 9, III
Foreign Agricultural Service 7, XV
Foreign Assets Control, Office of 31, V
Foreign Claims Settlement Commission of United States 45, V
Foreign Economic Development Service 7, XXI
Foreign Service Grievance Board 22, IX
Foreign Service Impasse Disputes Panel 22, XIV
Foreign Service Labor Relations Board 22, XIV
Foreign-Trade Zones Board 15, IV
Forest Service 36, II
General Accounting Office 4, I, II, III
General Sales Manager, Office of 7, XXV
General Services Administration
Contract Appeals Board 48, 61
Federal Acquisition Regulation 48, 5
Federal Information Resources Management Regulations 41, Subtitle E,
Ch. 201
Federal Property Management Regulations System 41, 101, 105
Federal Travel Regulation System 41, Subtitle F
Payment of Expenses Connected With the Death of Certain Employees 41,
303
Reduction in Meeting and Training Allowance Payments 41, 304
Relocation Allowances 41, 302
Travel Allowances 41, 301
Geological Survey 30, IV
Government Ethics, Office of 5, XVI
Government National Mortgage Association 24, III
Grants and Program Systems, Office of 7, XXXII
Great Lakes Pilotage 46, III
Harry S. Truman Scholarship Foundation 45, XVIII
Health and Human Services, Department of 45, Subtitle A
Child Support Enforcement, Office of 45, III
Community Services, Office of 45, X
Family Assistance, Office of 45, II
Family Support Administration 45, II, III, IV, X
Federal Acquisition Regulation 48, 3
Food and Drug Administration 21, I
Health Care Financing Administration 42, IV
Human Development Services Office 45, XIII
Inspector General, Office of 42, V
Public Health Service 42, I
Refugee Resettlement, Office of 45, IV
Social Security Administration 20, III; 45, IV
Health Care Financing Administration 42, IV
Housing and Urban Development, Department of
Community Planning and Development, Office of Assistant Secretary for
24, V, VI
Equal Opportunity, Office of Assistant Secretary for 24, I
Federal Acquisition Regulation 48, 24
Government National Mortgage Association 24, III
Housing -- Federal Housing Commissioner, Office of Assistant
Secretary for 24, II, VIII, X, XX
Inspector General, Office of 24, XII
Mortgage Insurance and Loan Programs Under Emergency Homeowners'
Relief Act 24, XV
Public and Indian Housing, Office of Assistant Secretary for 24, IX
Secretary, Office of 24, Subtitle B, VII
Solar Energy and Energy Conservation Bank 24, XI
Housing -- Federal Housing Commissioner, Office of Assistant
Secretary for 24, II, VIII, X, XX
Human Development Services Office 45, XIII
Immigration and Naturalization Service 8, I
Indian Affairs, Bureau of 25, I
Indian Arts and Crafts Board 25, II
Information Agency, United States 22, V; 48, 19
Information Resources Management, Office of, Agriculture Department
7, XXVII
Information Security Oversight Office 32, XX
Inspector General, Office of, Agriculture Department 7, XXVI
Inspector General, Office of, Health and Human Services Department
42, V
Inspector General, Office of, Housing and Urban Development
Department 24, XII
Inter-American Foundation 22, X
Intergovernmental Relations, Advisory Commission on 5, VII
Interior Department
Endangered Species Committee 50, IV
Federal Acquisition Regulation 48, 14
Federal Property Management Regulations System 41, 114
Fish and Wildlife Service, United States 50, I, IV
Geological Survey 30, IV
Indian Affairs, Bureau of 25, I
Indian Arts and Crafts Board 25, II
Land Management Bureau 43, II
Minerals Management Service 30, II
Mines, Bureau of 30, VI
National Park Service 36, I
Reclamation Bureau 43, I
Secretary of the Interior, Office of 43, Subtitle A
Surface Mining and Reclamation Appeals, Board of 30, III
Surface Mining Reclamation and Enforcement, Office of 30, VII
United States Fish and Wildlife Service 50, I, IV
Internal Revenue Service 26, I
International Boundary and Water Commission, United States and Mexico
22, XI
International Cooperation and Development Office, Department of
Agriculture 7, XXII
International Development, Agency for 22, II
International Development Cooperation Agency 22, XII
International Development, Agency for 22, II
Overseas Private Investment Corporation 22, VII
International Joint Commission, United States and Canada 22, IV
International Organizations Employees Loyalty Board 5, V
International Regulatory Agencies (Fishing and Whaling) 50, III
International Trade Administration 15, III; 19, III
International Trade Commission, United States 19, II
Interstate Commerce Commission 49, X
Japan-United States Friendship Commission 22, XVI
Joint Board for the Enrollment of Actuaries 20, VIII
Justice Department 28, I; 41, 128
Drug Enforcement Administration 21, II
Federal Acquisition Regulation 48, 28
Federal Claims Collection Standards 4, II
Federal Prison Industries, Inc. 28, III
Foreign Claims Settlement Commission of the United States 45, V
Immigration and Naturalization Service 8, I
Offices of Independent Counsel 28, VI
Prisons, Bureau of 28, V
Labor Department
Benefits Review Board 20, VII
Employees' Compensation Appeals Board 20, IV
Employment and Training Administration 20, V
Employment Standards Administration 20, VI
Federal Acquisition Regulation 48, 29
Federal Contract Compliance Programs, Office of 41, 60
Federal Procurement Regulations System 41, 50
Labor-Management Relations and Cooperative Programs, Bureau of 29, II
Labor-Management Standards, Office of 29, IV
Mine Safety and Health Administration 30, I
Occupational Safety and Health Administration 29, XVII
Pension and Welfare Benefits Administration 29, XXV
Public Contracts 41, 50
Secretary of Labor, Office of 29, Subtitle A
Veterans' Employment and Training, Office of the Assistant Secretary
for 41, 61; 20, IX
Wage and Hour Division 29, V
Workers' Compensation Programs, Office of 20, I
Labor-Management Relations and Cooperative Programs, Bureau of 29, II
Labor-Management Standards, Office of 29, IV
Land Management, Bureau of 43, II
Legal Services Corporation 45, XVI
Library of Congress 36, VII
Copyright Office 37, II
Management and Budget, Office of 5, III; 48, 99
Marine Mammal Commission 50, V
Maritime Administration 46, II
Merit Systems Protection Board 5, II
Micronesian Status Negotiations, Office for 32, XXVII
Mine Safety and Health Administration 30, I
Minerals Management Service 30, II
Mines, Bureau of 30, VI
Minority Business Development Agency 15, XIV
Miscellaneous Agencies 1, IV
Monetary Offices 31, I
Mortgage Insurance and Loan Programs Under the Emergency Homeowners'
Relief Act, Department of Housing and Urban Development 24, XV
National Aeronautics and Space Administration 14, V; 48, 18
National Agricultural Library 7, XLI
National Agricultural Statistics Service 7, XXXVI
National Archives and Records Administration 36, XII
National Bureau of Standards 15, II
National Capital Planning Commission 1, IV
National Commission for Employment Policy 1, IV
National Commission on Libraries and Information Science 45, XVII
National Credit Union Administration 12, VII
National Foundation on the Arts and the Humanities 45, XI
National Highway Traffic Safety Administration 23, II, III; 49, V
National Indian Gaming Commission 25, III
National Institute of Standards and Technology 15, II
National Labor Relations Board 29, I
National Marine Fisheries Service 50, II, IV
National Mediation Board 29, X
National Oceanic and Atmospheric Administration 15, IX; 50, II, III,
IV, VI
National Park Service 36, I
National Railroad Adjustment Board 29, III
National Railroad Passenger Corporation (AMTRAK) 49, VII
National Science Foundation 45, VI; 48, 25
National Security Council 32, XXI
National Security Council and Office of Science and Technology Policy
47, II
National Telecommunications and Information Administration 15, XXIII;
47, III
National Transportation Safety Board 49, VIII
Navy Department 32, VI; 48, 52
Neighborhood Reinvestment Corporation 24, XXV
Nuclear Regulatory Commission 10, I
Occupational Safety and Health Administration 29, XVII
Occupational Safety and Health Review Commission 29, XX
Office of Independent Counsel 28, VII
Office of Navajo and Hopi Indian Relocation 25, IV
Offices of Independent Counsel, Department of Justice 28, VI
Operations Office, Department of Agriculture 7, XXVIII
Overseas Private Investment Corporation 22, VII
Oversight Board 12, XV
Packers and Stockyards Administration 9, II
Panama Canal Commission 48, 35
Panama Canal Regulations 35, I
Patent and Trademark Office 37, I
Payment of Expenses Connected With the Death of Certain Employees 41,
303
Peace Corps 22, III
Pennsylvania Avenue Development Corporation 36, IX
Pension and Welfare Benefits Administration, Department of Labor 29,
XXV
Pension Benefit Guaranty Corporation 29, XXVI
Personnel Management, Office of 5, I; 45, VIII; 48, 17
Federal Employees Health Benefits Acquisition Regulation 48, 16
Postal Rate Commission 39, III
Postal Service, United States 39, I
Postsecondary Education, Office of 34, VI
President's Commission on White House Fellowships 1, IV
Presidential Documents 3
Prisons, Bureau of 28, V
Productivity, Technology and Innovation, Assistant Secretary
(Commerce) 37, IV
Property Management Regulations System, Federal 41, Subtitle C
Public Contracts, Department of Labor 41, 50
Public Health Service 42, I
Railroad Retirement Board 20, II
Reclamation Bureau 43, I
Reduction in Meeting and Training Allowance Payments 41, 304
Refugee Resettlement, Office of 45, IV
Regional Action Planning Commissions 13, V
Relocation Allowances 41, 302
Research and Special Programs Administration 49, I
Resolution Trust Corporation 12, XVI
Rural Electrification Administration 7, XVII
Rural Telephone Bank 7, XVI
Saint Lawrence Seaway Development Corporation 33, IV
Science and Technology Policy, Office of 32, XXIV
Science and Technology Policy, Office of, and National Security
Council 47, II
Secret Service 31, IV
Securities and Exchange Commission 17, II
Selective Service System 32, XVI
Small Business Administration 13, I; 48, 22
Smithsonian Institution 36, V
Social Security Administration 20, III; 45, IV
Soil Conservation Service 7, VI
Solar Energy and Energy Conservation Bank, Department of Housing and
Urban Development 24, XI
Soldiers' and Airmen's Home, United States 5, XI
Special Counsel, Office of 5, VIII
Special Education and Rehabilitative Services, Office of 34, III
State Department 22, I
Federal Acquisition Regulation 48, 6
Surface Mining and Reclamation Appeals, Board of 30, III
Susquehanna River Basin Commission 18, VIII
Technology Administration 15, XI
Tennessee Valley Authority 18, XIII
Thrift Supervision Office, Department of the Treasury 12, V
Trade Representative, United States, Office of 15, XX
Transportation, Department of 44, IV
Coast Guard 33, I; 46, I, III; 49, IV
Commercial Space Transportation, Office of 14, III
Contract Appeals Board 48, 63
Federal Acquisition Regulation 48, 12
Federal Aviation Administration 14, I
Federal Highway Administration 23, I, II; 49, III
Federal Railroad Administration 49, II
Maritime Administration 46, II
National Highway Traffic Safety Administration 23, II, III; 49, V
Research and Special Programs Administration 49, I
Saint Lawrence Seaway Development Corporation 33, IV
Secretary of Transportation, Office of 14, II; 49, Subtitle A
Urban Mass Transportation Administration 49, VI
Transportation, Office of, Department of Agriculture 7, XXXIII
Travel Allowance 41, 301
Travel and Tourism Administration, United States 15, XII
Treasury Department 17, IV
Alcohol, Tobacco and Firearms, Bureau of 27, I
Comptroller of the Currency 12, I
Customs Service, United States 19, I
Engraving and Printing, Bureau of 31, VI
Federal Acquisition Regulation 48, 10
Federal Law Enforcement Training Center 31, VII
Fiscal Service 31, II
Foreign Assets Control, Office of 31, V
Internal Revenue Service 26, I
Monetary Offices 31, I
Secret Service 31, IV
Secretary of the Treasury, Office of 31, Subtitle A
Thrift Supervision Office 12, V
United States Customs Service 19, I
Truman, Harry S. Scholarship Foundation 45, XVIII
Under Secretary for Technology, Department of Commerce 37, V
United States and Canada, International Joint Commission 22, IV
United States Arms Control and Disarmament Agency 22, VI
United States Customs Service 19, I
United States Fish and Wildlife Service 50, I, IV
United States Information Agency 22, V; 48, 19
United States International Development Cooperation Agency 22, XII
United States International Trade Commission 19, II
United States Postal Service 39, I
United States Soldiers' and Airmen's Home 5, XI
United States Trade Representative, Office of 15, XX
United States Travel and Tourism Adminstration 15, XII
Urban Mass Transportation Administration 49, VI
Veterans Affairs Department 38, I; 48, 8
Veterans' Employment and Training, Office of the Assistant Secretary
for 41, 61; 20, IX
Vice President of the United States, Office of 32, XXVIII
Vocational and Adult Education, Office of 34, IV
Wage and Hour Division 29, V
Water Resources Council 18, VI
Workers' Compensation Programs, Office of 20, I
World Agriculture Outlook Board 7, XXXVIII
21 CFR 299.5 21 CFR Ch. I (4-1-92 Edition)
21 CFR 299.5 List of CFR Sections Affected
21 CFR 299.5 List of CFR Sections Affected
All changes in this volume of the Code of Federal Regulations which
were made by documents published in the Federal Register since January
1, 1986, are enumerated in the following list. Entries indicate the
nature of the changes effected. Page numbers refer to Federal Register
pages. The user should consult the entries for chapters and parts as
well as sections for revisions.
For the period before January 1, 1986, see ''List of CFR Sections
Affected, 1949-1963, 1964-1972, and 1973-1985'' published in seven
separate volumes.
21 CFR 299.5 1986
21 CFR
51 FR
Page
Chapter I
Mandatory compliance date 1-1-89 34085
201 Authority citation revised 8182,
41783, 43904
201.20 (a) revised 41783
201.22 Added; eff. 6-3-87 43904
201.314 (h) added; eff. 6-5-86 8182
207 Authority citation revised 7389
207.10 (f) revised; eff. 5-2-86 7389
210 Heading and authority citation revised; eff. 5-2-86 7389
210.3 (b) (13) and (14) revised; eff. 5-2-86 7389
211 Authority citation revised 24479
211.198 (a) amended 24479
Technical correction 28810
225 Authority citation revised 7389
225.1 (b) revised; eff. 5-2-86 7389
225.58 (b)(1) amended; (b)(2) removed; (c) revised; eff. 5-2-86
7390
225.115 (b)(2) amended; eff. 5-2-86 7390
225.120 -- 225.135 (Subpart F) Added; eff. 5-2-86 7390
225.142 -- 225.165 (Subpart G) Added; eff. 5-2-86 7390
225.180 (Subpart H) Added; eff. 5-2-86 7390
225.202 (Subpart I) Added; eff. 5-2-86 7390
226 Heading and authority citation revised; nomenclature change;
eff. 5-2-86 7390
21 CFR 299.5 1987
21 CFR
52 FR
Page
Chapter I
201 Authority citation revised 2111
201.20 (a) revised; (c) added 21509
201.21 Effective date deferred in part 12152
201.21 Added; eff. 4-20-87 2111
207 Authority citation revised 2682
207.20 (a) amended 2682
207.25 (b) (1) and (6) amended 2682
207.35 (b)(2)(iii) amended 2682
21 CFR 299.5 1988
21 CFR
53 FR
Page
Chapter I
Uniform compliance date 1-1-91 44861
201 Authority citation revised 4135
201.20 (c) suspended 49138
201.21 OMB number 4135
201.314 (h)(1) amended; (h)(5) removed 21637
(h)(1) corrected 24830
299 Authority citation revised 5369
299.4 (e) revised 5369
21 CFR 299.5 1989
21 CFR
54 FR
Page
Chapter I
200 Authority citation revised; sectional authority citations
removed 39635
201 Authority citation revised; sectional authority citations
removed 39635
202 Authority citation revised 39635
202.1 Authority citation removed 39635
207 Authority citation revised 39635
207.35 Authority citation removed 39635
210 Authority citation revised 39635
211 Authority citation revised 5228
Authority citation revised; sectional authority citations removed
39635
211.132 Revised; eff. 2-2-90 5228
225 Authority citation revised 39635
226 Authority citation revised 39635
250 Authority citation revised; sectional authority citations
removed 39635
290 Authority citation revised 39635
290.6 Authority citation removed 39635
291 Authority citation added; sectional authorities removed 8960
Authority citation revised 39635
291.505 Revised; eff. 4-3-89 8960
(b)(2)(i) and (d)(1)(iv) corrected 12531
299 Authority citation revised; sectional authority citations
removed 39635
21 CFR 299.5 1990
21 CFR
55 FR
Page
Chapter I
200.10 (c) amended 11576
201.57 (b)(2)(ii), (c)(2), (3)(i) and (v), (f)(9), (g)(2) and (4),
and (m)(1) amended 11576
201.58 Revised 11576
201.59 (a)(2) and (3) amended 11576
201.63 (e) added 27784
201.122 (b) amended 11576
201.200 (d) amended 11576
201.305 (d)(2) amended 11576
201.306 (a)(2) amended 11576
201.307 (c)(3) amended 11576
205 Added 38023
207.3 (a)(5) amended 11576
207.7 (a) and (d) amended 11576
207.20 (c) amended 11576
207.21 (a) amended 11576
207.22 (a) and (b) amended 11576
207.25 (b)(2) amended 11577
207.26 Amended 11577
207.35 (b)(3)(v) amended 11577
207.37 Introductory text and (b) amended 11577
207.40 (b) amended 11577
211.176 Amended 11577
211.194 (a)(2) footnote amended 11577
225.58 (b)(1) amended 11577
226.58 (e) footnote amended 11577
(d) amended 23703
250.10 (c) revised 11577
250.103 (d) revised 11577
250.106 (c) revised 11577
250.250 (c)(4) introductory text, (ii), and (v) amended 11577
299.4 (b) and (d) amended 11577
21 CFR 299.5 1991
21 CFR 299.5 1992
21 CFR
57 FR
Page
Chapter I
225.115 (b)(2) amended 6475
21
Food and Drugs
PARTS 200 TO 299
Revised as of April 1, 1992
CONTAINING
A CODIFICATION OF DOCUMENTS
OF GENERAL APPLICABILITY
AND FUTURE EFFECT
AS OF APRIL 1, 1992
With Ancillaries
Published by
the Office of the Federal Register
National Archives and Records
Administration
as a Special Edition of
the Federal Register
Washington, DC 20402-9328
21 CFR 299.5 Table of Contents
Page
Explanation v
Title 21:
Chapter I -- Food and Drug Administration, Department of Health and
Human Services (Continued) 3
Finding Aids:
Material Approved for Incorporation by Reference
Table of CFR Titles and Chapters
Alphabetical List of Agencies Appearing in the CFR
List of CFR Sections Affected
21 CFR 299.5 Explanation
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
regulation. Each title is divided into chapters which usually bear the
name of the issuing agency. Each chapter is further subdivided into
parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16 as of January 1
Title 17 through Title 27 as of April 1
Title 28 through Title 41 as of July 1
Title 42 through Title 50 as of October 1
The appropriate revision date is printed on the cover of each volume.
LEGAL STATUS
The contents of the Federal Register are required to be judicially
noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie
evidence of the text of the original documents (44 U.S.C. 1510).
HOW TO USE THE CODE OF FEDERAL REGULATIONS
The Code of Federal Regulations is kept up to date by the individual
issues of the Federal Register. These two publications must be used
together to determine the latest version of any given rule.
To determine whether a Code volume has been amended since its
revision date (in this case, April 1, 1992), consult the ''List of CFR
Sections Affected (LSA),'' which is issued monthly, and the ''Cumulative
List of Parts Affected,'' which appears in the Reader Aids section of
the daily Federal Register. These two lists will identify the Federal
Register page number of the latest amendment of any given rule.
EFFECTIVE AND EXPIRATION DATES
Each volume of the Code contains amendments published in the Federal
Register since the last revision of that volume of the Code. Source
citations for the regulations are referred to by volume number and page
number of the Federal Register and date of publication. Publication
dates and effective dates are usually not the same and care must be
exercised by the user in determining the actual effective date. In
instances where the effective date is beyond the cut-off date for the
Code a note has been inserted to reflect the future effective date. In
those instances where a regulation published in the Federal Register
states a date certain for expiration, an appropriate note will be
inserted following the text.
OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires Federal
agencies to display an OMB control number with their information
collection request. Many agencies have begun publishing numerous OMB
control numbers as amendments to existing regulations in the CFR. These
OMB numbers are placed as close as possible to the applicable
recordkeeping or reporting requirements.
OBSOLETE PROVISIONS
Provisions that become obsolete before the revision date stated on
the cover of each volume are not carried. Code users may find the text
of provisions in effect on a given date in the past by using the
appropriate numerical list of sections affected. For the period before
January 1, 1986, consult either the List of CFR Sections Affected,
1949-1963, 1964-1972, or 1973-1985, published in seven separate volumes.
For the period beginning January 1, 1986, a ''List of CFR Sections
Affected'' is published at the end of each CFR volume.
INCORPORATION BY REFERENCE
What is incorporation by reference? Incorporation by reference was
established by statute and allows Federal agencies to meet the
requirement to publish regulations in the Federal Register by referring
to materials already published elsewhere. For an incorporation to be
valid, the Director of the Federal Register must approve it. The legal
effect of incorporation by reference is that the material is treated as
if it were published in full in the Federal Register (5 U.S.C. 552(a)).
This material, like any other properly issued regulation, has the force
of law.
What is a proper incorporation by reference? The Director of the
Federal Register will approve an incorporation by reference only when
the requirements of 1 CFR part 51 are met. Some of the elements on
which approval is based are:
(a) The incorporation will substantially reduce the volume of
material published in the Federal Register.
(b) The matter incorporated is in fact available to the extent
necessary to afford fairness and uniformity in the administrative
process.
(c) The incorporating document is drafted and submitted for
publication in accordance with 1 CFR part 51.
Properly approved incorporations by reference in this volume are
listed in the Finding Aids at the end of this volume.
What if the material incorporated by reference cannot be found? If
you have any problem locating or obtaining a copy of material listed in
the Finding Aids of this volume as an approved incorporation by
reference, please contact the agency that issued the regulation
containing that incorporation. If, after contacting the agency, you
find the material is not available, please notify the Director of the
Federal Register, National Archives and Records Administration,
Washington DC 20408, or call (202) 523-4534.
CFR INDEXES AND TABULAR GUIDES
A subject index to the Code of Federal Regulations is contained in a
separate volume, revised annually as of January 1, entitled CFR Index
and Finding Aids. This volume contains the Parallel Table of Statutory
Authorities and Agency Rules (Table I), and Acts Requiring Publication
in the Federal Register (Table II). A list of CFR titles, chapters, and
parts and an alphabetical list of agencies publishing in the CFR are
also included in this volume.
An index to the text of ''Title 3 -- The President'' is carried
within that volume.
The Federal Register Index is issued monthly in cumulative form.
This index is based on a consolidation of the ''Contents'' entries in
the daily Federal Register.
A List of CFR Sections Affected (LSA) is published monthly, keyed to
the revision dates of the 50 CFR titles.
REPUBLICATION OF MATERIAL
There are no restrictions on the republication of material appearing
in the Code of Federal Regulations.
INQUIRIES AND SALES
For a summary, legal interpretation, or other explanation of any
regulation in this volume, contact the issuing agency. Inquiries
concerning editing procedures and reference assistance with respect to
the Code of Federal Regulations may be addressed to the Director, Office
of the Federal Register, National Archives and Records Administration,
Washington, DC 20408 (telephone 202-523-3517). All mail order sales are
handled exclusively by the Superintendent of Documents, Attn: New
Orders, P.O. Box 371954, Pittsburgh, PA 15250-7954. Charge orders may
be telephoned to the Government Printing Office order desk at
202-783-3238.
Martha L. Girard,
Director,
Office of the Federal Register.
April 1, 1992.
21 CFR 299.5 THIS TITLE
Title 21 -- Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300-end. The
first eight volumes, containing parts 1-1299, comprise Chapter I -- Food
and Drug Administration, Department of Health and Human Services. The
ninth volume, containing part 1300 to end, includes Chapter II -- Drug
Enforcement Administration, Department of Justice. The contents of
these volumes represent all current regulations codified under this
title of the CFR as of April 1, 1992.
The Table of Exempted Prescription Products to part 1308 appears in
the volume containing part 1300-End.
Redesignation tables for Chapter I -- Food and Drug Administration
appear in the Finding Aids section for the volumes containing parts
170-199 and 500-599.
For this volume, Ina C. Masters was Chief Editor. The Code of
Federal Regulations publication program is under the direction of
Richard L. Claypoole, assisted by Alomha S. Morris.
21 CFR 0.0 21 CFR Ch. I (4-1-92 Edition)
21 CFR 0.0 Food and Drug Administration, HHS
21 CFR 0.0 Title 21 -- Food and Drugs
21 CFR 0.0 (This book contains parts 300 to 499)
Part
chapter i -- Food and Drug Administration, Department of Health and
Human Services (Continued) 300
Cross References: Food Safety and Inspection Service, Department of
Agriculture: See Meat and Poultry Inspection, 9 CFR chapter III.
Federal Trade Commission: See Commercial Practices, 16 CFR chapter
I.
United States Customs Service, Department of the Treasury: See
Customs Duties, 19 CFR chapter I.
Internal Revenue Service, Department of the Treasury: See Internal
Revenue, 26 CFR chapter I.
Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury:
See Alcohol, Tobacco Products and Firearms, 27 CFR chapter I.
21 CFR 0.0 21 CFR Ch. I (4-1-92 Edition)
21 CFR 0.0 Food and Drug Administration, HHS
21 CFR 0.0 CHAPTER I -- FOOD AND DRUG ADMINISTRATION,
21 CFR 0.0 DEPARTMENT OF HEALTH AND HUMAN SERVICES -- Continued
21 CFR 0.0 (Parts 300 to 499)
Editorial Note: The Food and Drug Administration published a
document at 49 FR 41019, Oct. 19, 1984, establishing July 1, 1987, as a
uniform effective date for compliance for regulations affecting the
labeling of food products. At 51 FR 34085, Sept. 25, 1986, FDA
established January 1, 1989, as a new uniform effective date for
compliance. The new uniform effective date will apply only to final FDA
food labeling regulations published after July 1, 1986, and before
January 1, 1988.
21 CFR 0.0 SUBCHAPTER D -- DRUGS FOR HUMAN USE
Part
Page
300 General
310 New drugs
312 Investigational new drug application
314 Applications for FDA approval to market a new drug or an
antibiotic drug
320 Bioavailability and bioequivalence requirements
329 Habit-forming drugs
330 Over-the-counter (OTC) human drugs which are generally recognized
as safe and effective and not misbranded
331 Antacid products for over-the-counter (OTC) human use
332 Antiflatulent products for over-the-counter human use
333 Topical antimicrobial drug products for over-the-counter human
use
336 Antiemetic drug products for over-the-counter human use
338 Nighttime sleep-aid drug products for over-the-counter human use
340 Stimulant drug products for over-the-counter human use
341 Cold, cough, allergy, bronchodilator, and antiasthmatic drug
products for over-the-counter human use
344 Topical OTIC drug products for over-the-counter human use
346 Anorectal drug products for over-the-counter human use
349 Ophthalmic drug products for over-the-counter human use
357 Miscellaneous internal drug products for over-the-counter human
use
358 Miscellaneous external drug products for over-the-counter human
use
361 Prescription drugs for human use generally recognized as safe and
effective and not misbranded: Drugs used in research
369 Interpretative statements re warnings on drugs and devices for
over-the-counter sale
429 Drugs composed wholly or partly of insulin
430 Antibiotic drugs; general
431 Certification of antibiotic drugs
432 Packaging and labeling of antibiotic drugs
433 Exemptions from antibiotic certification and labeling
requirements
436 Tests and methods of assay of antibiotic and
antibiotic-containing drugs
440 Penicillin antibiotic drugs
441 Penem antibiotic drugs
442 Cepha antibiotic drugs
444 Oligosaccharide antibiotic drugs
446 Tetracycline antibiotic drugs
448 Peptide antibiotic drugs
449 Antifungal antibiotic drugs
450 Antitumor antibiotic drugs
452 Macrolide antibiotic drugs
453 Lincomycin antibiotic drugs
455 Certain other antibiotic drugs
460 Antibiotic drugs intended for use in laboratory diagnosis of
disease
461-499 (Reserved)
21 CFR 0.0 21 CFR Ch. I (4-1-92 Edition)
21 CFR 0.0 Food and Drug Administration, HHS
21 CFR 0.0 SUBCHAPTER D -- DRUGS FOR HUMAN USE
21 CFR 0.0 PART 300 -- GENERAL
21 CFR 0.0 Subpart A -- (Reserved)
21 CFR 0.0 Subpart B -- Combination Drugs
Sec.
300.50 Fixed-combination prescription drugs for humans.
21 CFR 0.0 Subpart C -- Substances Generally Prohibited From Drugs
300.100 Chlorofluorocarbon propellants.
21 CFR 0.0 Subpart A -- (Reserved)
21 CFR 0.0 Subpart B -- Combination Drugs
Authority: Secs. 301, 501, 502, 505, 507, 512, 601, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331, 351, 352, 355, 357,
360b, 361, 371).
21 CFR 300.50 Fixed-combination prescription drugs for humans.
The Food and Drug Administration's policy in administering the
new-drug, antibiotic, and other regulatory provisions of the Federal
Food, Drug, and Cosmetic Act regarding fixed combination dosage form
prescription drugs for humans is as follows:
(a) Two or more drugs may be combined in a single dosage form when
each component makes a contribution to the claimed effects and the
dosage of each component (amount, frequency, duration) is such that the
combination is safe and effective for a significant patient population
requiring such concurrent therapy as defined in the labeling for the
drug. Special cases of this general rule are where a component is
added:
(1) To enhance the safety or effectiveness of the principal active
component; and
(2) To minimize the potential for abuse of the principal active
component.
(b) If a combination drug presently the subject of an approved
new-drug application or antibiotic monograph has not been recognized as
effective by the Commissioner of Food and Drugs based on his evaluation
of the appropriate National Academy of Sciences-National Research
Council panel report, or if substantial evidence of effectiveness has
not otherwise been presented for it, then formulation, labeling, or
dosage changes may be proposed and any resulting formulation may meet
the appropriate criteria listed in paragraph (a) of this section.
(c) A fixed-combination prescription drug for humans that has been
determined to be effective for labeled indications by the Food and Drug
Administration, based on evaluation of the NAS-NRC report on the
combination, is considered to be in compliance with the requirements of
this section.
(40 FR 13496, Mar. 27, 1975)
21 CFR 300.50 Subpart C -- Substances Generally Prohibited From Drugs
21 CFR 300.100 Chlorofluorocarbon propellants.
The use of chlorofluorocarbons in human drugs as propellants in
self-pressurized containers is generally prohibited except as provided
by 2.125 of this chapter.
(43 FR 11317, Mar. 17, 1978)
21 CFR 300.100 Pt. 310
21 CFR 300.100 PART 310 -- NEW DRUGS
21 CFR 300.100 Subpart A -- General Provisions
Sec.
310.3 Definitions and interpretations.
310.4 Biologics; products subject to license control.
310.6 Applicability of ''new drug'' or safety or effectiveness
findings in drug efficacy study implementation notices and notices of
opportunity for hearing to identical, related, and similar drug
products.
21 CFR 300.100 Subpart B -- Specific Administrative Rulings and
Decisions
310.100 New drug status opinions; statement of policy.
310.101 FD&C Red No. 4; procedure for discontinuing use in new
drugs for ingestion; statement of policy.
310.103 New drug substances intended for hypersensitivity testing.
21 CFR 300.100 Subpart C -- New Drugs Exempted From
Prescription-Dispensing Requirements
310.200 Prescription-exemption procedure.
310.201 Exemption for certain drugs limited by new drug applications
to prescription sale.
21 CFR 300.100 Subpart D -- Records and Reports
310.303 Continuation of long-term studies, records, and reports on
certain drugs for which new drug applications have been approved.
310.304 Drugs that are subjects of approved new drug applications and
that require special studies, records, and reports.
310.305 Records and reports concerning adverse drug experiences on
marketed prescription drugs for human use without approved new drug
applications.
21 CFR 300.100 Subpart E -- Requirements for Specific New Drugs or
Devices
310.500 Digoxin products for oral use; conditions for marketing.
310.501 Patient package inserts for oral contraceptives.
310.502 Intrauterine devices for human use for the purpose of
contraception.
310.503 Requirements regarding certain radioactive drugs.
310.504 Amphetamines (amphetamine, dextroamphetamine, and their salts
and levamfetamine and its salts) for human use.
310.506 Use of vinyl chloride as an ingredient, including propellant,
of aerosol drug products.
310.507 Aerosol drug products for human use containing
1,1,-1-trichloroethane.
310.508 Use of certain halogenated salicylanilides as an inactive
ingredient in drug products.
310.509 Parenteral drug products in plastic containers.
310.510 Use of aerosol drug products containing zirconium.
310.513 Chloroform, use as an ingredient (active or inL otive) in
drug products.
310.515 Patient package inserts for estrogens.
310.516 Progestational drug products; labeling directed to the
patient.
310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea
class.
310.519 Drug products marketed as over-the-counter (OTC) daytime
sedatives.
310.525 Sweet spirits of nitre drug products.
310.526 Camphorated oil drug products.
310.527 Drug products containing active ingredients offered
over-the-counter (OTC) for external use as hair growers or for hair loss
prevention.
310.528 Drug products containing active ingredients offered
over-the-counter (OTC) for use as an aphrodisiac.
310.529 Drug products containing active ingredients offered
over-the-counter (OTC) for oral use as insect repellents.
310.532 Drug products containing active ingredients offered
over-the-counter (OTC) to relieve the symptoms of benign prostatic
hypertrophy.
310.533 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as an anticholinergic in cough-cold
drug products.
310.534 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as oral wound healing agents.
310.540 Drug products containing active ingredients offered
over-the-counter (OTC) for use as stomach acidifiers.
310.541 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hypophosphatemia.
310.542 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hyperphosphatemia.
310.545 Drug products containing certain active ingredients offered
over-the-counter (OTC) for certain uses.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-516,
520, 601(a), 701, 704, 705, 706 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 360b-360f, 360j,
361(a), 371, 374, 375, 376); secs. 215, 301, 302(a), 351, 354-360F of
the Public Health Service Act (42 U.S.C. 216, 241, 242(a), 262,
263b-263n).
21 CFR 300.100 Subpart A -- General Provisions
21 CFR 310.3 Definitions and interpretations.
As used in this part:
(a) The term act means the Federal Food, Drug, and Cosmetic Act, as
amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C.
321-392).
(b) Department means the Department of Health and Human Services.
(c) Secretary means the Secretary of Health and Human Services.
(d) Commissioner means the Commissioner of Food and Drugs.
(e) The term person includes individuals, partnerships, corporations,
and associations.
(f) The definitions and interpretations of terms contained in section
201 of the act shall be applicable to such terms when used in the
regulations in this part.
(g) New drug substance means any substance that when used in the
manufacture, processing, or packing of a drug, causes that drug to be a
new drug, but does not include intermediates used in the synthesis of
such substance.
(h) The newness of a drug may arise by reason (among other reasons)
of:
(1) The newness for drug use of any substance which composes such
drug, in whole or in part, whether it be an active substance or a
menstruum, excipient, carrier, coating, or other component.
(2) The newness for a drug use of a combination of two or more
substances, none of which is a new drug.
(3) The newness for drug use of the proportion of a substance in a
combination, even though such combination containing such substance in
other proportion is not a new drug.
(4) The newness of use of such drug in diagnosing, curing,
mitigating, treating, or preventing a disease, or to affect a structure
or function of the body, even though such drug is not a new drug when
used in another disease or to affect another structure or function of
the body.
(5) The newness of a dosage, or method or duration of administration
or application, or other condition of use prescribed, recommended, or
suggested in the labeling of such drug, even though such drug when used
in other dosage, or other method or duration of administration or
application, or different condition, is not a new drug.
(i) (Reserved)
(j) The term sponsor means the person or agency who assumes
responsibility for an investigation of a new drug, including
responsibility for compliance with applicable provisions of the act and
regulations. The ''sponsor'' may be an individual, partnership,
corporation, or Government agency and may be a manufacturer, scientific
institution, or an investigator regularly and lawfully engaged in the
investigation of new drugs.
(k) The phrase related drug(s) includes other brands, potencies,
dosage forms, salts, and esters of the same drug moiety, including
articles prepared or manufactured by other manufacturers: and any other
drug containing a component so related by chemical structure or known
pharmacological properties that, in the opinion of experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, it is prudent to assume or ascertain the
liability of similar side effects and contraindications.
(l) Special packaging as defined in section 2(4) of the Poison
Prevention Packaging Act of 1970 means packaging that is designed or
constructed to be significantly difficult for children under 5 years of
age to open or obtain a toxic or harmful amount of the substance
contained therein within a reasonable time and not difficult for normal
adults to use properly, but does not mean packaging which all such
children cannot open or obtain a toxic or harmful amount within a
reasonable time.
(m) (Reserved)
(n) The term radioactive drug means any substance defined as a drug
in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which
exhibits spontaneous disintegration of unstable nuclei with the emission
of nuclear particles or photons and includes any nonradioactive reagent
kit or nuclide generator which is intended to be used in the preparation
of any such substance but does not include drugs such as
carbon-containing compounds or potassium-containing salts which contain
trace quantities of naturally occurring radionuclides. The term
''radioactive drug'' includes a ''radioactive biological product'' as
defined in 600.3(ee) of this chapter.
(39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11,
1974; 40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR
7492, Feb. 22, 1985)
21 CFR 310.4 Biologics; products subject to license control.
(a) Except for radioactive biological products intended for human
use, a new drug shall not be deemed to be subject to section 505 of the
act if it is a drug licensed under the Public Health Service Act of July
1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or under the
animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832 (21
U.S.C. 151 et seq.)).
(b) A radioactive biological product (as defined in 600.3(ee) of
this chapter) intended for human use is subject to section 505 of the
act. Any license for such a radioactive biological product which is
issued under the Public Health Service Act of July 1, 1944 (58 Stat.
682, as amended (42 U.S.C. 201 et seq.)) and which has not been revoked
or suspended as of August 25, 1975 shall constitute an approved new drug
application in effect under the same terms and conditions as set forth
in such license and such portions of the establishment license relating
to such product, which include data and information required under Part
314 of this chapter for a new drug application. Any such radioactive
biological product for which licensure under the Public Health Service
Act is pending on August 25, 1975 shall, upon determination that it is
acceptable for licensure, be approved as a new drug application in lieu
of issuance of a biological product license.
(40 FR 31312, July 25, 1975)
21 CFR 310.6 Applicability of ''new drug'' or safety or effectiveness
findings in drug efficacy study implementation notices and notices of
opportunity for hearing to identical, related, and similar drug
products.
(a) The Food and Drug Administration's conclusions on the
effectiveness of drugs are currently being published in the Federal
Register as Drug Efficacy Study Implementation (DESI) Notices and as
Notices of Opportunity for Hearing. The specific products listed in
these notices include only those that were introduced into the market
through the new drug procedures from 1938-62 and were submitted for
review by the National Academy of Sciences-National Research Council
(NAS-NRC), Drug Efficacy Study Group. Many products which are identical
to, related to, or similar to the products listed in these notices have
been marketed under different names or by different firms during this
same period or since 1962 without going through the new drug procedures
or the Academy review. Even though these products are not listed in the
notices, they are covered by the new drug applications reviewed and thus
are subject to these notices. All persons with an interest in a product
that is identical, related, or similar to a drug listed in a drug
efficacy notice or a notice of opportunity for a hearing will be given
the same opportunity as the applicant to submit data and information, to
request a hearing, and to participate in any hearing. It is not
feasible for the Food and Drug Administration to list all products which
are covered by an NDA and thus subject to each notice. However, it is
essential that the findings and conclusions that a drug product is a
''new drug'' or that there is a lack of evidence to show that a drug
product is safe or effective be applied to all identical, related, and
similar drug products to which they are reasonably applicable. Any
product not in compliance with an applicable drug efficacy notice is in
violation of section 505 (new drugs) and/or section 502 (misbranding) of
the act.
(b)(1) An identical, related, or similar drug includes other brands,
potencies, dosage forms, salts, and esters of the same drug moiety as
well as of any drug moiety related in chemical structure or known
pharmacological properties.
(2) Where experts qualified by scientific training and experience to
evaluate the safety and effectiveness of drugs would conclude that the
findings and conclusions, stated in a drug efficacy notice or notice of
opportunity for hearing, that a drug product is a ''new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective are applicable to an identical, related, or similar drug
product, such product is affected by the notice. A combination drug
product containing a drug that is identical, related, or similar to a
drug named in a notice may also be subject to the findings and
conclusions in a notice that a drug product is a ''new drug'' or that
there is a lack of evidence to show that a drug product is safe or
effective.
(3) Any person may request an opinion on the applicability of such a
notice to a specific product by writing to the Food and Drug
Administration at the address shown in paragraph (e) of this section.
(c) Manufacturers and distributors of drugs should review their
products as drug efficacy notices are published and assure that
identical, related, or similar products comply with all applicable
provisions of the notices.
(d) The published notices and summary lists of the conclusions are of
particular interest to drug purchasing agents. These agents should take
particular care to assure that the same purchasing policy applies to
drug products that are identical, related, or similar to those named in
the drug efficacy notices. The Food and Drug Administration applies the
same regulatory policy to all such products. In many instances a
determination can readily be made as to the applicability of a drug
efficacy notice by an individual who is knowledgeable about drugs and
their indications for use. Where the relationships are more subtle and
not readily recognized, the purchasing agent may request an opinion by
writing to the Food and Drug Administration at the address shown in
paragraph (e) of this section.
(e) Interested parties may submit to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of
Compliance, HFD-300, 5600 Fishers Lane, Rockville, MD 20857, the names
of drug products, and of their manufacturers or distributors, that
should be the subject of the same purchasing and regulatory policies as
those reviewed by the Drug Efficacy Study Group. Appropriate action,
including referral to purchasing officials of various government
agencies, will be taken.
(f) This regulation does not apply to OTC drugs identical, similar,
or related to a drug in the Drug Efficacy Study unless there has been or
is notification in the Federal Register that a drug will not be subject
to an OTC panel review pursuant to 330.10, 330.11, and 330.5 of this
chapter.
(39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983;
50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990)
21 CFR 310.6 Subpart B -- Specific Administrative Rulings and Decisions
21 CFR 310.100 New drug status opinions; statement of policy.
(a) Over the years since 1938 the Food and Drug Administration has
given informal advice to inquirers as to the new drug status of
preparations. These drugs have sometimes been identified only by
general statements of composition. Generally, such informal opinions
were incorporated in letters that did not explicitly relate all of the
necessary conditions and qualifications such as the quantitative formula
for the drug and the conditions under which it was prescribed,
recommended, or suggested. This has contributed to misunderstanding and
misinterpretation of such opinions.
(b) These informal opinions that an article is ''not a new drug'' or
''no longer a new drug'' require reexamination under the Kefauver-Harris
Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval
of a new drug application is withdrawn under provisions of section
505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally
recognized as safe may become a ''new drug'' within the meaning of
section 201(p) of said act as amended by the Kefauver-Harris Act on
October 10, 1962. This is of special importance by reason of proposed
actions to withdraw approval of new drug applications for lack of
substantial evidence of effectiveness as a result of reports of the
National Academy of Sciences -- National Research Council on its review
of drug effectiveness; for example, see the notice published in the
Federal Register of January 23, 1968 (33 FR 818), regarding rutin,
quercetin, et al.
(c) Any marketed drug is a ''new drug'' if any labeling change made
after October 9, 1962, recommends or suggests new conditions of use
under which the drug is not generally recognized as safe and effective
by qualified experts. Undisclosed or unreported side effects as well as
the emergence of new knowledge presenting questions with respect to the
safety or effectiveness of a drug may result in its becoming a ''new
drug'' even though it was previously considered ''not a new drug.'' Any
previously given informal advice that an article is ''not a new drug''
does not apply to such an article if it has been changed in formulation,
manufacture control, or labeling in a way that may significantly affect
the safety of the drug.
(d) For these reasons, all opinions previously given by the Food and
Drug Administration to the effect that an article is ''not a new drug''
or is ''no longer a new drug'' are hereby revoked. This does not mean
that all articles that were the subjects of such prior opinions will be
regarded as new drugs. The prior opinions will be replaced by opinions
of the Food and Drug Administration that are qualified and current on
when an article is ''not a new drug,'' as set forth in this subchapter.
(39 FR 11680, Mar. 29, 1974)
21 CFR 310.101 FD&C Red No. 4; procedure for discontinuing use in new
drugs for ingestion; statement of policy.
(a) Section 81.10(d) of this chapter published December 11, 1964 (29
FR 16983), terminated the provisional listing of FD&C Red No. 4 for use
in drugs that may be ingested and canceled the effectiveness of
certificates for this color additive and mixtures containing it as of
June 9, 1965 ( 81.30(c) of this chapter), insofar as ingested drugs are
concerned. On August 19, 1965 (30 FR 10289), FD&C Red No. 4 was
restored to provisional listing by amendment to 81.1(a) of this
chapter, which restricted the use of color to the terms of 81.25 of
this chapter. The use of FD&C Red No. 4 or mixtures containing it in
the manufacture of ingested drugs (except for limited use as provided in
81.25 of this chapter) will result in adulteration and may constitute
grounds for withdrawing approval of drugs for which a new drug approval
is in effect.
(b) An approved supplemental new drug application will not be
required to provide for discontinuing the use of FD&C Red No. 4 in the
manufacture of articles that are the subject of approved new drug
applications, provided that the applicant submits to the Food and Drug
Administration a written notice of the date on which the change in
formulation will be put into effect.
(c) It will be the policy of the Food and Drug Administration to take
no action against a drug or applicant where a permitted color additive
is substituted for FD&C Red No. 4 in the manufacture of a drug prior to
receipt of a written notice of approval of a supplemental new drug
application, provided that the applicant submits a satisfactory
supplemental application meeting all the following conditions:
(1) The applicant submits a full list of the components and a full
statement of the composition of the drug.
(2) The date when the composition of the drug will be changed is
stated.
(3) The applicant submits data showing that the change in composition
does not interfere with any assay or other control procedures used in
manufacturing the drug, or that the assay and other control procedures
are revised to make them adequate.
(4) The data available to establish the stability of the revised
formulation are included, and if the data are too limited to support a
conclusion that the drug will retain its declared potency for a
reasonable marketing period, a commitment from the applicant:
(i) To test the stability of marketed batches at reasonable
intervals;
(ii) To submit the data as they become available; and
(iii) To recall from the market any batch found to fall below the
approved specifications for the drug.
(d) When a supplemental application proposes the change prescribed in
paragraph (c) of this section and the applicant informs the Food and
Drug Administration that the changes have been put into effect, such
notification will be regarded as an agreement by the applicant to an
extension of the time for formal action on the supplemental application.
(e) Except as provided in paragraph (c) of this section, no provision
of this statement of policy shall limit the authority of the Secretary
of Health and Human Services or of the Commissioner of Food and Drugs to
suspend or withdraw approval of a new-drug application as prescribed by
section 505(e) of the act or to initiate any other regulatory
proceedings with respect to a drug or applicant under the provisions of
the act.
(39 FR 11680, Mar. 29, 1974, as amended at 42 FR 15674, Mar. 22,
1977)
21 CFR 310.103 New drug substances intended for hypersensitivity
testing.
(a) The Food and Drug Administration is aware of the need in the
practice of medicine for the ingredients of a new drug to be available
for tests of hypersensitivity to such ingredients and therefore will not
object to the shipment of a new drug substance, as defined in 310.3(g),
for such purpose if all of the following conditions are met:
(1) The shipment is made as a result of a specific request made to
the manufacturer or distributor by a practitioner licensed by law to
administer such drugs, and the use of such drugs for patch testing is
not promoted by the manufacturer or distributor.
(2) The new drug substance requested is an ingredient in a marketed
new drug and is not one that is an ingredient solely in a new drug that
is legally available only under the investigational drug provisions of
this part.
(3) The label bears the following prominently placed statements in
lieu of adequate directions for use and in addition to complying with
the other labeling provisions of the act:
(i) ''Caution: Federal law prohibits dispensing without a
prescription''; and
(ii) ''For use only in patch testing''.
(4) The quantity shipped is limited to an amount reasonable for the
purpose of patch testing in the normal course of the practice of
medicine and is used solely for such patch testing.
(5) The new drug substance is manufactured by the same procedures and
meets the same specifications as the component used in the finished
dosage form.
(6) The manufacturer or distributor maintains records of all
shipments for this purpose for a period of 2 years after shipment and
will make them available to the Food and Drug Administration on request.
(b) When the requested new drug substance is intended for
investigational use in humans or the substance is legally available only
under the investigational drug provisions of part 312 of this chapter,
the submission of an ''Investigational New Drug Application'' (IND) is
required. The Food and Drug Administration will offer assistance to any
practitioner wishing to submit an Investigational New Drug Application.
(c) This section does not apply to drugs or their components that are
subject to the licensing requirements of the Public Health Service Act
of 1944, as amended. (See Subchapter F -- Biologies, of this chapter.)
(39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29,
1990)
21 CFR 310.103 Subpart C -- New Drugs Exempted From Prescription-Dispensing Requirements
21 CFR 310.200 Prescription-exemption procedure.
(a) Duration of prescription requirement. Any drug limited to
prescription use under section 503(b)(1)(C) of the act remains so
limited until it is exempted as provided in paragraph (b) or (e) of this
section.
(b) Prescription-exemption procedure for drugs limited by a new drug
application. Any drug limited to prescription use under section
503(b)(1)(C) of the act shall be exempted from prescription-dispensing
requirements when the Commissioner finds such requirements are not
necessary for the protection of the public health by reason of the
drug's toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, and he
finds that the drug is safe and effective for use in self-medication as
directed in proposed labeling. A proposal to exempt a drug from the
prescription-dispensing requirements of section 503(b)(1)(C) of the act
may be initiated by the Commissioner or by any interested person. Any
interested person may file a petition seeking such exemption, which
petition may be pursuant to Part 10 of this chapter, or in the form of a
supplement to an approved new drug application.
(c) New drug status of drugs exempted from the prescription
requirement. A drug exempted from the prescription requirement under
the provisions of paragraph (b) of this section is a ''new drug'' within
the meaning of section 201(p) of the act until it has been used to a
material extent and for a material time under such conditions except as
provided in paragraph (e) of this section.
(d) Prescription legend not allowed on exempted drugs. The use of
the prescription caution statement quoted in section 503(b) (4) of the
act, in the labeling of a drug exempted under the provisions of this
section, constitutes misbranding. Any other statement or suggestion in
the labeling of a drug exempted under this section, that such drug is
limited to prescription use, may constitute misbranding.
(e) Prescription-exemption procedure of OTC drug review. A drug
limited to prescription use under section 503(b)(1)(C) of the act may
also be exempted from prescription-dispensing requirements by the
procedure set forth in 330.13 of this chapter.
(39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976;
42 FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977)
21 CFR 310.201 Exemption for certain drugs limited by new-drug
applications to prescription sale.
(a) The prescription-dispensing requirements of section 503(b)(1)(C)
of the Federal Food, Drug, and Cosmetic Act are not necessary for the
protection of the public health with respect to the following drugs
subject to new drug applications:
(1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid)
preparations meeting all the following conditions:
(i) The N-acetyl-p-aminophenol is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The N-acetyl-p-aminophenol and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505 (b) of the act is approved for it.
(iv) The preparation contains not more than 0.325 gram (5 grains) of
N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not
more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of N-acetyl-p-aminophenol recommended or suggested
in the labeling do not exceed: For adults, 0.65 gram (10 grains) per
dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12
years of age, one-half of the maximum adult dose or dosage; for
children 3 to 6 years of age, one-fifth of the maximum adult dose or
dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against administration of the
drug to children under 3 years of age and against use of the drug for
more than 10 days, unless such uses are directed by a physician.
(viii) If the article is offered for use in arthritis or rheumatism,
the labeling prominently bears a statement that the beneficial effects
claimed are limited to the temporary relief of minor aches and pains of
arthritis and rheumatism and, in juxtaposition with directions for use
in such conditions, a conspicuous warning statement, such as ''Caution:
If pain persists for more than 10 days, or redness is present, or in
conditions affecting children under 12 years of age, consult a physician
immediately''.
(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations
meeting all the following conditions:
(i) The sodium gentisate is prepared, with or without other drugs, in
tablet or other dosage form suitable for oral use in self-medication,
and containing no drug limited to prescription sale under the provisions
of section 503(b)(1) of the act.
(ii) The sodium gentisate and all other components of the preparation
meet their professed standards of identity, strength, quality, and
purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.5 gram (7.7 grains) of
anhydrous sodium gentisate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
minor conditions as a simple analgesic.
(vi) The dosages of sodium gentisate recommended or suggested in the
labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of
2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of
age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against administration of the
drug to children under 6 years of age and against use of the drug for a
prolonged period, except as such uses may be directed by a physician.
(3) Isoamylhydrocupreine and zolamine hydrochloride (N,
N-dimethyl-N'-2-thiazolyl-N'-p-methoxybenzyl-ethyl- enediamine
hydrochloride) preparations meeting all the following conditions:
(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared
in dosage form suitable for self-medication as rectal suppositories or
as an ointment and containing no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all
other components of the preparation meet their professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.25 percent of
isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.
(v) If the preparation is in suppository form, it contains not more
than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0
milligrams of zolamine hydrochloride per suppository.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of local pain and itching associated with
hemorrhoids.
(vii) The directions provide for the use of not more than two
suppositories or two applications of ointment in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations, a clear warning statement against use of the
preparation in case of rectal bleeding, as this may indicate serious
disease.
(4) Phenyltoloxamine dihydrogen citrate
(N,N-dimethyl-(a-phenyl-O-toloxy) ethylamine dihydrogen citrate),
preparations meeting all the following conditions:
(i) The phenyltoloxamine dihydrogen citrate is prepared, with or
without other drugs, in tablet or other dosage form suitable for oral
use in self-medication, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The phenyltoloxamine dihydrogen citrate and all other components
of the preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 88 milligrams of
phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of
phenyltoloxamine) per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen
citrate (equivalent to 50 milligrams of phenyltoloxamine) per dose or
264 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150
milligrams of phenyltoloxamine) per 24-hour period; for children 6 to
12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age, except as directed by a physician, and
against driving a car or operating machinery while using the drug, since
it may cause drowsiness.
(b) If the article is offered for temporary relief of the symptoms of
colds, a statement that continued administration for such use should not
exceed 3 days, except as directed by a physician.
(5) through (7) (Reserved)
(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid.
-diethylaminoethyl ester hydrochloride;
diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting
all the following conditions:
(i) The dicyclomine hydrochloride is prepared with suitable antacid
and other components, in tablet or other dosage form for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The dicyclomine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 milligrams of
dicyclomine hydrochloride per dosage unit, or if it is in liquid form
not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use only
by adults and children over 12 years of age, in the temporary relief of
gastric hyperacidity.
(vi) The dosages recommended or suggested in the directions for use
do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30
milligrams in a 24-hour period.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations, clear warning statements against:
(a) Exceeding the recommended dosage.
(b) Prolonged use, except as directed by a physician, since
persistent or recurring symptoms may indicate a serious disease
requiring medical attention.
(c) Administration to children under 12 years of age except as
directed by a physician.
(9) (Reserved)
(10) Sodium fluoride preparations meeting all the following
conditions:
(i) The sodium fluoride is prepared, with other components, in a
dosage form suitable for household use as a dentifrice powder, and
containing no drug limited to prescription sale under the provisions of
section 503(b)(1) of the act.
(ii) The sodium fluoride and all other components of the preparation
meet their professed standards of identity, strength, quality, and
purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 milligrams of sodium
fluoride per gram and is packaged to contain not more than 300
milligrams of sodium fluoride per retail package.
(v) The preparation is labeled with adequate directions for use only
as a dentifrice by adults and children 6 years of age and over, and
includes instructions to rinse the mouth thoroughly after brushing the
teeth.
(vi) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement against use by children under 6 years of
age.
(11) Hexadenol (a mixture of tetracosanes and their oxidation
products) preparations meeting all the following conditions:
(i) The hexadenol is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The hexadenol and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 percent by weight of
hexadenol.
(v) The preparation is labeled with adequate directions for use by
external application in the treatment of minor burns and minor skin
irritations.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Use on serious burns or skin conditions or prolonged use, except
as directed by a physician.
(b) Spraying the preparation in the vicinity of eyes, mouth, nose, or
ears.
(12) Sulfur dioxide preparations meeting all the following
conditions:
(i) The sulfur dioxide is prepared with or without other drugs, in an
aqueous solution packaged in a hermetic container suitable for use in
self-medication by external application to the skin, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The sulfur dioxide and all other components of the preparation
meet their professed standards of identity, strength, quality, and
purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 grams of sulfur dioxide
per 100 milliliters of solution.
(v) The preparation is labeled with adequate directions for use by
external application to the smooth skin in the prevention or treatment
of minor conditions in which it is indicated.
(vi) The directions for use recommend or suggest not more than two
applications a day for not more than 1 week, except as directed by a
physician.
(13) Doxylamine succinate preparations meeting all the following
conditions:
(i) The doxylamine succinate is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The doxylamine succinate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 7.5 milligrams of
doxylamine succinate per dosage unit, or if it is in liquid form not
more than 1.5 milligrams of doxylamine succinate per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of the minor conditions in which it
is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 7.5 milligrams of doxylamine succinate per dose or
45 milligrams of doxylamine succinate per 24-hour period; for children
6 to 12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age, except as directed by a physician, and
against driving a car or operating machinery while using the drug, since
it may cause drowsiness.
(b) If the article is offered for temporary relief of the symptoms of
colds, a statement that continued administration for such use should not
exceed 3 days, except as directed by a physician.
(14) (Reserved)
(15) Sodium monofluorophosphate (Na2PO3F) preparations meeting all
the following conditions:
(i) The sodium monofluorophosphate is prepared with other components
in an aqueous solution suitable for household use as a dentifrice, and
containing no drug limited to prescription sale under the provisions of
section 503(b)(1) of the act.
(ii) The sodium monofluorophosphate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 60 milligrams of sodium
monofluorophosphate per milliliter and is packaged to contain not more
than 3.6 grams of sodium monofluorophosphate per retail package.
(v) The preparation is labeled with adequate directions for use only
as a dentifrice by adults and children 6 years of age and over, and
includes instructions to rinse the mouth thoroughly after brushing the
teeth.
(vi) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement against use by children under 6 years of
age.
(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations
meeting all the following conditions:
(i) The tuaminoheptane sulfate is prepared, with or without other
drugs, in an aqueous vehicle suitable for administration in
self-medication as nose drops, and containing no drug limited to
prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The preparation is packaged with a style of container or
assembly suited to self-medication by the recommended route of
administration, and delivering not more than 0.1 milliliter of the
preparation per drop.
(iii) The tuaminoheptane sulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iv) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(v) The tuaminoheptane sulfate content of the preparation does not
exceed 10 milligrams per milliliter.
(vi) The preparation is labeled with adequate directions for use in
the temporary relief of nasal congestion.
(vii) The dosages recommended or suggested in the directions for use
do not exceed the equivalent: For adults, 5 drops of a 1 percent
solution per nostril per dose, and 5 doses in a 24-hour period; for
children 1 to 6 years of age, 3 drops of a 1 percent solution per
nostril per dose, and 5 doses in a 24-hour period; for infants under 1
year of age, 2 drops of a 1 percent solution per nostril per dose, and 5
doses in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against use of more than 5 doses daily,
and against use longer than 4 days unless directed by a physician.
(b) A clear warning statement to the effect that frequent use may
cause nervousness or sleeplessness, and that individuals with high blood
pressure, heart disease, diabetes, or thyroid disease should not use the
preparation unless directed by a physician.
(17) (Reserved)
(18) Vibesate (a mixture of copolymers of hydroxy-vinyl
chlorideacetate, sebacic acid, and modified maleic rosin ester)
preparations meeting all the following conditions.
(i) The vibesate is prepared and packaged, with or without other
drugs, solvents, and propellants, in a form suitable for self-medication
by external application to the skin as a spray, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The vibesate and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 13 percent by weight of
vibesate.
(v) The preparation is labeled with adequate directions for use by
external application as a dressing for minor burns, minor cuts, or other
minor skin irritations.
(vi) The labeling bears in juxtaposition with the directions for use
clear warning statements against:
(a) Use on serious burns and on infected, deep, and puncture wounds
unless directed by a physician.
(b) Spraying the preparation near the eyes or other mucous membranes.
(c) Inhaling the preparation.
(d) Use near open flames.
(e) Puncturing the container or throwing the container into fire.
(19) Pramoxine hydrochloride (4-N-butoxyphenyl -morpholinopropyl
ether hydrochloride) preparations meeting all the following conditions:
(i) The pramoxine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The pramoxine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of pramoxine
hydrochloride.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the temporary relief of pain or
itching due to minor burns and sunburn, nonpoisonous insect bites, and
minor skin irritations.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Prolonged use.
(b) Application to large areas of the body.
(c) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(d) Use in the eyes or nose.
(20) Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-phenyl-
cyclopentyl-1-carboxylate citrate) preparations meeting all the
following conditions:
(i) The carbetanentane citrate is prepared, with or without other
drugs, in tablet or other dosage form suitable for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The carbetapentane citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, and application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
carbetapentane citrate per dosage unit; or if it is in liquid form, not
more than 1.5 milligrams of carbetapentane citrate per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of cough due to minor conditions in which it is
indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 30 milligrams of carbetapentane citrate per dose or
120 milligrams of carbetapentane citrate per 24-hour period; for
children 4 to 12 years of age, 7.5 milligrams per dose or 30 milligrams
per 24-hour period; for children 2 to 4 years of age, 4.0 milligrams
per dose or 16.0 milligrams per 24-hour period.
(vii) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears, in juxtaposition with the
dosage recommendations:
(a) A clear warning statement against administration of the drug to
children under 2 years of age, unless directed by a physician.
(b) Clear warning statements against use of the drug in the presence
of high fever or if cough persists, since persistent cough as well as
high fever may indicate the presence of a serious condition.
(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate)
preparations meeting all the following conditions:
(i) The pamabrom is prepared with appropriate amounts of a suitable
analgesic and with or without other drugs, in tablet or other dosage
form suitable for oral use in self-medication, and containing no drug
limited to prescription sale under the provisions of section 503(b)(1)
of the act.
(ii) The pamabrom and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 50 milligrams of pamabrom
per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the minor pains and discomforts that may occur a
few days before and during the menstrual period.
(vi) The dosages recommended or suggested in the labeling do not
exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour
period.
(22) Diphemanil methylsulfate
(4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate)
preparations meeting all the following conditions:
(i) The diphemanil methylsulfate is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The diphemanil methylsulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 2.0 percent of diphemanil
methylsulfate.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the relief of symptoms of mild
poison ivy, oak, and sumac and other minor irritations and itching of
the skin.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement, such as: ''Caution: If redness,
irritation, swelling, or pain persists or increases, discontinue use and
consult physician.''
(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone
hydrochloride; 4-n-butoxy- -piperidonopropiophenone hydrochloride)
preparations meeting all the following conditions:
(i) The dyclonine hydrochloride is prepared, with or without other
drugs, in a dosage form suitable for use as a cream or ointment in
self-medication by external application to the skin, or rectally, and
contains no drug limited to prescription sale under the provisions of
section 503(b)(1) of the act.
(ii) The dyclonine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of dyclonine
hydrochloride.
(v) The preparation is labeled with adequate directions for use:
(a) By external application to the skin for the temporary relief of
pain and itching in sunburn, nonpoisonous insect bites, minor burns,
cuts, abrasions, and other minor skin irritations.
(b) (Reserved)
(c) In the prevention or treatment of other minor conditions in which
it is indicated.
(vi) The labeling bears, in juxtaposition with the directions for
use, clear warning statements against:
(a) Continued use if redness, irritation, swelling, or pain persists
or increases, unless directed by a physician.
(b) Use in case of rectal bleeding, as this may indicate serious
disease.
(c) Use in the eyes.
(d) Prolonged use.
(e) Application to large areas of the body.
(f) Use for deep or puncture wounds or serious burns.
(24) Chlorothen citrate (chloromethapyrilene citrate;
N,N-dimethyl-N'-(2-pyridyl)-N '-(5-chloro-2-thenyl) ethylenediamine
citrate) preparations meeting all the following conditions:
(i) The chlorothen citrate is prepared, with or without other drugs,
in tablet or other dosage form suitable for oral use in self-medication,
and containing no drug limited to prescription sale under the provisions
of section 503(b)(1) of the act.
(ii) The chlorothen citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
chlorothen citrate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150
milligrams of chlorothen citrate per 24-hour period; for children 6 to
12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age or exceeding the recommended dosage,
unless directed by a physician, and against driving a car or operating
machinery while using the drug, since it may cause drowsiness.
(b) If the article is offered for the temporary relief of symptoms of
colds, a statement that continued administration for such use should not
exceed 3 days, unless directed by a physician.
(25) Chlorcyclizine hydrochloride (1-(p-chlorobenzhydryl) -4 -
methylpiperazine hydrochloride) preparations meeting all the following
conditions:
(i) The chlorcyclizine hydrochloride is prepared, with or without
other drugs, in tablet or other dosage form suitable for oral use in
self-medication, and containing no drug limited to prescription sale
under the provisions of section 503(b)(1) of the act.
(ii) The chlorcyclizine hydrochloride and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
chlorcyclizine hydrochloride per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 35 milligrams of chlorcyclizine hydrochloride per
dose or 75 milligrams of chlorcyclizine hydrochloride per 24-hour
period; for children 6 to 12 years of age, one-half of the maximum
adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age, or exceeding the recommended dosage
unless directed by a physician, and against driving a car or operating
machinery while taking the drug, since it may cause drowsiness.
(b) If the article is offered for the temporary relief of symptoms of
colds, a statement that continued administration for such use should not
exceed 3 days, unless directed by a physician.
(c) A clear warning statement against administration of the drug to
women who are pregnant or who may become pregnant, unless directed by a
physician, since this drug may have the potentiality of injuring the
unborn child.
(26) Methoxyphenamine hydrochloride (
-(o-methoxyphenyl)-isopropyl-methylamine hydrochloride;
1-(o-methoxyphenyl)-2-methylamino- propane hydrochloride) preparations
meeting all the following conditions:
(i) The methoxyphenamine hydrochloride is prepared with appropriate
amounts of a suitable antitussive, with or without other drugs, in a
dosage form suitable for oral use in self-medication, and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The methoxyphenamine hydrochloride and all other components of
the preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 3.5 milligrams of
methoxyphenamine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of cough due to minor conditions in which it is
indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per
dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour
period; for children 6 to 12 years of age, one-half of the maximum
adult dose or dosage.
(vii) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears, in juxtaposition with the
dosage recommendations:
(a) A clear warning statement against administration of the drug to
children under 6 years of age, unless directed by a physician.
(b) A clear warning statement to the effect that frequent or
prolonged use may cause nervousness, restlessness, or drowsiness, and
that individuals with high blood pressure, heart disease, diabetes, or
thyroid disease should not use the preparation unless directed by a
physician.
(c) A clear warning statement against use of the drug in the presence
of high fever or if cough persists, since persistent cough as well as
high fever may indicate the presence of a serious condition.
(27) Biphenamine hydrochloride (
-diethylaminoethyl-3-phenyl-2-hydroxy-benzoate hydrochloride)
preparations meeting all the following conditions:
(i) The biphenamine hydrochloride is prepared in a form suitable for
use as a shampoo and contains no drug limited to prescription sale under
the provisions of section 503(b)(1) of the act.
(ii) The biphenamine hydrochloride meets its professed standards of
identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1 percent of biphenamine
hydrochloride.
(v) The preparation is labeled with adequate directions for use for
the temporary relief of itching and scaling due to dandruff.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children.
(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium
chloride ophthalmic preparations meeting all the following conditions:
(i) The tyloxapol and benzalkonium chloride are prepared, with other
appropriate ingredients which are not drugs limited to prescription sale
under the provisions of section 503(b)(1) of the act, as a sterile,
isotonic aqueous solution suitable for use in self-medication on eye
prostheses.
(ii) The preparation is so packaged as to volume and type of
container as to afford adequate protection and be suitable for
self-medication with a minimum risk of contamination of the solution
during use. Any dispensing unit is sterile and so packaged as to
maintain sterility until the package is opened.
(iii) The tyloxapol, benzalkonium chloride, and other ingredients
used to prepare the isotonic aqueous solution meet their professed
standards of identity, strength, quality, and purity.
(iv) An application pursuant to section 505(b) of the act is approved
for the drug.
(v) The preparation contains 0.25 percent of tyloxapol and 0.02
percent of benzalkonium chloride.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children and the labeling bears, in juxtaposition with the
dosage recommendations, a clear warning that if irritation occurs,
persists, or increases, use of the drug should be discontinued and a
physician consulted. The labeling includes a statement that the dropper
or other dispensing tip should not touch any surface, since this may
contaminate the solution.
(29) Tolnaftate (O-2-naphthyl m,N-dimethylthiocarbanilate;
C19H17NOS) preparations meeting all the following conditions:
(i) The tolnaftate is prepared, with or without other drugs, in a
cream, solution, or powder dosage form suitable for use in
self-medication by external application to the skin and containing no
drug limited to prescription sale under the provisions of section
503(b)(1) of the act.
(ii) The tolnaftate and all other components of the preparation meet
their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1 percent of tolnaftate.
(v)(a) The preparation, if in cream or solution form, is labeled with
adequate directions for use by external application to the skin for the
relief of the burning and itching of athlete's foot and ringworm of the
body.
(b) The preparation, if in powder dosage form, is labeled with
adequate directions for use by external application to the skin to help
prevent athlete's foot reinfection.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children, and the labeling bears in juxtaposition with the
directions for use:
(a) If in a cream or solution dosage form, clear warnings that:
(1) If burning or itching do not improve within 10 days or if they
become worse, use of the preparation should be discontinued and a
physician consulted.
(2) The preparation is for external use only.
(3) The preparation should be kept out of the eyes.
(4) The preparation is not recommended for nail or scalp infections.
(b) If in a powder dosage form, clear warnings that:
(1) If irritation occurs, use of the preparation should be
discontinued and a physician consulted.
(2) The preparation is for external use only.
(3) The preparation should not be used on scalp or hairy areas.
(4) The preparation should be kept out of the eyes.
(39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19,
1977; 52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR
31779, Aug. 3, 1990)
21 CFR 310.201 Subpart D -- Records and Reports
21 CFR 310.303 Continuation of long-term studies, records, and reports
on certain drugs for which new drug applications have been approved.
(a) A new drug may not be approved for marketing unless it has been
shown to be safe and effective for its intended use(s). After approval,
the applicant is required to establish and maintain records and make
reports related to clinical experience or other data or information
necessary to make or facilitate a determination of whether there are or
may be grounds under section 505(e) of the act for suspending or
withdrawing approval of the application. Some drugs, because of the
nature of the condition for which they are intended, must be used for
long periods of time -- even a lifetime. To acquire necessary data for
determining the safety and effectiveness of long-term use of such drugs,
extensive animal and clinical tests are required as a condition of
approval. Nonetheless, the therapeutic or prophylactic usefulness of
such drugs may make it inadvisable in the public interest to delay the
availability of the drugs for widespread clinical use pending completion
of such long-term studies. In such cases, the Food and Drug
Administration may approve the new drug application on condition that
the necessary long-term studies will be conducted and the results
recorded and reported in an organized fashion. The procedures required
by paragraph (b) of this section will be followed in order to list such
a drug in 310.304.
(b) A proposal to require additional or continued studies with a drug
for which a new drug application has been approved may be made by the
Commissioner on his own initiative or on the petition of any interested
person, pursuant to Part 10 of this chapter. Prior to issuance of such
a proposal, the applicant will be provided an opportunity for a
conference with representatives of the Food and Drug Administration.
When appropriate, investigators or other individuals may be invited to
participate in the conference. All requirements for special studies,
records, and reports will be published in 310.304.
(39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976;
42 FR 15674, Mar. 22, 1977)
21 CFR 310.304 Drugs that are subjects of approved new drug
applications and that require special studies, records, and reports.
Listed below are the new drugs and requirements referred to in
310.303:
(a) (Reserved)
(b) Methadone. Methadone may be used as an analgesic in severe pain,
for the detoxification of narcotic addicts, and as an oral substitute
for heroin or other morphine-like drugs, in the maintenance treatment of
narcotic addicts, pursuant to the conditions established in 291.505.
Further data and information are required to establish the safety and
effectiveness of methadone under a variety of conditions during
widespread and long-term use. In view of the tremendous public health
and social problems associated with the use of heroin, the demonstrated
usefulness of methadone in treatment, the lack of a safe and effective
alternative drug or treatment modality, the need for additional safety
and effectiveness data on methadone for narcotic addict treatment and
the danger to health that could be created by uncontrolled distribution
and use of methadone for narcotic addict treatment, the Commissioner of
Food and Drugs finds that it is not in the public interest either to
withhold the drug from the market until it has been proved safe and
effective under all conditions of use for narcotic addict treatment or
to grant full approval for unrestricted distribution, prescription,
dispensing, or administration of methadone for this use. The
Commissioner therefore concludes that it is essential to the public
interest to prescribe detailed conditions for safe and effective use of
methadone for narcotic addict treatment, utilizing the IND and NDA
control mechanisms and the authority granted under the Comprehensive
Drug Abuse Prevention and Control Act of 1970, to assure that the
required additional information for assessing the safety and
effectiveness of methadone is obtained, to maintain close control over
the safe distribution, administration, and dispensing of the drug, and
to detail responsibilities for such control. The conditions established
in 291.505 constitute a determination of the appropriate methods of
professional practice in the medical treatment of the narcotic addiction
of various classes of narcotic addicts with respect to the use of
methadone, pursuant to section 4 of the Comprehensive Drug Abuse
Prevention and Control Act of 1970.
(39 FR 11680, Mar. 29, 1974, as amended at 41 FR 9546, Mar. 5, 1976;
41 FR 28263, July 9, 1976; 42 FR 46710, Sept. 16, 1977)
21 CFR 310.305 Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new drug
applications.
(a) Scope. FDA is requiring manufacturers, packers, and distributors
of marketed prescription drug products that are not the subject of an
approved new drug or abbreviated new drug application to establish and
maintain records and make reports to FDA of (1) all serious, unexpected
adverse drug experiences associated with the use of their drug products
and (2) any significant increase in the frequency of a serious, expected
adverse drug experience. These reports will enable FDA to protect the
public health by helping to monitor the safety of marketed drug products
and to assure that these drug products are not adulterated or
misbranded.
(b) Definitions. The following definitions of terms apply to this
section:
(1) FDA means the Food and Drug Administration.
(2) Adverse drug experience means any adverse event associated with
the use of a drug in humans, whether or not considered drug related,
including the following: an adverse event occurring in the course of
the use of a drug product in professional practice; an adverse event
occurring from drug overdose, whether accidental or intentional; an
adverse event occurring from drug abuse; an adverse event occurring
from drug withdrawal; and any significant failure of expected
pharmacological action.
(3) Unexpected means an adverse drug experience that is not listed in
the current labeling for the drug product and includes an event that may
be symptomatically and pathophysiologically related to an event listed
in the labeling, but differs from the event because of greater severity
or specificity. For example, under this definition, hepatic necrosis
would be unexpected (by virtue of greater severity) if the labeling only
referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the labeling only listed cerebral vascular
accidents.
(4) Serious means an adverse drug experience that is fatal or
life-threatening, is permanently disabling, requires inpatient
hospitalization, or is a congenital anomaly, cancer, or overdose.
(5) Increased frequency means an increase in the rate of occurrence
of a particular adverse drug experience, e.g., an increased number of
reports of a particular adverse drug experience after appropriate
adjustment for drug exposure.
(c) Reporting requirements -- 15-day ''Alert reports.'' (1)(i) Any
person whose name appears on the label of a marketed prescription drug
product as its manufacturer, packer, or distributor shall report to FDA
each adverse drug experience received or otherwise obtained that is both
serious and unexpected as soon as possible but in any case within 15
working days of initial receipt of the information. Each report shall
be accompanied by a copy of the current labeling for the drug product.
(ii) A person identified in paragraph (c)(1)(i) of this section is
not required to submit a 15-day ''Alert report'' for an adverse drug
experience obtained from a postmarketing study (whether or not conducted
under an investigational new drug application) unless the applicant
concludes that there is a reasonable possibility that the drug caused
the adverse experience.
(2) Each person identified in paragraph (c)(1) of this section shall
submit one copy of each report to the Division of Epidemiology and
Surveillance (HFD-730), Center for Drug Evaluation and Research, Food
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(3) Each person identified in paragraph (c)(1) of this section shall
promptly investigate all serious, unexpected adverse drug experiences
that are the subject of these 15-day Alert reports and shall submit
followup reports within 15 working days of receipt of new information or
as requested by FDA. If additional information is not obtainable, a
followup report may be required that describes briefly the steps taken
to seek additional information and the reasons why it could not be
obtained.
(4) Each person identified in paragraph (c)(1) of this section shall
review periodically (at least once each year) the frequency of reports
of adverse drug experiences that are both serious and expected, received
or otherwise obtained, and report any significant increase in frequency
as soon as possible but in any case within 15 working days of
determining that a significant increase in frequency exists. Reports of
a significant increase in frequency are required to be submitted in
narrative form (including the time period on which the increased
frequency is based, the method of analysis, and the interpretation of
the results), rather than using Form FDA-1639.
(5) In order to avoid unnecessary duplication in the submission of,
and followup to, reports required in this section, including reports
required by paragraph (c)(4) of this section, a packer's or
distributor's obligations may be met by submission of all reports of
serious adverse drug experiences to the manufacturer of the drug
product. If a packer or distributor elects to submit these adverse drug
experience reports to the manufacturer rather than to FDA, it shall
submit each report to the manufacturer within 3 working days of its
receipt by the packer or distributor, and the manufacturer shall then
comply with the requirements of this section even if its name does not
appear on the label of the drug product. Under this circumstance, the
packer or distributor shall maintain a record of this action which shall
include:
(i) A copy of each drug experience report.
(ii) Date the report was received by the packer or distributor.
(iii) Date the report was submitted to the manufacturer.
(iv) Name and address of the manufacturer.
(6) Each report submitted to FDA under this section shall bear
prominent identification as to its contents, i.e., ''15-day Alert
report'' or ''15-day Alert report -- followup.''
(d) Reporting form. (1) Except as provided in paragraph (d)(3) of
this section, each person identified in paragraph (c)(1) of this section
shall submit each report of a serious and unexpected adverse drug
experience on a Form FDA-1639 (Drug Experience Report).
(2) Each completed Form FDA-1639 should pertain only to an individual
patient.
(3) Instead of using Form FDA-1639, a manufacturer, packer, or
distributor may use a computer-generated FDA-1639 or other alternative
format (e.g., a computer-generated tape or tabular listing) provided
that:
(i) The content of the alternative format is equivalent in all
elements of information to those specified in Form FDA-1639, and
(ii) The format is agreed to in advance by the Division of
Epidemiology and Surveillance (HFD-730).
(4) Single copies of Form FDA-1639 may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the
PHS Forms and Publications Distribution Center, 12100 Parklawn Dr.,
Rockville, MD 20857.
(e) Patient privacy. Manufacturers, packers, and distributors should
not include in reports under this section the names and addresses of
individual patients; instead, the manufacturer, packer, and distributor
should assign a unique code number to each report, preferably not more
than eight characters in length. The manufacturer, packer, and
distributor should include the name of the reporter from whom the
information was received. Names of patients, individual reporters,
health care professionals, hospitals, and geographical identifiers in
adverse drug experience reports are not releasable to the public under
FDA's public information regulations in Part 20 of this chapter.
(f) Recordkeeping. (1) Each manufacturer, packer, and distributor
shall maintain for a period of 10 years records of all adverse drug
experiences required under this section to be reported or reviewed
periodically for a significant increase in frequency, including raw data
and any correspondence relating to the adverse drug experiences, and the
records required to be maintained under paragraph (c)(5) of this
section.
(2) Manufacturers and packers may retain the records required in
paragraph (f)(1) of this section as part of its complaint files
maintained under 211.198 of this chapter.
(3) Manufacturers, packers, and distributors shall permit any
authorized FDA employee, at all reasonable times, to have access to and
copy and verify the records established and maintained under this
section.
(g) Disclaimer. A report or information submitted by a manufacturer,
packer, or distributor under this section (and any release by FDA of
that report or information) does not necessarily reflect a conclusion by
the manufacturer, packer, or distributor, or by FDA, that the report or
information constitutes an admission that the drug caused or contributed
to an adverse effect. The manufacturer, packer, or distributor need not
admit, and may deny, that the report or information submitted under this
section constitutes an admission that the drug caused or contributed to
an adverse effect.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0210)
(51 FR 24779, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987;
55 FR 11578, Mar. 29, 1990)
21 CFR 310.305 Subpart E -- Requirements for Specific New Drugs or Devices
21 CFR 310.500 Digoxin products for oral use; conditions for
marketing.
(a) Studies have shown evidence of clinically significant differences
in bio-availability in different batches of certain marketed digoxin
products for oral use from single manufacturers as well as in batches of
these products produced by different manufacturers. These differences
were observed despite the fact that the products met compendial
specifications. Other studies have shown that there is a sufficient
correlation between bioavailability in vivo and the dissolution rate of
digoxin tablets in vitro to make the dissolution test an important
addition to the compendial standards. Because of the potential for
serious risk to cardiac patients using digoxin products which may vary
in bioavailability, the Commissioner of Food and Drugs has determined
that immediate action must be taken to assure the uniformity of all
digoxin products for oral use. The Commissioner is of the opinion that
digoxin products for oral use are new drugs within the meaning of
section 201(p) of the Federal Food, Drug, and Cosmetic Act for which
approved new drug applications are required. The Commissioner has
determined that, because of questions raised regarding the
bioavailability of digoxin products for oral use, there is sufficient
evidence to invoke the authority under section 505(j) of the act to
fully investigate this question and to facilitate a determination of
whether there is a ground for withdrawal of approval of the drug product
under section 505(e) of the act. Marketing of these products may be
continued only under the following conditions:
(1) Digoxin products for oral use, other than tablets: Any person
marketing digoxin products for oral use, other than tablets, shall
submit to the Food and Drug Administration on or before February 21,
1974, an abbreviated new drug application for these products. Any such
drug product then on the market which is not the subject of an
application submitted for the drug product shall be subject to
regulatory procedures under section 505 of the act. In addition to the
information specified in 314.50 of this chapter, the application shall
contain:
(i) A full list of the articles used as components of the digoxin
product, specifications for components, detailed identification and
analytical procedures used to assure that the components meet
established specifications of identity, strength, quality, and purity
and a complete description of the manufacturing process.
(ii) The source of the digoxin used in the formulation including the
name and address of the supplier.
(iii) A statement that stability studies will be conducted to
establish a suitable expiration date for the digoxin product in the form
in which it is distributed.
(iv) A statement that the product label will contain a suitable
expiration date. In the absence of any stability test data, this
expiration date shall be no longer than one year after the batch is
manufactured. If the expiration date is greater than one year,
supporting stability data shall be included in the application.
(v) Labeling that is in compliance with all requirements of the act
and regulations promulgated thereunder, the pertinent parts of which are
as indicated in paragraph (e) of this section.
(vi) A statement that the applicant will initiate recall of all
stocks of the drug product outstanding when so requested by the Food and
Drug Administration.
(vii) A statement that the applicant intends to conduct in vivo
bioavailability tests and that the applicant, under the records and
reports provisions of section 505(k) of the act, will:
(a) Within 30 days after the submission of the application, submit to
the Food and Drug Administration the protocol which the applicant
proposes to follow in conducting these in vivo bioavailability tests.
The protocol shall contain all of the essential elements set forth in
paragraph (d) of this section. The tests shall not be initiated prior
to receiving notification from the Food and Drug Administration that the
bioavailability protocol has been reviewed and either approved or its
deficiencies delineated.
(b) Within 180 days after receiving notification from the Food and
Drug Administration that the bioavailability protocol has been reviewed,
submit to the Food and Drug Administration the results of the in vivo
bioavailability tests.
(2) Digoxin tablets: Any person marketing digoxin tablets, in
addition to complying with all of the requirements of paragraph (a)(1)
of this section, shall include in their abbreviated new drug
application:
(i) A statement that the applicant will establish procedures to test
each lot of digoxin tablets prior to releasing the batch for
distribution to assure that the batch meets all of The United States
Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but
not limited to, potency, content uniformity, and dissolution and either
(a) that the quantity of digoxin dissolved at one hour is not more than
95 percent of the assayed amount of digoxin or (b) that the quantity of
digoxin dissolved at 15 minutes is not more than 90 percent of the
assayed amount of digoxin.
(ii) A statement that finished product specifications shall be
established to include provisions to assure that the range of average
one-hour dissolution values among batches of digoxin tablets does not
exceed 20 percent.
(3) Before releasing for distribution any batch of digoxin tablets
manufactured after January 22, 1974, the manufacturer shall:
(i) Test a sample of the batch to assure that the batch meets all of
the requirements of The United States Pharmacopeia (USP XVIII) including
but not limited to, potency, content uniformity, and dissolution and
either (a) that the quantity of digoxin dissolved at one hour is not
more than 95 percent of the assayed amount of digoxin or (b) that the
quantity of digoxin dissolved at 15 minutes is not more than 90 percent
of the assayed amount of digoxin.
(ii) Submit a sample of the batch to the Food and Drug Administration
according to the procedures set forth in paragraph (g) of this section.
Results of tests conducted on the batch by or for the manufacturer and
the batch production record shall accompany the sample.
(iii) Withhold the batch from distribution until he is notified by
the Food and Drug Administration that the sample was tested and found to
meet all of the requirements in The United States Pharmacopeia (USP
XVIII) for potency, content uniformity, and dissolution and either (a)
that the quantity of digoxin dissolved at one hour is not more than 95
percent of the assayed amount of digoxin or (b) that the quantity of
digoxin dissolved at 15 minutes is not more than 90 percent of the
assayed amount of digoxin.
(iv) Submit a sample of each batch of digoxin tablets as provided for
in paragraph (a)(3)(ii) of this section until he is notified by the Food
and Drug Administration that he is released from the certification
program. This notification will be made on the basis of sample test
results, inspectional findings regarding compliance with current good
manufacturing practice, and compliance with all other requirements of
this section and any other directives issued by the Food and Drug
Administration as a condition for release from the certification
program.
(4) Any manufacturer who has distributed any batch of digoxin tablets
which does not meet the compendial requirement for dissolution, when
tested by the method in The United States Pharmacopeia (USP XVIII),
shall initiate recall of the subject batch when so requested by the Food
and Drug Administration.
(b) Failure of an applicant to submit the protocol and/or the results
of the in vivo bioavailability tests showing adequate evidence of the
product's bioavailability within the times specified in paragraph
(a)(1)(vii) of this section and/or to comply with all of the
certification requirements of paragraph (a)(3) of this section shall be
justification for withdrawal of approval of the application under
section 505(e) of the act.
(c) Any product reformulation or change in manufacturing process will
require the submission of a supplement to the approved abbreviated new
drug application containing adequate data to demonstrate the
bioavailability of the reformulated product. Food and Drug
Administration approval of the supplement is required before the
reformulated product is marketed. The Food and Drug Administration
recommends that, where digoxin tablets are reformulated, manufacturers
reformulate their product to achieve dissolution of 70 to 90 percent at
one hour when tested by all three methods (i.e., the USP method, and the
''paddle-water'' and ''paddle-acid'' methods) described in paragraph (h)
of this section.
(d) The protocol for the in vivo bioavailability tests required in
paragraphs (a) and (c) of this section shall employ a three-way
crossover design using the digoxin test product; a reference digoxin
tablet supplied, on request, by the Food and Drug Administration; and
bulk digoxin USP in an oral solution. Appropriate venous blood and
urinary samples are to be collected and analyzed. The method shall be
capable of detecting the difference between the reference tablet and the
reference oral solution. Bioavailability of the test product shall be
demonstrated if a mean absorption of at least 75 percent of the combined
mean of the two reference standards is observed. Assistance in
developing a protocol for a particular dosage formulation may be
obtained by contacting the Food and Drug Administration, Center for Drug
Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD
20857.
(e) Parts of the digoxin product labeling indicated below shall be as
follows:
Digoxin is one of the cardiac (or digitalis) glycosides, a closely
related group of drugs having in common specific and powerful effects on
the myocardium. These drugs are found in a number of plants. The term
''digitalis'' is used to designate the whole group. Typically, the
glycosides are composed of three portions: a steroid nucleus, a lactone
ring, and a sugar (hence ''glycosides'').
(This section should include a chemical and physical description of
digoxin and the same quantitative ingredient information as that
required on the label.)
The digitalis glycosides have qualitatively the same therapeutic
effects on the heart. They (1) increase the force of myocardial
contraction, (2) increase the refractory period of the atrioventricular
(A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node
and conduction system via the parasympathetic and sympathetic nervous
systems.
Gastrointestinal absorption of digoxin is a passive process. About
50-75 percent of digoxin in tablet form is absorbed. Digoxin is only
20-25 percent bound to plasma proteins and is predominantly excreted by
the kidneys unmetabolized unless there is significant renal failure.
Renal excretion of digoxin is proportional to glomerular filtration rate
and is largely independent of urine flow. Digoxin is not effectively
removed from the body by dialysis, exchange transfusion, or during
cardiopulmonary bypass, presumably because of tissue binding. In
subjects with normal renal function, digoxin is excreted exponentially
with an average half-life of 36 hours, resulting in the loss of 35-40
percent of the body stores daily.
Serum levels and pharmacokinetics are essentially unchanged by
massive weight loss, suggesting that lean body mass should be used in
dosage calculations. The peak blood level from oral dosing with tablets
occurs 1-3 hours after administration. The onset of therapeutic action
of digoxin after oral tablets is 1-2 hours, with the peak therapeutic
effect occurring 6-8 hours after dosing.
1. Congestive heart failure, all degrees, is the primary indication.
The increased cardiac output due to digoxin results in diuresis and
general amelioration of the disturbances characteristic of right (venous
congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart
failure.
Digoxin, generally, is most effective in ''low output'' failure and
less effective in ''high output'' (bronchopulmonary insufficiency,
infection, hyperthyroidism) heart failure.
Digoxin should be continued after heart failure is abolished unless
some known precipitating factor is corrected.
2. Atrial fibrillation, especially when the ventricular rate is
elevated. Digoxin rapidly reduces ventricular rates and eliminates the
pulse deficit. Palpitation, precordial distress or weakness are
relieved and any concomitant congestive failure ameliorated.
Digoxin should be continued in doses necessary to maintain the
desired ventricular rate and other clinical effects.
3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm
may appear. Frequently the flutter is converted to atrial fibrillation
with a slow ventricular rate. Stopping digoxin at this point may be
followed by restoration of sinus rhythm, especially if the flutter was
of the paroxysmal type. It is preferable, however, to continue digoxin
if failure ensues or if atrial flutter is a frequent occurrence.
4. Paroxysmal atrial tachycardia. Oral digoxin may be used,
especially if the condition is resistant to lesser measures. Depending
on the urgency, a more rapid acting parenteral preparation may be
preferable to initiate digitalization, although if heart failure has
ensued or paroxysms recur frequently, digoxin should be maintained by
oral administration.
Digoxin is not indicated in sinus tachycardia unless due to heart
failure.
5. Cardiogenic shock. The drug is often employed, especially when
the condition is accompanied by pulmonary edema. Digoxin seems to
affect adversely shock due to septicemia from gram negative bacteria.
The presence of toxic effects (See ADVERSE REACTIONS section) induced
by any digitalis preparation is a contraindication to all of the
gylcosides.
Allergy, though rare, does occur. It may not extend to all
preparations, and another may be tried.
Ventricular fibrillation.
Digitalis alone or with other drugs has been promoted for use in the
treatment of obesity. This use of digoxin or other digitalis glycosides
is unwarranted. Moreover, since they may cause potentially fatal
arrhythmias or other adverse effects, the use of these drugs in the
treatment of obesity is dangerous.
Many of the arrhythmias for which digoxin is advised closely resemble
those reflecting digoxin intoxication. If the possibility of digoxin
intoxication cannot be excluded, cardiac glycosides should be
temporarily withheld if permitted by the clinical situation.
The patient with congestive heart failure may complain of nausea and
vomiting. These symptoms may also be indications on digoxin
intoxication. A clinical determination of the cause of these symptoms
must be attempted before further drug administration.
Patients with renal insufficiency require smaller than usual doses of
digoxin. See ACTION section for mechanism.
Atrial arrhythmias associated with hypermetabolic states are
particularly resistant to digoxin treatment. Care must be taken to
avoid digoxin toxicity if digoxin is used to help the arrhythmia.
Digoxin is not indicated for the treatment of ventricular tachycardia
unless congestive heart failure supervenes after a protracted episode
not itself due to digoxin.
Potassium depletion sensitizes the myocardium to digoxin, and
toxicity may develop even with the usual dosage. Hypokalemia may also
alter the rate of onset and intensity of the positive inotropic effect
of digoxin. Therefore, it is desirable to maintain normal serum
potassium levels in patients being treated with digoxin.
Potassium wastage may result from diuretic or corticosteriod therapy,
hemodialysis, and from suction of gastrointestinal secretions. It may
accompany malnutrition, diarrhea, prolonged vomiting, old age, and
long-standing congestive heart failure. In general, rapid changes in
serum potassium or other electrolytes are to be avoided, and intravenous
treatment with potassium should be reserved only for special
circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRODUCED
BY OVERDOSAGES section).
Patients with acute myocardial infarction, severe pulmonary disease,
or far advanced heart failure may be more sensitive to digoxin and more
prone to disturbances of rhythm.
Calcium affects contractility and excitability of the heart in a
manner similar to that of digoxin. Calcium may produce serious
arrhythmias in digitalized patients.
In myxedema the digoxin requirements are less because excretion rate
is decreased and blood levels are significantly higher.
In incomplete A-V block, especially in patients subject to
Stokes-Adams attacks, advanced or complete heart block may develop if
digoxin is given. Heart failure in these patients can usually be
controlled by other measures and by increasing the heart rate.
Patients with chronic constructive pericarditis may respond
unfavorably to digoxin.
Patients with idiopathic hypertrophic subaortic stenosis must be
managed extremely carefully. Unless cardiac failure is severe, it is
doubtful whether digoxin should be employed.
Renal insufficiency delays the excretion of digoxin, and dosage must
be adjusted accordingly in patients with renal disease. Note: This
applies also to potassium administration should it become necessary.
Electrical conversion of arrhythmias may require reduction of digoxin
dosage.
Gynecomastia, uncommon.
Overdosage or toxic effects.
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most
common early symptoms of overdosages in the adult (but rarely
conspicuous in infants). Uncontrolled heart failure may also produce
such symptoms.
Central nervous system: Visual disturbances (blurred vision, yellow
vision), headache, weakness, apathy.
Cardiac disturbances (arrhythmias): Ventricular premature beats are
the most common, except in infants and young children. Paroxysmal and
nonparoxysmal nodal rhythms, atrioventricular (interference)
disassociation and paroxysmal atrial tachycardia (PAT) with block are
also common arrhythmias due to digoxin overdosage. Conduction
disturbances: Excessive slowing of the pulse is a clinical sign of
digoxin overdosage. Atrioventricular block of increasing degree may
proceed to complete heart block. Note: The electrocardiogram is
fundamental in determining the presence and nature of these cardiac
toxic disturbances. Digoxin may also induce other changes (as of the ST
segment), but these provide no measure of the degree of digitalization.
Digoxin should be discontinued until all signs of toxicity are
abolished. Discontinuation may be all that is necessary if toxic
manifestations are not severe and appear after the time for peak effect
of the drug.
Potassium salts are commonly used. Potassium chloride in divided
oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION
section for pediatric dosage) may be given provided renal function is
adequate.
When correction of the arrhythmia is urgent and the serum potassium
level is low or normal, potassium should be administered intravenously
in a solution of 5 percent dextrose in water. A total of 40-100
milliequivalents (30 milliequivalents per 500 milliliters) is given at
the rate of 20 milliequivalents per hour unless limited by pain due to
local irritation.
Additional amounts may be given if the arrhythmia is uncontrolled and
the potassium well tolerated.
Continuous electrocardiographic monitoring should be performed to
watch for any evidence of potassium toxicity, e.g., peaking of T waves,
and to observe the effect on the arrhythmia so that the infusion may be
promptly stopped when the desired effect is achieved.
Caution: Potassium should not be used and may be dangerous for
severe or complete heart block due to digoxin and not related to any
tachycardia.
Other agents that have been approved for the treatment of digoxin
intoxication include procainamide, lidocaine, and propranolol.
Oral digoxin is administered slowly or rapidly as required until the
desired therapeutic effect is obtained without symptoms of overdosage.
The amount can be predicted approximately from the lean body mass of the
patient with allowances made for excretion during the time taken to
induce digitalization.
Subsequent maintenance dosage is also determined tentatively by the
amount necessary to sustain the desired therapeutic effect.
Recommended dosages are practical average figures that may require
considerable modification as dictated by individual sensitivity or
associated conditions. Diminished renal function is the most important
factor requiring modification of recommended or average doses. (See
WARNINGS and PRECAUTIONS sections.)
The average amount of digoxin that patients must accumulate to be
digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization
may be accomplished by any of several approaches that vary in dosage and
frequency of administration, but reach the same endpoint in terms of
total amount accumulated.
In previously undigitalized patients, a single loading dose of
0.5-0.75 milligram orally usually produces a detectable effect in 1-2
hours that becomes maximal in 6-8 hours. Additional doses of 0.25-0.5
milligram may be given cautiously at 6-8 hour intervals to full
digitalization.
In previously undigitalized patients, institution of daily
maintenance therapy (0.125-0.5 milligram, see next paragraph) without a
loading dose results in development of a steady-state plateau
concentrations in about 7 days in patients with normal renal function.
The average daily oral maintenance dose is 0.125-0.5 milligram,
usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram
should be considered the average maintenance dose.
In patients with renal impairment, digoxin excretion is impaired and
serum half-life is prolonged (see ACTION section). Digitalizing and
maintenance doses are lower than those recommended for patients with
normal renal functions. Signs of digoxin toxicity develop sooner in
patients with renal impairment, and it takes longer for toxic signs and
symptoms to disappear. Because of the prolonged half-life, a longer
period of time is required to achieve an initial or new steady-state
plateau in patients with renal impairment than in patients with normal
renal function.
It cannot be overemphasized that the values given are averages and
substantial individual variation can be expected.
(If pediatric dosage is available, the labeling sections above should
be expanded to include the following information.)
Newborn infants display considerable variability in their tolerance
to digoxin, depending on their degree of maturity.
Premature and immature infants are particularly sensitive, and dosage
must be reduced and digitalization should be even more individualized
and cautiously approached than in more mature infants. Impaired renal
function must also be carefully taken into consideration.
Congestive heart failure accompanying acute glomerulonephritis
requires extreme care in digitalization. A relatively low total dose
administered in divided doses and concomitant use of antihypertensive
drugs has been recommended. ECG monitoring is essential. Digoxin
should be discontinued as soon as possible.
Patients with idiopathic hypertrophic subaortic stenosis must be
managed extremely carefully. Unless cardiac failure is severe, it is
doubtful whether digoxin should be employed.
Patients with rheumatic carditis, especially when severe, are
unusually sensitive to digoxin and prone to disturbances of rhythm. If
heart failure develops, digitalization may be initiated with relatively
low doses; then it can be cautiously increased until a beneficial
effect is obtained. If a therapeutic trial does not result in
improvement, the drug should be considered ineffective and be
discontinued.
Note: Digitalis glycosides are an important cause of accidental
poisoning in children.
Dosage must be carefully titrated and differences in the
bioavailability of parenteral preparations, elixirs, and tablets should
be taken into account when switching patients from one preparation to
another.
Electrocardiographic monitoring may be necessary to avoid
intoxication.
Premonitory signs of toxicity in the newborn are undue slowing of the
sinus rate, sinoatrial arrest, and prolongation of PR interval.
Toxic signs differ from the adult in a number of respects. Cardiac
arrhythmias are the more reliable and frequent signs of toxicity.
Vomiting and diarrhea, neurologic and visual disturbances are rare as
initial signs.
Premature ventricular systoles are rarely seen; nodal and atrial
systoles are more frequent.
Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial
tachycardia with A-V block particularly are more common manifestations
of toxicity in children. Ventricular arrhythmias are rare.
(See adult section for other recommendations for the treatment of
arrhythmias produced by overdosages and for additional recommendations
and cautions regarding the use of potassium.) Potassium preparations may
be given orally in divided doses totaling 1-1.5
milliequivalents/kilogram (1 gram K contains 13.4 milliequivalents).
When correction of the arrhythmia is urgent, approximately 0.5
milliequivalents/kilogram of potassium per hour may be given, with
careful electrocardiographic monitoring, as a solution of 20
milliequivalents or less per 500 milliliters in 5 percent dextrose in
water. The total dose should generally not exceed 2 milliequivalents of
potassium/kilogram.
Digitalization must be individualized. Generally, premature and
immature infants are particularly sensitive, requiring reduced dosage
that must be determined by careful titration.
Oral Dosage. Beyond the immediate newborn period, children require
proportionally greater doses than adults on the basis of body weight or
surface area. The recommended oral digitalizing dosages in children
with normal renal function are:
Newborn infants (normal), up to 1 month, require 40-60
micrograms/kilogram.
Infants, 1 month to 2 years, require approximately 60-80
micrograms/kilogram.
Children 2 years to 10 years, require 40-60 micrograms/kilogram.
Children, over 10 years of age, require adult dosages in proportion
to their body weight.
Maintenance therapy is 20-30 percent of the digitalizing dose
administered each day.
Long term use of digoxin is indicated in almost all infants who have
been digitalized for acute congestive heart failure unless the cause is
transient. Many favor maintaining digoxin until at least 2 years of age
in all infants with paroxysmal atrial tachycardia or in those who show
either definite or latent failure.
Many children with severe inoperable congenital defects need digoxin
throughout childhood and often for life.
(f) Abbreviated new drug applications shall be submitted to the Food
and Drug Administration, Center for Drug Evaluation and Research, Office
of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.
(g) All samples of digoxin tablets required by paragraph (a)(3) of
this section to be submitted to the Food and Drug Administration shall
be handled as follows:
(1) The sample shall consist of 6 subsamples of 1000 tablets each
collected at random from throughout the manufacturing run. Each of the
6 subsamples shall be identified with the name of the product, the
labeled potency, the date of manufacture, the batch number, and the name
and address of the manufacturer.
(2) The sample together with the batch production record and results
of all tests conducted by or for the manufacturer to determine the
product's identity, strength, quality, and purity, content uniformity
and dissolution shall be submitted to the Department of Health and Human
Services, Public Health Service, FDA National Center for Drug Analysis,
1114 Market St., St. Louis, MO 63101. The outer wrapper shall be
identified ''SAMPLE -- DIGOXIN CERTIFICATION.''
(h) The Food and Drug Administration is aware of data with two in
vitro methods, in addition to that described in The United States
Pharmacopeia (USP XVIII), developed to measure digoxin tablets
dissolution. These two methods, the so-called ''paddle-water'' and
''paddle-acid'' methods, are described below and are identical with the
exception of the nature of the dissolution medium used in the procedures
(i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6
percent volume/volume)). The dissolution apparatus used in these two
methods differs significantly from the apparatus described in the method
in the compendium. The Food and Drug Administration is aware that the
three methods (i.e., USP, ''paddle-water,'' and ''paddle-acid'') show
significant differences in dissolution in comparative tests on some
formulations. Definitive bioavailability data to compare the relative
value of each of these methods to predict bioavailability of the few
formulations where the methods show significant differences in
dissolution rate are not now available. Manufacturers who conduct
research utilizing the ''paddle-water'' and ''paddle-acid'' methods,
particularly in comparison with the method in The United States
Pharmacopeia, shall submit any data obtained using these methods to the
Food and Drug Administration pursuant to section 505(k) of the act.
(1) Dissolution apparatus.
(Note: Throughout this procedure use scrupulously clean glassware,
which previously has been rinsed with dilute hydrochloric acid,
distilled or deionized water, then with alcohol, and carefully dried.
Take precautions to prevent contamination from airborne, fluorescent
particles and from metal and rubber surfaces.) The apparatus consists of
a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No.
26220 or equivalent), a motor, and a polytetrafluoroethylene stirring
blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a
glass stirring shaft (Sargent 5-76636, 14.5 inch length; or
equivalent). The water bath may be of any convenient size that permits
keeping the water temperature uniformly at 37 C. 0.5 C. throughout
the test. The vessel is spherical, and is provided with three ports at
the top, one of which is centered. The lower half of the vessel is 65
millimeters in inside radius and the vessel's nominal capacity is 1000
milliliters. The glass stirring shaft from the motor is placed in the
center port, and one of the outer ports may be used for insertion of a
thermometer. Samples may be removed for analysis through the other
port. The motor is fitted with a speed-regulating device that allows
the motor speed to be held at 50 rpm 2 rpm. The motor is suspended
above the vessel in such a way that it may be raised or lowered to
position the stirring blade. The glass stirring shaft is 10 millimeters
in diameter and about 37 centimeters in length. It must run true on the
motor axis without perceptible wobble. The polytetrafluoroethylene
stirring blade is 4 millimeters thick and forms a section of a circle,
whose diameter is 83 millimeters and which is subtended by parallel
chords of 42 and 77 millimeters. The blade is positioned horizontally,
with the 42-millimeter edge down, 2.5 centimeters 0.2 centimeter above
the lowest inner surface of the vessel.
(2) Reagents -- (i) Dissolution medium. For ''paddle-water,'' use
distilled or deionized water. For ''paddle-acid,'' use dilute
hydrochloric acid (0.6 percent volume/volume). Use the same batch of
dissolution medium throughout the test.
(ii) Standard solutions. Accurately weigh approximately 25
milligrams of The United States Pharmacopeia Digoxin Reference Standard,
dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter
volumetric flask and add 95 percent ethanol to volume and mix. Dilute
10.0 milliliters of this first solution to 100.0 milliliters with 95
percent ethanol and mix for the second solution. Just prior to use,
individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of
the second solution with dissolution medium to 50.0 milliliters. These
solutions are equivalent to 20, 40, 60, 80, and 100 percent of
dissolution, respectively, for a 0.25 milligram digoxin tablet.
(iii) Extraction solvent. Prepare a solvent containing 6 volumes of
chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol,
analytical reagent grade.
(iv) Ascorbic acid-methanol solution. Prepare a solution containing
2 milligrams of ascorbic acid, analytical reagent grade, per 1
milliliter of methanol, absolute, analytical reagent grade.
(v) Hydrochloric acid, concentrated reagent grade.
(vi) Hydrogen peroxide-methanol solution. On the day of use, dilute
2.0 milliliters of recently assayed 30 percent hydrogen peroxide,
reagent grade, with methanol, absolute, analytical reagent grade to
100.0 milliliters. Store in a refrigerator. Just prior to use, dilute
2.0 milliliters of this solution with methanol to 100.0 milliliters.
(3) Procedure -- (i) Dissolution. Place 500 milliliters of
dissolution medium in the vessel, immerse it in the constant-temperature
bath set at 37 C. 0.5 C., and allow the dissolution medium to assume
the temperature of the bath. Position the shaft so that there is a
distance of 2.5 centimeters 0.2 centimeter between the midpoint of the
bottom of the blade and the bottom of the vessel. With the stirrer
operating at a speed of 50 rpm 2 rpm, place 1 tablet into the flask.
After 60 minutes, accurately timed, withdraw 25 milliliters, using a
glass syringe connected to a glass sampling tube, of solution from a
point midway between the stirring shaft and the wall of the vessel, and
approximately midway in depth. Filter the solution promptly after
withdrawal, using a suitable membrane filter of not greater than 0.8
micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a
suitable holder (Millipore Swinnex SX00 025 00, or equivalent),
discarding the first 100 milliliters of filtrate. This is the test
solution. Repeat the dissolution procedure on 5 additional tablets.
(ii) Extraction. Transfer 10.0 milliliters of each of the six
filtrates, 10.0 milliliters of each of the five standard solutions, and
10.0 milliliters of dissolution medium, to provide a blank, in separate
60-milliliter separators. Extract each solution with two 10-milliliter
portions of extraction solvent. Combine the extracts of each solution
in separate, glass-stoppered, 50-milliliter conical flasks, and
evaporate on a steam bath with the aid of a stream of nitrogen to
dryness, rinsing the sides of the flasks with extraction solvent. Take
care to ensure that all traces of solvent are removed, but avoid
prolonged heating. For convenience the residues may be stored in a
vacuum desiccator overnight.
(iii) Measurement of fluorescence. Begin with the standard
solutions, and keep all flasks in the same sequence throughout, so that
the elapsed time from addition of reagents to reading of fluorescence is
the same for each. Carry the test solutions, standard solutions, and
the blank through the determination in one group. Add the following
three reagents in as rapid a sequence as possible, swirling after each
addition, treating 1 flask at a time, in the order named: 1.0
milliliter of ascorbic acid-methanol solution, 3.0 milliliters of
concentrated hydrochloric acid, and 1.0 milliliter of hydrogen
peroxide-methanol solution. Insert the stoppers in the flasks, and
after 2 hours, measure the fluorescence at about 485 millimicrons, using
excitation at about 372 millimicrons. In order to provide a check on
the stability of the fluorometer, reread one or more standard solutions.
Correct each reading for the blank and plot a standard curve of
fluorescence versus precentage dissolution. Determine the percentage
dissolution of digoxin in the test solutions by reading from the
standard graph.
(iv) Digoxin tablets formulated so that the quantity of digoxin
dissolved at one hour, when tested by the method in The United States
Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed
amount of digoxin and so that the quantity of digoxin dissolved at 15
minutes is greater than 90 percent of the assayed amount of digoxin are
new drugs which may be marketed only with an approved full new drug
application as provided for in 314.50 of this chapter. The application
shall include, but not be limited to, clinical studies establishing
significantly greater bioavailability than digoxin tablets meeting
compendial requirements and dosage recommendations based on clinical
studies establishing the safe and effective use of the bioavailable
digoxin product. Marketing of these digoxin products will be allowed
only under a proprietary or trade name, established name, and labeling
which differs from that used for digoxin tablets that meet all of the
requirements in The United States Pharmacopeia (USP XVIII) and that are
formulated so that either (a) the quantity of digoxin dissolved at one
hour is not more than 95 percent of the assayed amount of digoxin or (b)
the quantity of digoxin dissolved at 15 minutes is not more than 90
percent of the assayed amount of digoxin. New drug applications for
these digoxin products shall be submitted to the Food and Drug
Administration, Center for Drug Evaluation and Research, Office of Drug
Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.
(39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30,
1976; 41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR
11578, Mar. 29, 1990)
Effective Date Note: The provisions of 21 CFR 310.500(a)(1) as they
apply to the submission of abbreviated new drug applications are stayed
until 30 days after such time as a decision is reached regarding
revision of the product labeling set forth in 310.500(e). See 39 FR
9184, Mar. 8, 1974. However, the stay is removed insofar as it affects
labeling requirements for digoxin products. See 41 FR 43136, Sept. 30,
1976.
21 CFR 310.501 Patient package inserts for oral contraceptives.
(a) Requirement for a patient package insert. The safe and effective
use of oral contraceptive drug products requires that patients be fully
informed of the benefits and the risks involved in their use. An oral
contraceptive drug product that does not comply with the requirements of
this section is misbranded under section 502 of the Federal Food, Drug,
and Cosmetic Act. Each dispenser of an oral contraceptive drug product
shall provide a patient package insert to each patient (or to an agent
of the patient) to whom the product is dispensed, except that the
dispenser may provide the insert to the parent or legal guardian of a
legally incompetent patient (or to the agent of either). The patient
package insert is required to be placed in or accompany each package
dispensed to the patient.
(b) Distribution requirements. (1) For oral contraceptive drug
products, the manufacturer and distributor shall provide a patient
package insert in or with each package of the drug product that the
manufacturer or distributor intends to be dispensed to a patient.
(2) Patient package inserts for oral contraceptives dispensed in
acute-care hospitals or long-term care facilities will be considered to
have been provided in accordance with this section if provided to the
patient before administration of the first oral contraceptive and every
30 days thereafter, as long as the therapy continues.
(c) Contents of patient package insert. A patient package insert for
an oral contraceptive drug product is required to contain the following:
(1) The name of the drug.
(2) A summary including a statement concerning the effectiveness of
oral contraceptives in preventing pregnancy, the contraindications to
the drug's use, and a statement of the risks and benefits associated
with the drug's use.
(3) A statement comparing the effectiveness of oral contraceptives to
other methods of contraception.
(4) A boxed warning concerning the increased risks associated with
cigarette smoking and oral contraceptive use.
(5) A discussion of the contraindications to use, including
information that the patient should provide to the prescriber before
taking the drug.
(6) A statement of medical conditions that are not contraindications
to use but deserve special consideration in connection with oral
contraceptive use and about which the patient should inform the
prescriber.
(7) A warning regarding the most serious side effects of oral
contraceptives.
(8) A statement of other serious adverse reactions and potential
safety hazards that may result from the use of oral contraceptives.
(9) A statement concerning common, but less serious side effects
which may help the patient evaluate the benefits and risks from the use
of oral contraceptives.
(10) Information on precautions the patients should observe while
taking oral contraceptives, including the following:
(i) A statement of risks to the mother and unborn child from the use
of oral contraceptives before or during early pregnancy;
(ii) A statement concerning excretion of the drug in human milk and
associated risks to the nursing infant;
(iii) A statement about laboratory tests which may be affected by
oral contraceptives; and
(iv) A statement that identifies activities and drugs, foods, or
other substances the patient should avoid because of their interactions
with oral contraceptives.
(11) Information about how to take oral contraceptives properly,
including information about what to do if the patient forgets to take
the product, information about becoming pregnant after discontinuing use
of the drug, a statement that the drug product has been prescribed for
the use of the patient and should not be used for other conditions or
given to others, and a statement that the patient's pharmacist or
practitioner has a more technical leaflet about the drug product that
the patient may ask to review.
(12) A statement of the possible benefits associated with oral
contraceptive use.
(13) The following information about the drug product and the patient
package insert:
(i) The name and place of business of the manufacturer, packer, or
distributor, or the name and place of business of the dispenser of the
product.
(ii) The date, identified as such, of the most recent revision of the
patient package insert placed prominently immediately after the last
section of the labeling.
(d) Other indications. The patient package insert may identify
indications in addition to contraception that are identified in the
professional labeling for the drug product.
(e) Labeling guidance texts. The Food and Drug Administration issues
informal labeling guidance texts under 10.90(b)(9) of this chapter to
provide assistance in meeting the requirements of this section. A
request for a copy of the guidance texts should be directed to the
Center for Drug Evaluation and Research, Division of Metabolism and
Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857.
(f) Requirement to supplement approved application. Holders of
approved applications for oral contraceptive drug products that are
subject to the requirements of this section are required to submit
supplements under 314.70(c) of this chapter to provide for the labeling
required by this section. Such labeling may be put into use without
advance approval by the Food and Drug Administration.
(54 FR 22587, May 25, 1989)
21 CFR 310.502 Intrauterine devices for human use for the purpose of
contraception.
(a) New drug status of certain intrauterine devices for human use for
the purpose of contraception. (1) The Food and Drug Administration has
become aware of the increased clinical use for the purpose of
contraception of intrauterine devices (IUD's) that incorporate heavy
metals, drugs, or other active substances. The amount of local
irritation caused by such active materials has been reported as being
correlated, in animal studies, to the efficacy of such devices in
achieving their contraceptive effect. Several investigators have
reported different pregnancy rates which appear to be dependent on the
type of metal used and/or the amount of exposed surface of the metal.
Drugs have been incorporated with otherwise inert intrauterine devices
to increase the contraceptive effect, decrease adverse reactions, or
provide increased medical acceptability.
(2) Intrauterine devices used for the purpose of contraception and
incorporating heavy metals, drugs, or other active substances to
increase the contraceptive effect, to decrease adverse reactions, or to
provide increased medical acceptability, are not generally recognized as
safe and effective for contraception and are new drugs within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act.
A completed and signed ''Investigational New Drug Application'' set
forth in part 312 of this chapter) must therefore be submitted to cover
clinical investigations to obtain evidence that such preparations are
safe and effective for this use. An approved new drug application is
required for the marketing of such articles.
(b) Labeling of intrauterine contraceptive devices considered new
drugs (drug IUD's). The intrauterine contraceptive device is a popular
method of contraception used by several million women in the United
States. Although this method of contraception is generally safe and
effective, certain complications and side effects may result from its
use. A Food and Drug Administration review of the labeling of
intrauterine contraceptive devices currently marketed in the United
States reveals that information necessary for the safe and effective use
of these products is not uniformly available to either the practitioner
or the patient. Based on the review of the labeling and on the
recommendations of the Ad Hoc Obstetric-Gynecology Advisory Committee,
the Commissioner has concluded that in the interest of safe and
effective use, and prevention of misleading labeling, there is a need to
establish uniform physician and patient labeling for such drugs.
(1) Labeling accompanying each drug IUD and directed to the physician
shall be substantially as follows, adjusted where appropriate to the
requirements of a particular drug IUD.
Description shall include the following information:
1. Proprietary or established name of the IUD.
2. Major ingredients or composition.
3. Model.
4. Physical dimensions (size and shape).
5. Description of components in package or system.
6. A statement that the product is sterile.
7. Other characteristics.
The manufacturer shall include information on the mode of action or
principles of the IUD's design. At a minimum, the statement should
provide that IUD's seem to interfere in some manner with nidation in the
endometrium, probably through foreign body reaction in the uterus.
The labeling may include indications and usages other than those
stated below, provided that an approved new drug application is in
effect.
(Name of drug IUD) is indicated for contraception.
IUD's should not be inserted when the following conditions exist:
1. Pregnancy or suspicion of pregnancy.
2. Abnormalities of the uterus resulting in distortion of the uterine
cavity.
3. Acute pelvic inflammatory disease or a history of repeated pelvic
inflammatory disease.
4. Post partum endometritis or infected abortion in the past 3
months.
5. Known or suspected uterine or cervical malignancy including
unresolved, abnormal ''Pap'' smear.
6. Genital bleeding of unknown etiology.
7. Untreated acute cervicitis until infection is controlled.
8. Copper-containing IUD's should not be inserted in presence of
diagnosed Wilson's Disease.
9. Known allergy to copper. (For copper-containing IUD's.)
1. Pregnancy -- a. Long-term effects. -- Long-term effects on the
offspring when pregnancy occurs with (name of drug IUD) in place are
unknown.
b. Septic abortion. Reports have indicated an increased incidence of
septic abortion associated in some instances with septicemia, septic
shock, and death in patients becoming pregnant with an IUD in place.
Most of these reports have been associated with the mid-trimester of
pregnacy. In some cases, the initial symptoms have been insidious and
not easily recognized. If pregnancy should occur with an IUD in place,
the IUD should be removed if the string is visible or, if removal proves
to be or would be difficult, termination of the pregnancy should be
considered and offered the patient as an option bearing in mind that the
risks associated with an elective abortion increase with gestational
age.
c. Continuation of pregnancy. If the patient chooses to continue the
pregnancy, she must be warned of the increased risk of spontaneous
abortion and of the increased risk of sepsis, including death if the
pregnancy continues with the IUD in place. The patient must be closely
observed and she must be advised to report all abnormal symptoms, such
as flu-like syndrome, fever, abdominal cramping and pain, bleeding, or
vaginal discharge immediately because generalized symptoms of septicemia
may be insidious.
2. Ectopic pregnancy. a. A pregnancy that occurs with an IUD in
place is more likely to be ectopic than a pregnancy occurring without an
IUD in place. Accordingly, patients who become pregnant while using the
IUD should be carefully evaluated for the possibility of an ectopic
pregnancy.
b. Special attention should be directed to patients with delayed
menses, slight metrorrhagia and/or unilateral pelvic pain and to those
patients who wish to terminate a pregnancy because of IUD failure to
determine whether ectopic pregnancy has occurred.
3. Pelvic infection. Pelvic infection may occur with the IUD in
place and at times result in the development of tubo-ovarian abscesses
or general peritonitis. Appropriate aerobic and anaerobic
bacteriologocal studies should be done and antibiotic therapy initiated.
If the infection does not show a marked clinical improvement within 24
to 48 hours, the IUD should be removed and the continuing treatment
reassessed based upon the results of culture and sensitivity tests.
4. Embedment. Partial penetration or lodging of the IUD in the
edometrium can result in difficult removals.
5. Perforation. Partial or total perforation of the uterine wall or
cervix may occur with the use of IUD's. The possibility of perforation
must be kept in mind during insertion and at the time of any subsequent
examination. If perforation occurs, the IUD should be removed.
Adhesions, foreign body reactions, and intestinal obstruction may result
if an IUD is left in the peritioneal cavity.
6. Congenital anomalies. Systemically administered sex steroids,
including progestational agents, have been associated with an increased
risk of congenital anomalies. It is not known whether such anomalies
could occur when pregnancy is continued with a progesterone-containing
IUD in place.
1. Patient counseling. Prior to insertion the physician, nurse, or
other trained health professional must provide the patient with the
Patient Brochure. The patient should be given the opportunity to read
the brochure and discuss fully any questions she may have concerning the
IUD as well as other methods of contraception.
2. Patient evaluation and clinical considerations. a. A complete
medical history should be obtained to determine conditions that might
influence the selection of an IUD. Physical examination should include
a pelvic examination, ''Pap'' smear, gonorrhea culture and, if
indicated, appropriate tests for other forms of venereal disease.
b. The uterus should be carefully sounded prior to insertion to
determine the degree of patency of the endocervical canal and the
internal os, and the direction and depth of the uterine cavity. In
occasional cases, severe cervical stenosis may be encountered. Do not
use excessive force to overcome this resistance.
c. The uterus should sound to a depth of 6 to 8 centimeters (cm).
Insertion of an IUD into a uterine cavity measuring less than 6.5 cm by
sounding may increase the incidence of expulsion, bleeding, and pain.
d. The possibility of insertion in the presence of an existing
undetermined pregnancy is reduced if insertion is performed during or
shortly following a menstrual period. The IUD should not be inserted
post partum or postabortion until involution of the uterus is completed.
The incidence of perforation and expulsion is greater if involution is
not completed.
e. IUD's should be used with caution in those patients who have an
anemia or a history of menorrhagia or hypermenorrhea. Patients
experiencing menorrhagia and/or metrorrhagia following IUD insertion may
be at risk for the development of hypochromic microcytic anemia. Also,
IUD's should be used with caution in patients receiving anticoagulants
or having a coagulopathy.
f. Syncope, bradycardia or other neurovascular episodes may occur
during insertion or removal of IUD's especially in patients with a
previous disposition to these conditions.
g. Patients with valvular or congenital heart disease are more prone
to develop subacute bacterial endocarditis than patients who do not have
valvular or congenital heart disease. Use of an IUD in these patients
may represent a potential source of septic emboli.
h. Use of an IUD in those patients with acute cervicitis should be
postponed until proper treatment has cleared up the infection.
i. Since an IUD may be expelled or displaced, patients should be
reexamined and evaluated shortly after the first postinsertion menses,
but definitely within 3 months after insertion. Thereafter annual
examination with appropriate medical and laboratory examination should
be carried out. The IUD should be replaced every ---- years
(information to be supplied by manufacturer).
j. The patient should be told that some bleeding and cramps may occur
during the first few weeks after insertion, but if her symptoms continue
or are severe she should report them to her physician. She should be
instructed on how to check after each menstrual period to make certain
that the thread still protrudes from the cervix, and she should be
cautioned that there is no contraceptive protection if the IUD is
expelled. She should be cautioned not to pull on the thread and
displace the IUD. If partial expulsion occurs, removal is indicated and
a new IUD may be inserted. The patient should be told to return in ----
years for replacement of the IUD.
k. The use of medical diathermy (shortwave and microwave) in patients
with metal-containing IUD's may cause heat injury to the surrounding
tissue. Therefore, medical diathermy to the abdominal and sacral areas
should not be used.
l. Copper-containing IUD's -- A copper induced urticarial allergic
skin reaction may develop in women wearing a copper-containing IUD. If
symptoms of such an allergic response occur, the patient should be
instructed to tell the consulting physician that a copper-bearing device
is being worn.
These adverse reactions are not listed in any order of frequency or
severity.
Reported adverse reactions include: endometritis, spontaneous
abortion, septic abortion, septicemia, perforation of the uterus and
cervix, embedment, fragmentation of the IUD, pelvic infection,
vaginitis, leukorrhea, cervical erosion, pregnancy, ectopic pregnancy,
difficult removal, complete or partial expulsion of the IUD,
intermenstrual spotting, prolongation of menstrual flow, anemia, pain
and cramping, dysmenorrhea backaches, dyspareunia, neurovascular
episodes including bradycardia, and syncope secondary to insertion.
Perforation into the abdomen has been followed by abdominal adhesions,
intestinal penetration, intestinal obstruction, and cystic masses in the
pelvis
For copper-containing IUD's the following adverse reaction should
also be added: urticarial allergic skin reaction.
Directions for use shall include the following:
1. Insertion technique.
2. Requirements for replacement and removal (including information on
whether the IUD should be replaced periodically and, if so, how often).
Different event rates have been recorded with the use of different
IUD's. Inasmuch as these rates are usually derived from separate
studies conducted by different investigators in several population
groups, they cannot be compared with precision. Furthermore, event
rates tend to be lower as clinical experience is expanded, possibly due
to retention in the clinical study of those patients who accept the
treatment regimen and do not discontinue due to adverse reactions or
pregnancy. In clincial trials conducted by (name of sponsor) with the
(name of drug IUD), use effectiveness was determined as follows for
parous and nulliparous women, as tabulated by the life table method.
(Rates are expressed as events per 100 women through 12 and 24 months of
use.) This experience is based on (number) women/months of use,
including (number) women who completed 12 months of use and (number)
women who completed 24 months of use.
(2) Labeling, in sufficient quantities to be available to patients
who express interest in IUD's, shall accompany each drug IUD (packaged
separately from the sterile packaging), be made available to the
patient, and contain the following information:
This brochure provides information on the use of intrauterine
contraceptive devices (IUD's). There are other birth control methods
that may be suitable. Before deciding which type of birth control
method to use, you should read this brochure and have the opportunity to
discuss fully with your doctor any questions you may have about the IUD
and other methods of contraception.
IUD's are small articles of various sizes and shapes which are
inserted into the uterus (womb). The purpose of the IUD is to prevent
pregnancy.
How the IUD prevents pregnancy is not completely understood. Several
theories have been suggested. IUD's seem to interfere in some manner
with the implantation of the fertilized egg in the lining of the uterine
cavity. The IUD does not prevent ovulation.
The effectiveness of the IUD is measured by the pregnancy rate of
women who use it and the rate of adverse reactions and side effects
requiring removal of the IUD.
Different pregnancy and adverse reaction rates have been reported
with the use of different IUD's. Because these rates are usually
derived from separate studies conducted by different investigators in
several population groups, they cannot be compared with precision.
In clinical trials with (name of drug IUD), ------ patients completed
------ cycles or months in use. The incdience of unplanned pregnancies
was ------ per 100 woman years or ------ women out of 100 became
pregnant in a year while using an IUD. The incidence of adverse
reactions requiring medical removal of the IUD is ------ per 100 woman
years or ------ women out of 100 discontinued using the IUD for medical
reasons.
Before you have an IUD inserted, you should tell your doctor if you
have ever had, or suspect you have ever had, any of the following
conditions which might make the IUD unsuitable as a method of
contraception for you:
Abnormalities of the uterus (womb).
Allergy to copper.
Anemia.
Bleeding between periods.
Cancer of the uterus (womb) or cervix.
Fainting attacks.
Heart disease.
Heart murmur.
Heavy menstrual flow.
Infection of the uterus (womb) or cervix.
Pelvic infection (plus in fallopian tubes).
Prior IUD use.
Prior uterine surgery.
Recent abortion or miscarriage.
Recent pregnancy.
Severe mentstrual cramps.
Suspected or possible pregnancy.
Suspicious or abnormal ''Pap'' smear.
Unexplained genital bleeding.
Vaginal discharge or infection.
Venereal disease.
Wilson's disease.
The following adverse reactions and side effects have been reported
and may occur after the IUD is inserted:
Anemia.
Backache.
Blood poisoning (septicemia).
Bowel obstruction.
Cervical infection.
Complete or partial expulsion.
Cysts on ovaries and tubes.
Delayed menstruation.
Difficult removal.
Embedment.
Fainting at the time of insertion or removal.
Fragmentation of the IUD.
Intermenstrual spotting.
Internal abdominal adhesions.
Pain and cramps.
Painful intercourse.
Pelvic infection.
Perforation of the uterus (womb) or cervix.
Pregnancy outside the uterus (womb) (tubal or ovarian).
Prolonged or heavy menstrual flow.
Septic abortion (infected miscarriage) followed in some cases by
blood poisoning (septicemia) which can lead to death.
Spontaneous abortion (miscarriage).
Vaginal discharge and infection.
If you decide on the IUD as your method of birth control, read the
following information and instructions carefully. Please keep this
brochure so that you may refer to it. If you have any questions,
consult your doctor.
Description shall include the following information:
1. Proprietary or established name of the drug IUD.
2. Model.
3. Physical dimensions (size and shape).
4. Composition (metal or plastic).
5. Color and number of the tail or threads.
6. Other characteristics.
1. Checking your IUD. A tail or thread is attached to the IUD so you
can check to see if it is still in place since the IUD can come out of
the uterus (womb) without your knowing it. This occurs most often
during or right after a menstrual period.
Follow these steps to make sure your IUD is in place:
a. Wash your hands.
b. Assume the squatting postion or seat yourself on the toilet.
c. Insert the index or middle finger high in vagina and locate the
cervix (mouth of the uterus (womb)). The cervix feels firm like the tip
of your nose.
d. Feel for the tail or thread of the IUD, which should be in the
cervix high in your vagina.
e. If your can feel the tail or thread it is likely that the IUD is
in place and working. You should not pull on the tail or thread. This
may displace the IUD.
f. After each menstrual period, you should check to make sure the
tail or thread is in place in the cervix. You may check for the tail or
thread more often if you wish.
g. If you think the IUD has come out or has been displaced (e.g., you
cannot feel the tail or thread or you can feel the IUD itself), use
another birth control method, such as contraceptive vaginal foam, cream,
or jelly, or condoms (rubbers), until you can be checked. (These
alternative methods are not as effective as the IUD.) Call your doctor
for an examination.
h. You should return to see your doctor as soon as possible after
your next menstrual period, after insertion of your IUD, but no later
than 3 months after insertion. This will allow the doctor to make sure
that the IUD is in the correct position.
i. After your first checkup, you should be checked at least once a
year by your doctor.
2. Continuation and removal. While you are wearing the IUD, you may
use tampons and take douches, if this is your usual practice. With some
IUD's, you may wear the IUD until you wish to become pregnant. With
other IUD's it is necessary that they be replaced every year or so in
order for you to continue being protected against pregnancy. Check with
your doctor concerning this. You should return to your doctor if you
wish to have the IUD removed.
The following may occur during or after the IUD is inserted:
1. Some bleeding occurs following insertion in most women. Because
of this, your doctor may choose to insert your IUD during or at the end
of your menstrual period. This also reduces the possibility that you
are pregnant at the time of IUD insertion.
2. Bleeding between menstrual periods, usually in the form of
spotting, may occur during the first 2 or 3 months after insertion. The
first few menstrual periods after the insertion may be heavier and
longer. If these conditions continue for longer than 2 or 3 months,
consult your doctor.
3. Pain, usually in the form of uterine cramps or low backache, may
occur at the time of insertion and last for a few days. Simple pain
medication usually relieves the cramping.
4. Fainting may occur at the time of insertion or removal of an IUD.
This passes quickly and is not usually serious.
5. The IUD may be expelled during the first two or three menstrual
cycles following insertion. Expulsion increases the risk of an
unplanned pregnancy. Although not as effective as the IUD, the use of a
second contraceptive method, such as a contraceptive vaginal foam,
cream, or jelly, or condoms (rubbers) is recommended.
1. Call your doctor for any of the following reasons:
a. Severe or prolonged bleeding. If the flow is heavier and lasts
much longer than your usual menstrual flow, you may need to have the IUD
removed to prevent the development of anemia.
b. Pelvic pain and cramps. This could mean an infection has
developed requiring treatment.
c. Exposure to venereal disease (VD). If exposure to venereal
disease is suspected, report for examination and treatment promptly.
Failure to do so could result in serious pelvic infection because use of
an IUD in itself does not prevent venereal disease.
d. Tail or thread disappearance. If you cannot feel the tail or
thread coming through the cervix, it is possible that the IUD has been
expelled or displaced or that perforation has occurred. If any of these
has occurred, you are no longer protected from becoming pregnant. Use
another birth control method, such as contraceptive vaginal foam, cream,
or jelly, or condoms (rubbers), until you can be checked. (These
alternative methods e not as effective as the IUD.)
2. Do not undergo medical diathermy (including shortwave or
microwave) treatments to the abdomen or lower back areas if you are
wearing a metal IUD. These treatments may cause heat injury to the
surrounding tissues.
Some women become pregnant while using an IUD. If you miss your
menstrual period, or if you have a scanty flow during your period, or if
you supect that you might be pregnant, see your doctor right away.
Serious complication of sepsis (severe infection), septic abortion
(infected miscarriage), and death have occurred when a pregnancy
continues with an IUD in place. Most of the occurrences of these
serious complications have been reported in the middle third of
pregnancy.
If your doctor confirms that you are pregnant, he should remove the
IUD if the tail is visible. Removal of an IUD in pregnancy decreases
the likelihood of serious complications.
If removal of your IUD proves to be difficult, you and your doctor
should discuss at that time the question of continuing the pregnancy in
view of the serious complications that may occur. In reaching a
decision as to whether or not to have an abortion, it should be
remembered that the risks associated with terminating a pregnancy
increase with the length of time you are pregnant.
(3) Any drug IUD that is not labeled as required by this section and
that is either introduced or delivered for introduction into interstate
commerce, or held for sale after shipment in interstate commerce after
November 7, 1977, is misbranded pursuant to section 502 of the act.
However, a drug IUD in the possession of an independent wholesaler, a
retailer, or a licensed practitioner before November 7, 1977, is not
misbranded if labeling required by paragraph (b)(2) of this section is
furnished to such independent wholesalers, retailers, or licensed
practitioners in sufficient quantities to accompany each device in their
possession.
(4) The holder of an approved new drug application for such device,
as described in paragraph (a)(2) of this section, shall submit a
supplement to his application to provide for the labeling described in
paragraphs (b) (1) and (2) of this section. The supplement shall be
submitted before November 7, 1977, under the provisions of 314.70 of
this chapter. The labeling may be put into use without advance approval
by the Food and Drug Administration.
(c) Applicability. Paragraphs (a) and (b) of this section do not
apply to the following intrauterine contraceptive devices, which are
subject to the requirements of 801.427 of this chapter:
(1) Intrauterine devices fabricated solely from inactive materials,
e.g., inactive plastics or metals.
(2) Intrauterine devices with substances added to improve the
physical characteristics if such substances do not contribute to
contraception through chemical action on or within the body and are not
dependent upon being metabolized for the achievement of the
contraceptive purpose.
(3) Intrauterine devices that contain a component, such as barium,
added exclusively for the purpose of visualization by x-ray.
(42 FR 23777, May 10, 1977; 42 FR 25854, May 20, 1977; 42 FR 35155,
July 8, 1977; 55 FR 11578, Mar. 29. 1990)
21 CFR 310.503 Requirements regarding certain radioactive drugs.
(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and
Drugs exempted investigational radioactive new drugs from part 312 of
this chapter provided they were shipped in complete conformity with the
regulations issued by the Nuclear Regulatory Commission. This exemption
also applied to investigational radioactive biologics.
(b) It is the opinion of the Nuclear Regulatory Commission, and the
Food and Drug Administration that this exemption should not apply for
certain specific drugs and that these drugs should be appropriately
labeled for uses for which safety and effectiveness can be demonstrated
by new-drug applications or through licensing by the Public Health
Service in the case of biologics. Continued distribution under the
investigational exemption when the drugs are intended for established
uses will not be permitted.
(c) Based on its experience in regulating investigational radioactive
pharmaceuticals, the Nuclear Regulatory Commission has compiled a list
of reactor-produced isotopes for which it considers that applicants may
reasonably be expected to submit adequate evidence of safety and
effectiveness for use as recommended in appropriate labeling. Such use
may include, among others, the uses in this tabulation:
(d)(1) In view of the extent of experience with the isotopes listed
in paragraph (c) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that such isotopes should not
be distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(2) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ''chemical form'' and intended for
the uses stated, is terminated on March 3, 1972, except as provided in
paragraph (d)(3) of this section.
(3) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ''chemical form'' and intended for
the uses stated, for which drug a new drug application or a
''Investigational New Drug Application'' was submitted prior to March 3,
1972, or for which biologic an application for product license or
''Investigational New Drug Application'' was submitted prior to March 3,
1972, is terminated on August 20, 1976, unless an approvable notice was
issued on or before August 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on November 20, 1976, whichever occurs
first.
(e) No exemption from section 505 of the act or from part 312 of this
chapter is in effect or has been in effect for radioactive drugs
prepared from accelerator-produced radioisotopes, naturally occurring
isotopes, or nonradioactive substances used in conjunction with
isotopes.
(f)(1) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling;
such use may include, among others, the uses in this tabulation:
(2) In view of the extent of experience with the isotopes listed in
paragraph (f)(1) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that they should not be
distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(3) Any manufacturer or distributor interested in continuing to ship
in interstate commerce drugs containing the isotopes listed in paragraph
(f)(1) of this section for any of the indications listed, shall submit,
on or before August 25, 1975 to the Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, a new drug application or a ''Investigational New Drug
Application'' for each such drug for which the manufacturer or
distributor does not have an approved new drug application pursuant to
section 505(b) of the act. If the drug is a biologic, a
''Investigational New Drug Application'' or an application for a license
under section 351 of the Public Health Service Act shall be submitted to
the Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20014, in lieu of any
submission to the Center for Drug Evaluation and Research.
(4) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (f)(1) of this section, in the ''chemical form'' and intended
for the uses stated, is terminated on August 26, 1975 except as provided
in paragraph (f)(5) of this section.
(5)(i) Except as provided in paragraph (f)(5)(ii) of this section,
the exemption referred to in paragraph (a) of this section, as applied
to any drug containing any of the isotopes listed in paragraph (f)(1) of
this section, in the ''chemical form'' and intended for the uses stated,
for which drug a new drug application or ''Investigational New Drug
Application'' was submitted to the Center for Drug Evaluation and
Research on or before August 25, 1975 is terminated on August 20, 1976,
unless an approvable notice was issued on or before August 20, 1976, in
which case the exemption is terminated either upon the subsequent
issuance of a nonapprovable notice for the new drug application or on
November 20, 1976, whichever occurs first.
(ii) The exemption referred to in paragraph (a) of this section, as
applied to any biologic containing any of the isotopes listed in
paragraph (f)(1) of this section in the ''chemical form'' and intended
for the uses stated, for which biologic an application for product
license or ''Investigational New Drug Application'' was submitted to the
Center for Biologics Evaluation and Research on or before August 25,
1975 is terminated on October 20, 1976, unless an approvable notice was
issued on or before October 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on January 20, 1977, whichever occurs
first.
(g) The exemption referred to in paragraph (a) of this section, as
applied to any drug intended solely for investigational use as part of a
research project, which use had been approved on or before July 25, 1975
in accordance with 10 CFR 35.11 (or equivalent regulation of an
Agreement State) is terminated on February 20, 1976 if the manufacturer
of such drug or the sponsor of the investigation of such drug submits on
or before August 25, 1975 to the Food and Drug Administration, Bureau of
Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following
information:
(1) The research project title;
(2) A brief description of the purpose of the project;
(3) The name of the investigator responsible;
(4) The name and license number of the institution holding the
specific license under 10 CFR 35.11 (or equivalent regulation of an
Agreement State);
(5) The name and maximum amount per subject of the radionuclide used;
(6) The number of subjects involved; and
(7) The date on which the administration of the radioactive drugs is
expected to be completed.
(h) The exemption referred to in paragraph (a) of this section, as
applied to any drug not referred to in paragraphs (d), (f), and (g) of
this section, is terminated on August 26, 1975.
(39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25,
1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR
42947, Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29,
1990)
21 CFR 310.504 Amphetamines (amphetamine, dextroamphetamine, and their
salts and levamfetamine and its salts) for human use.
(a) Amphetamine and dextroamphetamine and their salts. (1) Pursuant
to the drug efficacy requirements of the Federal Food, Drug, and
Cosmetic Act, the National Academy of Sciences-National Research
Council, Drug Efficacy Study Group, has evaluated certain dosage forms
of amphetamines and other sympathomimetic stimulant drugs intended for
use in the treatment of obesity and for other uses. The Academy found
that such drugs as a class have been shown to have a generally
short-term anorectic action. They further commented that clinical
opinion on the contribution of the sympathomimetic stimulants in a
weight reduction program varies widely, the anorectic effect of these
drugs often plateaus or diminishes after a few weeks, most studies of
them are for short periods, no available evidence shows that use of
anorectic alters the natural history of obesity, some evidence indicates
that anorectic effects may be strongly influenced by the suggestibility
of the patient, and reservations exist about the adequacy of the
controls in some of the clinical studies. Their significant potential
for drug abuse was also cited.
(2) In addition to those dosage forms that were reviewed for efficacy
by the Academy, other dosage forms of amphetamine drugs are on the
market that were not cleared through the new drug procedures. While
certain amphetamines were marketed prior to enactment of the Federal
Food, Drug, and Cosmetic Act in 1938, some of the conditions of use
subsequently prescribed, recommended, or suggested in their labeling
(for example, for the treatment of obesity) differ from uses claimed for
the amphetamines before said enactment. Such uses have not been cleared
through the effectiveness provisions of the Drug Amendments of 1962
(Pub. L. 87-781 which amended the Federal Food, Drug, and Cosmetic Act).
These drugs are very extensively used in the treatment of obesity. The
extent of use for such purposes as narcolepsy and minimal brain
dysfunction in children is believed to be minor as compared with the
total usage of these drugs. Because of their stimulant effect on the
central nervous system, they have a potential for misuse by those to
whom they are available through a physician's prescription, and their
abuse by those who obtain them through illicit channels is well
documented. Production data indicate that amphetamines have been
produced and prescribed in quantities greatly in excess of demonstrated
medical needs.
(3) Pursuant to a notice published in the Federal Register of August
8, 1970 (35 FR 12652), which required the submission of new drug
applications as a condition for continued marketing of amphetamines, 106
new drug applications for amphetamines or amphetamine-containing drug
products were received. The data submitted in those applications, and
data obtained from other sources concerning anorectic drugs, generally
supported the efficacy of anorectic drugs.
(b) On the basis of currently available evidence derived from
short-term studies, the Commissioner concludes that single drug entity
oral dosage forms of amphetamine or dextroamphetamine are effective in
the management of exogenous obesity as a short-term (a few weeks)
adjunct in a regimen of weight reduction, based on caloric restrictions,
for patients in whom obesity is refractory to other measures. For
purposes of this regulation, a mixture of dextroamphetamine and
amphetamine is ordinarily regarded as a single drug entity.
(c) The Food and Drug Administration is not aware of data providing
substantial evidence of the effectiveness of levamfetamine and its salts
and regards these preparations as new drugs requiring approved full new
drug applications.
(d) In view of the well-documented history of abuse of parenteral
amphetamines, the severe risk of drug dependence, and the availability
of safer alternative parenteral drugs which are equally effective for
recognized non-anorectic indications, the Food and Drug Administration
regards parenteral amphetamines as lacking evidence of safety.
(e) Any combination drug containing amphetamine or dextroamphetamine
is regarded as a new drug requiring an approved full new drug
application as a condition for marketing. Data in new drug applications
are required to fulfill the criteria set forth in 300.50 of this
chapter governing fixed combination prescription drugs for humans.
(f) New drug applications have been received from persons marketing
orally administered single entity amphetamine or dextroamphetamine
dosage forms. Any other person who intends to market such drug is
required to submit to the Food and Drug Administration an abbreviated
application under 314.55 of this chapter.
(g) The labeling conditions for single entity oral dosage forms of
amphetamine and dextroamphetamine and their salts are as follows:
(1) The label shall bear the statement ''Caution: Federal law
prohibits dispensing without prescription''.
(2) The drug shall be labeled to comply with all requirements of the
act and regulations. The labeling shall bear adequate information for
safe and effective use of the drug. The indications for use are:
Narcolepsy.
Minimal brain dysfunction in children (hyperkinetic behavior
disorders), as an aid to general management.
Management of exogenous obesity as short-term (a few weeks) adjunct
in a regimen of weight reduction based on caloric restriction, for
patients in whom obesity is refractory to other measures.
(3) Complete labeling guidelines are available from the Food and Drug
Administration.
(h) Regulatory proceedings will be initiated with regard to any such
drug within the jurisdiction of the act which is not in accord with this
regulation.
(39 FR 11680, Mar. 29, 1974, as amended at 41 FR 10885, Mar. 15,
1976; 55 FR 11578, Mar. 29, 1990)
21 CFR 310.506 Use of vinyl chloride as an ingredient, including
propellant, of aerosol drug products.
(a) Vinyl chloride has been used as a propellant in aerosol drug
preparations. Evidence indicates that vinyl chloride inhalation can
result in acute toxicity manifested by dizziness, headache,
disorientation, and unconsciousness where inhaled at high
concentrations. Cardiac effects, bone changes, and degenerative changes
in the brain, liver, and kidneys have been reported in animals. Studies
also demonstrate carcinogenic effects in animals as a result of
inhalation exposure to vinyl chloride. Recently, vinyl chloride has
been linked to liver disease, including liver cancer, in workers engaged
in the polymerization of vinyl chloride.
(b) The Commissioner finds that there is a lack of general
recognition by qualified experts of the safety or effectiveness of
aerosol drug preparations containing vinyl chloride as an ingredient,
including propellant. Therefore, any such product containing vinyl
chloride is a new drug and a new drug application approved under section
505 of the Federal Food, Drug, and Cosmetic Act is required for
marketing.
(c) Clinical investigations designed to obtain evidence that any
aerosol drug preparation containing vinyl chloride as an ingredient,
including propellant, is safe and effective for the purpose intended,
must comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug within the jurisdiction of the act which is not in
accord with this regulation is subject to regulatory action.
(39 FR 30830, Aug. 26, 1974, as amended at 55 FR 11578, Mar. 29,
1990)
21 CFR 310.507 Aerosol drug products for human use containing
1,1,1-trichloroethane.
(a) Trichloroethane has been used in aerosol drug products as a
solvent for the active ingredients and to reduce the vapor pressure of
the propellants. It is potentially toxic to the cardiovascular system,
i.e., can sensitize the heart to epinephrine. At a sufficiently large
concentration, it is a potent anesthetic agent. Deaths associated with
aerosol decongestant products intended to be inhaled and containing
trichloroethane have been reported. Most of the deaths resulted from
abuse or gross misuse of the preparations.
(b) The Food and Drug Administration finds that there is a lack of
general recognition by qualified experts of the safety or effectiveness
of trichloroethane in aerosol drug products intended for inhalation
either directly or indirectly. Any aerosol drug product containing
trichloroethane and labeled, represented, or advertised for use by
inhalation is a new drug and subject to regulatory proceedings unless it
is the subject of a new drug application approved pursuant to section
505 of the Federal Food, Drug, and Cosmetic Act.
(c) Clinical investigations designed to obtain evidence that any
aerosol drug product containing trichloroethane and labeled,
represented, or advertised for use by inhalation either directly or
indirectly is safe and effective for the purposes intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Regulatory proceedings will be initiated with regard to any such
drug within the jurisdiction of the act which is not in accord with this
regulation on January 16, 1978.
(42 FR 63387, Dec. 16, 1977, as amended at 55 FR 11578, Mar. 29,
1990)
21 CFR 310.508 Use of certain halogenated salicylanilides as an
inactive ingredient in drug products.
(a) Halogenated salicylanilides (tribromsalan (TBS,
3,4',5-tribromosalicylanilide), dibromsalan (DBS, 4',
5-dibromosalicylanilide), metabromsalan (MBS, 3,
5-dibromosalicylanilide), and 3,3', 4,5'-tetrachlorosalicylanilide
(TC-SA)) have been used as active or inactive ingredients in a number of
over-the-counter (OTC) drug products, largely antibacterial soaps, for
antimicrobial, preservative, and other purposes. These halogenated
salicylanilides are potent photosensitizers and can cause disabling skin
disorders. In some instances the photosensitization may persist for
prolonged periods as a severe reaction without further exposure to these
chemicals. Safer alternative antimicrobial agents are available.
(b) These halogenated salicylanilides are not generally recognized as
safe and effective for use as active or inactive ingredients in any drug
products. Therefore, any drug product containing such a halogenated
salicylanilide as an ingredient at any level for any purpose is a new
drug within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act for which an approved new drug application pursuant to
section 505 of the act and Part 314 of this chapter is required for
marketing.
(c) Clinical investigations designed to obtain evidence that any drug
product containing a halogenated salicylanilide as an ingredient at any
level for any purpose is safe and effective for the purpose intended
must comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product initially introduced into interstate
commerce after December 1, 1975, that is not in compliance with this
section is subject to regulatory action.
(40 FR 50530, Oct. 30, 1975, as amended at 55 FR 11578, Mar. 29,
1990)
21 CFR 310.509 Parenteral drug products in plastic containers.
(a) Any parenteral drug product packaged in a plastic immediate
container is not generally recognized as safe and effective, is a new
drug within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act, and requires an approved new drug application as a
condition for marketing. A ''Investigational New Drug Application'' set
forth in part 312 of this chapter is required for clinical
investigations designed to obtain evidence of safety and effectiveness.
(b) It is common medical practice to add various drugs to containers
of large volume parenteral drug products for single administration to
the patient, although in many cases the safety and effectiveness of that
practice has not been demonstrated. Accordingly the Commissioner of
Food and Drugs concludes that reports of a full investigation of the
compatibility of the immediate container of certain large volume
parenteral drugs with certain other drugs that may be added regularly to
the parenteral delivery system is necessary under section 505(k) of the
act to determine whether there is ground for requiring revision of the
labeling to provide for safer use of the large volume parenteral drug
products or ground for withdrawing approval, under section 505(e) of the
act, of any of the approved new drug applications for the products. As
used in this section, the term ''large volume parenteral drug product''
means a terminally sterilized aqueous drug product packaged in a
single-dose container with a capacity of 100 milliliters or more and
intended to be administered or used intravenously in a human.
(c) Each holder of an approved new drug application (NDA) for a large
volume parenteral drug product for intravenous use in humans that is
packaged in a plastic container shall submit the following to the Food
and Drug Administration:
(1) The protocol that the NDA holder proposes to follow in conducting
compatibility studies for its large volume parenteral drug product and
each additive drug listed in paragraph (d) of this section, on or before
April 16, 1979.
(2) A status report of the ongoing studies 9 months after the
applicant has received written acceptance of the protocol from the Food
and Drug Administration.
(3) The final report at the completion of the compatibility studies
within 24 months following acceptance of the protocol by the Food and
Drug Administration.
(d) Reports of compatibility studies with each of the following drugs
shall be submitted under paragraph (c) of this section for each large
volume parenteral drug product for intravenous use in humans that is
packaged in a plastic immediate container, unless a waiver is granted
under paragraph (e) of this section for a specific drug product:
Aminophylline
Amphotericin
Ampicillin
Calcium gluconate
Carbenicillin
Cephalosporins
Chloramphenicol
Chloramphenicol sodium succinate
Clindamycin phosphate
Cyclophosphamide
Cytarabine
Diphenhydramine
Erythromicins
Fluorouracil
Gentamicin
Heparin
Hydrocortisone sodium succinate
Insulin
Isoproterenol
Kanamycin
Levarterenol
Lidocaine
Lincomycin
Magnesium sulfate
Metaraminol
Methicillin
Methotrexate
Methyldopa
Oxacillin
Oxytocin
Penicillin G
Potassium chloride
Sodium bicarbonate
Sodium chloride
Tetracyclines
Vitamins (single-entity and multiple vitamin products)
(e) The required submission of a report of a compatibility study of a
large volume parenteral drug product packaged in plastic and any
additive drug listed in paragraph (d) of this section may be waived upon
a showing that the report is unnecessary or techniques are not available
for conducting a compatibility study that would produce meaningful data.
A request for a waiver shall be submitted to the Director of the
Division of Surgical-Dental Drug Products (HFD-160), Center for Drug
Evaluation and Research, Food and Drug Administration, Department of
Health and Human Services, 5600 Fishers Lane, Rockville, MD 20857.
(f) Until the results of the compatibility studies are evaluated, a
large volume parenteral drug product for intravenous use in humans that
is packaged in a plastic immediate container on or after April 16, 1979
is misbranded unless its labeling contains a warning that includes the
following information:
(1) A statement that additives may be incompatible.
(2) A statement that, if additive drugs are introduced into the
parenteral system, aseptic techniques should be used and the solution
should be thoroughly mixed.
(3) A statement that a solution containing an additive drug should
not be stored.
(g) After February 13, 1979, the Food and Drug Administration shall
approve a new drug application for a large volume parenteral drug
product for intravenous use in humans that is packaged in a plastic
immediate container if all of the following conditions are met:
(1) The application is otherwise approvable.
(2) The application contains the results of studies to determine the
compatibility of the large volume parenteral drug product's plastic
container with drugs that may be added regularly to the parenteral
delivery system.
(h) After February 13, 1979, the Food and Drug Administration shall
approve a new drug application for a drug product intended to be added
to a parenteral delivery system that includes a large volume parenteral
drug product for intravenous use in humans that is packaged in a plastic
immediate container if all of the following conditions are met:
(1) The application is otherwise approvable.
(2) The application contains the results of studies to determine the
compatibility of the additive drug product with the plastic immediate
container of marketed large volume parenteral drug products for
intravenous use in humans.
(i) Holders of new drug applications for large volume parenteral drug
products that are subject to this section and who must submit
supplements under 314.70(c)(2) of this chapter to provide for the
labeling required under paragraph (f) of this section may put the
labeling into use without advance approval by the Food and Drug
Administration.
(j) This section does not apply to a biological product licensed
under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).
(43 FR 58562, Nov. 15, 1978, as amended at 50 FR 8996, Mar. 6, 1985;
55 FR 11578, Mar. 29, 1990)
Effective Date Note: For a document staying the effectiveness of
310.509 (g) and (h), see 44 FR 14540, Mar. 13, 1979.
21 CFR 310.510 Use of aerosol drug products containing zirconium.
(a) Aerosol products containing zirconium have been used in
over-the-counter drug products as antiperspirants. Based upon the lack
of toxicological data adequate to establish a safe level for use and the
adverse benefit-to-risk ratio, such aerosol products containing
zirconium cannot be considered generally recognized as safe for use in
drug products. The benefit from using aerosol drug products containing
zirconium is insignificant when compared to the risk. Safer alternative
antiperspirant products are available.
(b) Any aerosol drug product containing zirconium is a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act for which an approved new drug application pursuant to
section 505 of the act and Part 314 of this chapter is required for
marketing.
(c) Clinical investigations designed to obtain evidence that any
aerosol drug product containing zirconium is safe for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product introduced in interstate commerce after
September 15, 1977 that is not in compliance with this section is
subject to regulatory action.
(42 FR 41376, Aug. 16, 1977, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.513 Chloroform, use as an ingredient (active or inactive) in
drug products.
(a) Chloroform has been used as an ingredient in drug products, such
as cough preparations, liniments, and toothpastes. Although considered
safe for many years, recent information has become available associating
chloroform with carcinogenic effects in animals. Studies conducted by
the National Cancer Institute have demonstrated that the oral
administration of chloroform to mice and rats induced hepatocellular
carcinomas (liver cancer) in mice and renal tumors in male rats.
(b) Any drug product containing chloroform as an ingredient is a new
drug within the meaning of section 201(p) of the act and misbranded and
is subject to regulatory action under sections 301, 502, and 505 of the
act. Any drug product containing chloroform in residual amounts from
its use as a processing solvent during manufacture, or as a byproduct
from the synthesis of an ingredient, is not, for the purpose of this
section, considered to contain chloroform as an ingredient.
(c) Any holder of an approved new drug application for a drug product
containing chloroform as an ingredient shall submit to the Food and Drug
Administration on or before July 29, 1976 a supplemental application
providing for a revised formulation removing chloroform as an
ingredient.
(1) The supplemental application shall contain:
(i) A full list of articles used as components and a full statement
of the composition of the drug product.
(ii) The date that the composition of the drug product will be
changed.
(iii) Data showing that the change in composition does not interfere
with any assay or other control procedures used in manufacturing the
drug product, or that the assay and other control procedures are revised
to make them adequate.
(iv) Data available to establish the stability of the revised
formulation and, if the data are too limited to support a conclusion
that the drug will retain its declared potency for a reasonable
marketing period, a commitment from the applicant:
(a) To test the stability of marketed batches at reasonable
intervals;
(b) To submit the data as they become available; and
(c) To recall from the market any batch found to fall outside the
approved specifications for the drug.
(v) Copies of the label and all other labeling to be used for the
drug product (a total of 12 copies if in final printed form, 4 copies if
in draft form).
(2) If such drug product now contains more than one percent
chloroform, the revised formulation containing no chloroform shall not
be marketed before the receipt of written notice of approval of the
supplemental application by the Food and Drug Administration.
(3) If such drug product now contains one percent or less chloroform,
the revised formulation containing no chloroform may be marketed,
subject to the conditions of 314.70(c) of this chapter, after
submission of the supplemental application but prior to the receipt of
written notice of its approval by the Food and Drug Administration.
(d) Any sponsor of a ''Investigational New Drug Application'' (IND)
for a drug product containing chloroform as an ingredient shall amend
the IND on or before July 29, 1976 to revise the formulation removing
chloroform as an ingredient.
(e) The Commissioner will initiate action to withdraw approval of an
application or terminate an IND in accordance with the applicable
provisions of section 505 of the act and Parts 312 and 314 of this
chapter upon failure of a holder of an approved new drug application or
sponsor of an IND to comply with the provisions of paragraph (c) or (d)
of this section.
(41 FR 26845, June 29, 1976, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.515 Patient package inserts for estrogens.
(a) Requirement for a patient package insert. FDA concludes that the
safe and effective use of drug products containing estrogens requires
that patients be fully informed of the benefits and risks involved in
the use of these drugs. Accordingly, except as provided in paragraph
(e) of this section, each estrogen drug product restricted to
prescription distribution, including products containing estrogens in
fixed combinations with other drugs, shall be dispensed to patients with
a patient package insert containing information concerning the drug's
benefits and risks. An estrogen drug product that does not comply with
the requirements of this section is misbranded under section 502(a) of
the Federal Food, Drug, and Cosmetic Act.
(b) Distribution requirements. (1) For estrogen drug products, the
manufacturer and distributor shall provide a patient package insert in
or with each package of the drug product that the manufacturer or
distributor intends to be dispensed to a patient.
(2) In the case of estrogen drug products in bulk packages intended
for multiple dispensing, and in the case of injectables in multiple-dose
vials, a sufficient number of patient labeling pieces shall be included
in or with each package to assure that one piece can be included with
each package or dose dispensed or administered to every patient. Each
bulk package shall be labeled with instructions to the dispensor to
include one patient labeling piece with each package dispensed or, in
the case of injectables, with each dose administered to the patient.
This section does not preclude the manufacturer or labeler from
distributing additional patient labeling pieces to the dispensor.
(3) Patient package inserts for estrogens dispensed in acute-care
hospitals or long-term care facilities will be considered to have been
provided in accordance with this section if provided to the patient
before administration of the first estrogen and every 30 days
thereafter, as long as the therapy continues.
(c) Patient package insert contents. A patient package insert for an
estrogen drug product is required to contain the following information:
(1) The name of the drug.
(2) The name and place of business of the manufacturer, packer, or
distributor.
(3) A statement regarding the benefits and proper uses of estrogens.
(4) The contraindications to use, i.e., when estrogens should not be
used.
(5) A description of the most serious risks associated with the use
of estrogens.
(6) A brief summary of other side effects of estrogens.
(7) Instructions on how a patient may reduce the risks of estrogen
use.
(8) The date, identified as such, of the most recent revision of the
patient package insert.
(d) Guidance language. The Food and Drug Administration issues
informal labeling guidance texts under 10.90(b)(9) of this chapter to
provide assistance in meeting the requirements of paragraph (c) of this
section. Requests for a copy of the guidance text should be directed to
the Center for Drug Evaluation and Research, Division of Metabolism and
Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857.
(e) Exemptions. This section does not apply to estrogen-progestogen
oral contraceptives. Labeling requirements for these products are set
forth in 310.501.
(f) Requirement to supplement approved application. Holders of
approved applications for estrogen drug products that are subject to the
requirements of this section must submit supplements under 314.70(c) of
this chapter to provide for the labeling required by paragraph (a) of
this section. Such labeling may be put into use without advance
approval by the Food and Drug Administration.
(55 FR 18723, May 4, 1990)
21 CFR 310.516 Progestational drug products; labeling directed to the
patient.
(a) The Commissioner of Food and Drugs concludes that the safe and
effective use of any progestational drug product requires that patients
be informed that there is an increased risk of birth defects in children
whose mothers have taken this drug during the first 4 months of
pregnancy. Accordingly, except as provided by paragraph (d) of this
section, any progestational drug product that is the subject of a new
drug application approved either before or after October 9, 1962 and all
identical, related, or similar drug products as defined in 310.6,
whether or not the subject of an approved new drug application, shall be
dispensed to patients with labeling in lay language containing such a
warning. The patient labeling shall be provided as a separate printed
leaflet independent of any additional materials.
(b) The patient labeling shall specifically include the following:
(1) Name of the drug.
(2) Name and place of business of the manufacturer, packer, or
distributor.
(3) A warning that there is an increased risk of birth defects in
children whose mothers take this drug during the first 4 months of
pregnancy.
(4) A brief discussion of the nature of the risks of birth defects
resulting from the use of these drugs during the first 4 months of
pregnancy.
(5) A brief statement that these drugs are no longer considered safe
as a test for pregnancy.
(6) A statement that the patient should inform her physician as soon
as possible if she discovers that she was pregnant when she took the
drug.
(c) The patient labeling shall be printed in accordance with the
following specifications:
(1) The minimum letter size shall be one-sixteenth of an inch in
height.
(2) Letter heights pertain to the lower-case letter ''o'' or its
equivalent that shall meet the minumim height standard.
(3) Type used shall conform to the minimum letter height. The body
copy shall contain 1-point leading, noncondensed type, and shall not
contain any light-face type or small capital letters.
(d) This section does not apply to a progestogen-containing product
intended for contraception, which shall be labeled according to the
requirements of 310.501.
(e)(1) Patient labeling for each progestational drug product shall be
provided in or with each package intended to be dispensed to the
patient. Patient labeling for drug products dispensed in acute-care
hospitals or long-term care facilities will be considered to have been
provided in accordance with this section if provided to the patient
before first administration of the drug and every 30 days thereafter, as
long as the therapy continues.
(2) In the case of progestational drug products in bulk packages
intended for multiple dispensing, a sufficient number of
patient-labeling pieces shall be included in or shall accompany each
bulk package to assure that one can be included with each package
dispensed to every patient. Each bulk package shall be labeled with
instructions to the dispenser to include one patient-labeling piece with
each package dispensed to the patient. This section does not preclude
the manufacturer or labeler from distributing additional
patient-labeling pieces to the dispenser.
(3) In the case of progestational drug products for injection, each
package shall include a sufficient number of patient-labeling pieces for
the volume of the vial, and instructions to the practitioner
administering the drug to give one patient-labeling piece to each
premenopausal woman, except those in whom childbearing is impossible,
receiving the drug.
(4) This section does not apply to oral dosage forms labeled solely
for the treatment of advanced cancer.
(5) Any progestational drug product, except as noted in paragraphs
(d) and (e)(4) of this section, that is not labeled as required by this
section and is either introduced or delivered for introduction into
interstate commerce, or held for sale after shipment in interstate
commerce, is misbranded under section 502 of the Federal Food, Drug, and
Cosmetic Act. However, a progestational drug product in the possession
of a wholesaler or retailer before December 12, 1978, is not misbranded
if adequate numbers of copies of the patient labeling are furnished to
the wholesaler or retailer to permit any retail purchaser after that
date to obtain such labeling with the product. The requirement that any
progestational drug product be dispensed with patient labeling, as
applied to physicians who dispense or administer the drug, will not be
effective for supplies in their possession on the effective date, but
will apply only to supplies received thereafter.
(f) The Food and Drug Administration has available guideline patient
labeling for progestational drug products that includes information
responsive to all items specified in paragraph (b) of this section.
This labeling was published in a separate notice appearing in the
Federal Register of January 12, 1989. Any person may rely on this
labeling as complying with paragraph (b) of this section.
(g) Holders of approved new drug applications for progestational drug
products that are subject to the requirements of this section shall
submit supplements under 314.70(c) of this chapter to provide for the
labeling required by paragraph (a) of this section.
(43 FR 47181, Oct. 13, 1978, as amended at 46 FR 53657, Oct. 30,
1981; 54 FR 1163, Jan. 12, 1989)
21 CFR 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea
class.
(a) The University Group Diabetes Program clinical trial has reported
an association between the administration of tolbutamide and increased
cardiovascular mortality. The Food and Drug Administration has
concluded that this reported association provides adequate basis for a
warning in the labeling. In view of the similarities in chemical
structure and mode of action, the Food and Drug Administration also
believes it is prudent from a safety standpoint to consider that the
possible increased risk of cardiovascular mortality from tolbutamide
applies to all other sulfonylurea drugs as well. Therefore, the
labeling for oral hypoglycemic drugs of the sulfonylurea class shall
include a warning concerning the possible increased risk of
cardiovascular mortality associated with such use, as set forth in
paragraph (b) of this section.
(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class
shall include in boldface type at the beginning of the ''Warnings''
section of the labeling the following statement:
The administration of oral hypoglycemic drugs has been reported to be
associated with increased cardiovascular mortality as compared to
treatment with diet alone or diet plus insulin. This warning is based
on the study conducted by the University Group Diabetes Program (UGDP),
a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying
vascular complications in patients with non-insulin-dependent diabetes.
The study involved 823 patients who were randomly assigned to one of
four treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a
fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2 1/2 times that of patients
treated with diet alone. A significant increase in total mortality was
not observed, but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the opportunity for
the study to show an increase in overall mortality. Despite controversy
regarding the interpretation of these results, the findings of the UGDP
study provide an adequate basis for this warning. The patient should be
informed of the potential risks and advantages of (name of drug) and of
alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was
included in this study, it is prudent from a safety standpoint to
consider that this warning may also apply to other oral hypoglycemic
drugs in this class, in view of their close similarities in mode of
action and chemical structure.
(49 FR 14331, Apr. 11, 1984)
21 CFR 310.519 Drug products marketed as over-the-counter (OTC) daytime
sedatives.
(a) Antihistamines, bromides, and scopolamine compounds, either
singly or in combinations, have been marketed as ingredients in
over-the-counter (OTC) drug products for use as daytime sedatives. The
following claims have been made for daytime sedative products:
''occasional simple nervous tension,'' ''nervous irritability,''
''nervous tension headache,'' ''simple nervousness due to common every
day overwork and fatigue,'' ''a relaxed feeling,'' ''calming down and
relaxing,'' ''gently soothe away the tension,'' ''calmative,''
''resolving that irritability that ruins your day,'' ''helps you
relax,'' ''restlessness,'' ''when you're under occasional stress . . .
helps you work relaxed.'' Based on evidence presently available, there
are no ingredients that can be generally recognized as safe and
effective for use as OTC daytime sedatives.
(b) Any OTC drug product that is labeled, represented, or promoted as
an OTC daytime sedative (or any similar or related indication) is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act for which an approved new drug
application under section 505 of the act and Part 314 of this chapter is
required for marketing.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted as an OTC daytime sedative (or
any similar or related indication) is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC daytime sedative drug product introduced into interstate
commerce after December 24, 1979, that is not in compliance with this
section is subject to regulatory action.
(44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended
at 55 FR 11579, Mar. 29, 1990)
21 CFR 310.525 Sweet spirits of nitre drug products.
(a) Historically, sweet spirits of nitre has been present as an
ingredient in over-the-counter (OTC) drug products for various uses.
Based upon the lack of adequate data to establish effectiveness for any
use and the adverse benefit-to-risk ratio, sweet spirits of nitre drug
products cannot be considered generally recognized as safe and
effective. The benefit from using sweet spirits of nitre for any use is
insignificant when compared to the risk.
(b) Any drug product containing sweet spirits of nitre is misbranded
under section 502 of the Federal Food, Drug, and Cosmetic Act and is a
new drug within the meaning of section 201(p) of the act for which an
approved new drug application under section 505 of the act and Part 314
of this chapter is required for marketing.
(c) Clinical investigations designed to obtain evidence that any drug
product containing sweet spirits of nitre for any use is safe and
effective for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) Any drug product containing sweet spirits of nitre in interstate
commerce after June 27, 1980, that is not in compliance with this
section is subject to regulatory action.
(45 FR 43401, June 27, 1980, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.526 Camphorated oil drug products.
(a) Historically, camphorated oil (also known as camphor liniment), a
solution of 20 percent camphor in cottonseed oil, has been marketed as
an over-the-counter (OTC) drug product for various uses, primarily as a
topical counterirritant or liniment. A large number of accidental
ingestions of camphorated oil, often mistaken for castor oil, cod liver
oil, mineral oil, olive oil, cough medicine, or other drug products,
have been reported and toxicity has often resulted, primarily in infants
and young children. Because of the potential hazard for poisoning to
occur, the benefit from using any drug product containing camphor in oil
or from using any camphor-containing drug product that is labeled as
''camphorated oil'' or ''camphor liniment,'' or any similar name such as
''camphor oil'' or ''camphorated liniment,'' for any use, is
insignificant when compared to the risk. Based upon the adverse
benefit-to-risk ratio, camphorated oil, any drug product containing
camphor in oil, or any other drug product containing camphor that is
represented, suggested, or purported to be camphorated oil, such as a
product labeled ''camphor liniment,'' ''camphor oil,'' ''camphorated
liniment,'' or any similar name, cannot be considered generally
recognized as safe.
(b) Any camphorated oil drug product, any drug product containing
camphor in oil, or any other drug product containing camphor that is
represented, suggested or purported to be camphorated oil, e.g.,
''camphor liniment,'' ''camphor oil,'' ''camphorated liniment,'' is
misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act
and is a new drug within the meaning of section 201(p) of the act for
which an approved new drug application under section 505 of the act and
Part 314 of this chapter is required for marketing.
(c) Clinical investigations designed to obtain evidence that any
camphorated oil drug product, any drug product containing camphor in
oil, or any other drug product containing camphor that is represented,
suggested, or purported to be camphorated oil, e.g., ''camphor
liniment,'' ''camphor oil,'' ''camphorated liniment,'' is safe for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) Any such drug product in interstate commerce after September 21,
1982 that is not in compliance with this section is subject to
regulatory action.
(47 FR 41720, Sept. 21, 1982, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.527 Drug products containing active ingredients offered
over-the-counter (OTC) for external use as hair growers or for hair loss
prevention.
(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid,
biotin and all other B-vitamins, dexpanthenol, estradiol and other
topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20,
polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction
of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat
germ oil have been marketed as ingredients in OTC drug products for
external use as hair growers or for hair loss prevention. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients intended for OTC
external use as a hair grower or for hair loss prevention. Based on
evidence currently available, all labeling claims for OTC hair grower
and hair loss prevention drug products for external use are either
false, misleading, or unsupported by scientific data. Therefore, any
OTC drug product for external use containing an ingredient offered for
use as a hair grower or for hair loss prevention cannot be considered
generally recognized as safe and effective for its intended use.
(b) Any OTC drug product that is labeled, represented, or promoted
for external use as a hair grower or for hair loss prevention is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
new drug application under section 505 of the act and Part 314 of this
chapter is required for marketing. In the absence of an approved new
drug application, such product is also misbranded under section 502 of
the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for OTC external use as a hair
grower or for hair loss prevention is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in Part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(54 FR 28777, July 7, 1989)
21 CFR 310.528 Drug products containing active ingredients offered
over-the-counter (OTC) for use as an aphrodisiac.
(a) Any product that bears labeling claims that it will arouse or
increase sexual desire, or that it will improve sexual performance, is
an aphrodisiac drug product. Anise, cantharides, don qual, estrogens,
fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice,
mandrake, methyltestosterone, minerals, nux vomica, Pega Palo,
sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine
hydrochloride, and yohimbinum have been present as ingredients in such
drug products. Androgens (e.g., testosterone and methyltestosterone)
and estrogens are powerful hormones when administered internally and are
not safe for use except under the supervision of a physician. There is
a lack of adequate data to establish general recognition of the safety
and effectiveness of any of these ingredients, or any other ingredient,
for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC
use are either false, misleading, or unsupported by scientific data.
The following claims are examples of some that have been made for
aphrodisiac drug products for OTC use: ''acts as an aphrodisiac;''
''arouses or increases sexual desire and improves sexual performance;''
''helps restore sexual vigor, potency, and performance;'' ''improves
performance, staying power, and sexual potency;'' and ''builds virility
and sexual potency.'' Based on evidence currently available, any OTC
drug product containing ingredients for use as an aphrodisiac cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or prompted
for use as an aphrodisiac is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the
act), for which an approved new drug application under section 505 of
the act and Part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for OTC use as an aphrodisiac
is safe and effective for the purpose intended must comply with the
requirements and procedures governing the use of investigational new
drugs set forth in Part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(54 FR 28786, July 7, 1989)
21 CFR 310.529 Drug products containing active ingredients offered
over-the-counter (OTC) for oral use as insect repellents.
(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an
ingredient in over-the-counter (OTC) drug products for oral use as an
insect repellent (an orally administered drug product intended to keep
insects away). There is a lack of adequate data to establish the
effectiveness of this, or any other ingredient for OTC oral use as an
insect repellent. Labeling claims for OTC orally administered insect
repellent drug products are either false, misleading, or unsupported by
scientific data. The following claims are examples of some that have
been made for orally administered OTC insect repellent drug products:
''Oral mosquito repellent,'' ''mosquitos avoid you,'' ''bugs stay
away,'' ''keep mosquitos away for 12 to 24 hours,'' and ''the newest way
to fight mosquitos.'' Therefore, any drug product containing ingredients
offered for oral use as an insect repellent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for oral use as an insect repellent is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for
which an approved new drug application under section 505 of the act and
Part 314 of this chapter is required for marketing. In the absence of
an approved new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted OTC for oral use as an insect
repellent is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product in interstate commerce after December 17,
1985, that is not in compliance with this section is subject to
regulatory action.
(40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.532 Drug products containing active ingredients offered
over-the-counter (OTC) to relieve the symptoms of benign prostatic
hypertrophy.
(a) The amino acids glycine, alanine, and glutamic acid (alone or in
combination) and the ingredient sabal have been present in
over-the-counter (OTC) drug products to relieve the symptoms of benign
prostatic hypertrophy, e.g., urinary urgency and frequency, excessive
urinating at night, and delayed urination. There is a lack of adequate
data to establish general recognition of the safety and effectiveness of
these or any other ingredients for OTC use in relieving the symptoms of
benign prostatic hypertrophy. In addition, there is no definitive
evidence that any drug product offered for the relief of the symptoms of
benign prostatic hypertrophy would alter the obstructive or inflammatory
signs and symptoms of this condition. Therefore, self-medication with
OTC drug products might unnecessarily delay diagnosis and treatment of
progressive obstruction and secondary infections. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use in relieving the symptoms of benign prostatic hypertrophy cannot
be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted to
relieve the symptoms of benign prostatic hypertrophy is regarded as a
new drug within the meaning of section 201(p) of the Federal Food, Drug,
and Cosmetic Act (the act), for which an approved application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved application, such product is
also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for OTC use to relieve the
symptoms of benign prostatic hypertrophy is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After August 27, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(55 FR 6930, Feb. 27, 1990)
21 CFR 310.533 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as an anticholinergic in cough-cold
drug products.
(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids
as contained in Atropa belladonna and Datura stramonium have been
present as ingredients in cough-cold drug products for use as an
anticholinergic. Anticholinergic drugs have been marketed OTC in
cough-cold drug products to relieve excessive secretions of the nose and
eyes, symptoms that are commonly associated with hay fever, allergy,
rhinitis, and the common cold. Atropine sulfate for oral use as an
anticholinergic is probably safe at dosages that have been used in
marketed cough-cold products (0.2 to 0.3 milligram); however, there are
inadequate data to establish general recognition of the effectiveness of
this ingredient. The belladonna alkaloids, which contain atropine (d,
dl hyoscyamine) and scopolamine (l-hyoscine), are probably safe for oral
use at dosages that have been used in marketed cough-cold products (0.2
milligram) but there are inadequate data to establish general
recognition of the effectiveness of these ingredients as an
anticholinergic for cough-cold use. Belladonna alkaloids for inhalation
use, as contained in Atropa belladonna and Datura stramonium, are
neither safe nor effective as an OTC anticholinergic. There are
inadequate safety and effectiveness data to establish general
recognition of the safety and/or effectiveness or any of these
ingredients, or any other ingredient, for OTC use as an anticholinergic
in cough-cold drug products.
(b) Any OTC cough-cold drug product that is labeled, represented, or
promoted for use as an anticholinergic is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and Part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
cough-cold drug product labeled, represented, or promoted for OTC use as
an anticholinergic is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
cough-cold drug product that is labeled, represented, or promoted for
use as an anticholinergic may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
(50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990)
21 CFR 310.534 Drug products containing active ingredients offered
over-the-counter (OTC) for human use as oral wound healing agents.
(a) Allantoin, carbamide peroxide in anhydrous glycerin, water
soluble chlorophyllins, and hydrogen peroxide in aqueous solution have
been present in oral mucosal injury drug products for use as oral wound
healing agents. Oral wound healing agents have been marketed as aids in
the healing of minor oral wounds by means other than cleansing and
irrigating, or by serving as a protectant. Allantoin, carbamide
peroxide in anhydrous glycerin, water soluble chlorophyllins, and
hydrogen peroxide in aqueous solution are safe for use as oral wound
healing agents, but there are inadequate data to establish general
recognition of the effectiveness of these ingredients as oral wound
healing agents.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as an oral wound healing agent is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and Part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for OTC use as an oral wound
healing agent is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any OTC drug
product that is labeled, represented, or promoted for use as an oral
wound healing agent may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
(51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29,
1990)
21 CFR 310.540 Drug products containing active ingredients offered
over-the-counter (OTC) for use as stomach acidifiers.
(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted
hydrochloric acid, and pepsin have been present as ingredients in
over-the-counter (OTC) drug products for use as stomach acidifiers.
Because of the lack of adequate data to establish the effectiveness of
these or any other ingredients for use in treating achlorhydria and
hypochlorhydria, and because such conditions are asymptomatic, any OTC
drug product containing ingredients offered for use as a stomach
acidifier cannot be considered generally recognized as safe and
effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for use as a stomach acidifier is regarded as a new drug within the
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act,
for which an approved new drug application under section 505 of the act
and Part 314 of this chapter is required for marketing. In the absence
of an approved new drug application, such product is also misbranded
under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted as a stomach acidifier for OTC
use is safe and effective for the purpose intended must comply with the
requirements and procedures governing the use of investigational new
drugs set forth in Part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
drug product initially introduced or initially delivered for
introduction into interstate commerce that is not in compliance with
this section is subject to regulatory action.
(53 FR 31271, Aug. 17, 1988)
21 CFR 310.541 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hypophosphatemia.
(a) Hypophosphatemia is a condition in which an abnormally low plasma
level of phosphate occurs in the blood. This condition is not amenable
to self-diagnosis or self-treatment. Treatment of this condition should
be restricted to the supervision of a physician. For this reason, any
drug product containing ingredients offered for OTC use in the treatment
of hypophosphatemia cannot be considered generally recognized as safe
and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hypophosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for OTC use in the treatment
of hypophosphatemia is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of his chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(55 FR 19858, May 11, 1990)
21 CFR 310.542 Over-the-counter (OTC) drug products containing active
ingredients offered for use in the treatment of hyperphosphatemia.
(a) Hyperphosphatemia is a condition in which an abnormally high
plasma level of phosphate occurs in the blood. This condition in not
amenable to self-diagnosis or self-treatment. Treatment of this
condition should be restricted to the supervision of a physician. For
this reason, any drug product containing ingredients offered for OTC use
in the treatment of hyperphosphatemia cannot be considered generally
recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for
OTC use in the treatment of hyperphosphatemia is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved application under section
505 of the act and part 314 of this chapter is required for marketing.
In the absence of an approved application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for use in the treatment of
hyperphosphatemia is safe and effective for the purpose intended must
comply with the requirements and procedures governing use of
investigational new drugs set forth in part 312 of this chapter.
(d) After November 12, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(55 FR 19858, May 11, 1990)
21 CFR 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) A number of active ingredients have been present in OTC drug
products for various uses, as described below. However, based on
evidence currently available, there are inadequate data to establish
general recognition of the safety and effectiveness of these ingredients
for the specified uses:
(1) Topical acne drug products.
Alcloxa
Alkyl isoquinolinium bromide
Aluminum chlorohydrex
Aluminum hydroxide
Benzocaine
Benzoic acid
Boric acid
Calcium polysulfide
Calcium thiosulfate
Camphor
Chloroxylenol
Chloxyquin
Coal tar
Dibenzothiophene
Estrone
Magnesium aluminum silicate
Magnesium sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Povidone-iodine
Pyrilamine maleate
Resorcinol (as single ingredient)
Resorcinol monoacetate (as single ingredient)
Salicylic acid (over 2 up to 5 percent)
Sodium borate
Sodium thiosulfate
Tetracaine hydrochloride
Thymol
Vitamin E
Zinc oxide
Zinc stearate
Zinc sulfide
(2) Anticaries drug products.
Hydrogen fluoride
Sodium carbonate
Sodium monofluorophosphate (6 percent rinse)
Sodium phosphate
(3) Antidiarrheal drug products.
Aluminum hydroxide
Atropine sulfate
Calcium carbonate
Carboxymethylcellulose
Glycine
Homatropine methylbromide
Hyoscyamine sulfate
Lactobacillus acidophilus
Lactobacillus bulgaricus
Opium, powdered
Opium tincture
Paregoric
Phenyl salicylate
Scopolamine hydrobromide
Zinc phenolsulfonate
(4) Antiperspirant drug products.
Alum, potassium
Aluminum bromohydrate
Aluminum chloride (alcoholic solutions)
Aluminum chloride (aqueous solution) (aerosol only)
Aluminum sulfate
Aluminum sulfate, buffered (aerosol only)
Sodium aluminum chlorohydroxy lactate
(5) Boil treatment drug products.
Aminacrine hydrochloride
Bismuth subnitrate
Calomel
Camphor
Cholesterol
Ergot fluidextract
Hexachlorophene
Isobutamben
Juniper tar
Lanolin
Magnesium sulfate
Menthol
Methyl salicylate
Oxyquinoline sulfate
Petrolatum
Phenol
Pine tar
Rosin
Rosin cerate
Sassafras oil
Thymol
Zinc oxide
(6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug
products -- (i) Antihistamine drug products.
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride
(ii) Nasal decongestant drug products.
Allyl isothiocyanate
Camphor (lozenge)
Creosote, beechwood (oral)
Eucalyptol (lozenge)
Eucalyptol (mouthwash)
Eucalyptus oil (lozenge)
Eucalyptus oil (mouthwash)
Menthol (mouthwash)
Peppermint oil (mouthwash)
Thenyldiamine hydrochloride
Thymol
Thymol (lozenge)
Thymol (mouthwash)
Turpentine oil
(7) Dandruff/seborrheic dermatitis/psoriasis drug products.
Alkyl isoquinolinium bromide
Allantoin
Benzalkonium chloride
Benzethonium chloride
Boric acid
Calcium undecylenate
Captan
Chloroxylenol
Colloidal oatmeal
Cresol, saponated
Ethohexadiol
Eucalyptol
Juniper tar
Lauryl isoquinolinium bromide
Methol (Does not apply to the use of menthol as an antipruritic when
used in combination with the Category I antidandruff ingredient coal
tar)
Mercury oleate
Methylbenzethonium chloride
Methyl salicylate
Phenol
Phenolate sodium
Pine tar
Povidone-iodine
Resorcinol
Sodium borate
Sodium salicylate
Thymol
Undecylenic acid
(8) Digestive aid drug products.
Bismuth sodium tartrate
Calcium carbonate
Cellulase
Dehydrocholic acid
Dihydroxyaluminum sodium carbonate
Duodenal substance
Garlic, dehydrated
Glutamic acid hydrochloride
Hemicellulase
Homatropine methylbromide
Magnesium hydroxide
Magnesium trisilicate
Ox bile extract
Pancreatin
Pancrelipase
Papain
Peppermint oil
Pepsin
Sodium bicarbonate
Sodium citrate
Sorbitol
(9) Exocrine pancreatic insufficiency drug products.
Hemicellulase
(10) External analgesic drug products -- (i) Analgesic and anesthetic
drug products.
Aspirin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eugenol
Hexylresorcinol
Methapyrilene hydrochloride
Salicylamide
Thymol
(ii) Counterirritant drug products.
Chloral hydrate
Eucalyptus oil
(iii) Male genital desensitizer drug products.
Benzyl alcohol
Camphorated metacresol
Ephedrine hydrochloride
(11) Ingrown toenail relief drug products.
Chloroxylenol
Urea
(12) Laxative drug products -- (i) Bulk laxatives.
Agar
Carrageenan (degraded)
Carrageenan (native)
Guar gun
(ii) Saline laxative.
Tartaric acid
(iii) Stool softener.
Poloxamer 188
(iv) Stimulant laxatives.
Aloin
Bile salts/acids
Calcium pantothenate
Calomel
Colocynth
Elaterin resin
Frangula
Gamboge
Ipomea
Jalap
Ox bile
Podophyllum resin
Prune concentrate dehydrate
Prune powder
Rhubarb, Chinese
Sodium Oleate
(13) Nailbiting and thumbsucking deterrent drug products.
Denatonium benzoate
(14) Oral health care drug products (nonantimicrobial).
Antipyrine
Camphor
Cresol
Dibucaine
Dibucaine hydrochloride
Eucalyptol
Lidocaine
Lidocaine hydrochloride
Methly salicylate
Myrrh tincture
Pyrilamine maleate
Sorbitol
Sugars
Tetracaine
Tetracaine hydrochloride
Thymol
(15) Topical otic drug products for the prevention of swimmer's ear.
Acetic acid
(16) Poison treatment drug products.
Ipecac fluidextract
Ipecac tincture
Zinc sulfate
(17) Skin bleaching drug products.
Mercury, ammoniated
(18) Skin protectant drug products.
Allantoin (wound healing claims only)
Sulfur
Tannic acid
Zinc acetate (wound healing claims only)
(19) Smoking deterrent drug products.
Clove
Coriander
Eucalyptus oil
Ginger, Jamaica
Lemon oil, terpeneless
Licorice root extract
Menthol
Methyl salicylate
Quinine ascorbate
Silver nitrate
Thymol
21 CFR 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(20) Weight control drug products.
Alcohol
Alfalfa
Alginic acid
Anise oil
Arginine
Ascorbic acid
Bearberry
Biotin
Bone marrow, red
Buchu
Buchu, potassium extract
Caffeine
Caffeine citrate
Calcium
Calcium carbonate
Calcium caseinate
Calcium lactate
Calcium pantothenate
Carboxymethylcellulose sodium
Carrageenan
Cholecalcierol
Choline
Chondrus
Citric acid
Cnicus benedictus
Copper
Copper gluconate
Corn oil
Corn syrup
Corn silk, potassium extract
Cupric sulfate
Cyanocobalamin (vitamin B12)
Cystine
Dextrose
Docusate sodium
Ergocalciferol
Ferric ammonium citrate
Ferric pyrophosphate
Ferrous fumarate
Ferrous gluconate
Ferrous sulfate (iron)
Flax seed
Folic acid
Fructose
Guar gum
Histidine
Hydrastis canadensis
Inositol
Iodine
Isoleucine
Juniper, potassium extract
Karaya gum
Kelp
Lactose
Lecithin
Leucine
Liver concentrate
Lysine
Lysine hydrochloride
Magnesium
Magnesium oxide
Malt
Maltodextrin
Manganese citrate
Mannitol
Methionine
Methylcellulose
Mono- and di-glycerides
Niacinamide
Organic vegetables
Pancreatin
Pantothenic acid
Papain
Papaya enzymes
Pepsin
Phenacetin
Phenylalanine
Phosphorus
Phytolacca
Pineapple enzymes
Plantago seed
Potassium citrate
Pyridoxine hydrochloride (vitamin B6)
Riboflavin
Rice polishings
Saccharin
Sea minerals
Sesame seed
Sodium
Sodium bicarbonate
Sodium caseinate
Sodium chloride (salt)
Soybean protein
Soy meal
Sucrose
Thiamine hydrochloride (vitamin B1)
Thiamine mononitrate (vitamin B1 mononitrate)
Threonine
Tricalcium phosphate
Tryptophan
Tyrosine
Uva ursi, potassium extract
Valine
Vegetable
Vitamin A
Vitamin A acetate
Vitamin A palmitate
Vitamin E
Wheat germ
Xanthan gum
Yeast
(b) Any OTC drug product that is labeled, represented, or promoted
for the uses specified and containing any active ingredient(s) as
specified in paragraph (a) of this section is regarded as a new drug
within the meaning of section 210(p) of the Federal Food, Drug, and
Cosmetic Act (the act), for which an approved new drug application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug
product labeled, represented, or promoted for the OTC uses and
containing any active ingredient(s) as specified in paragraph (a) of
this section is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC drug product that is not in compliance with this section
is subject to regulatory action if initially introduced or initially
delivered for introduction into interstate commerce after the dates
specified in paragraphs (d)(1) and (d)(2) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(19) of this section; and
(2) February 10, 1992, for products subject to paragraph (a)(20) of
this section.
(55 FR 46919, Nov. 7, 1990; 55 FR 49973, Dec. 3, 1990, as amended at
56 FR 37798, Aug. 08, 1991; 56 FR 46823, Sept. 16, 1991; 56 FR 63568,
Dec. 4, 1991; 57 FR 3526, Jan. 30, 1992)
Effective Date Note: At 56 FR 63568, Dec. 4, 1991, in 310.545
paragraph (a)(7) was amended by removing the entry ''Methol'' including
the parenthetical statement and alphabetically adding the entry
''Menthol'', the introductory text of paragraph (d) was revised, and
paragraph (d)(3) was added, effective December 4, 1992. For the
convenience of the reader, the text in effect as of December 4, 1992
appears as follows:
310.545 Drug products containing certain active ingredients offered
over-the-counter (OTC) for certain uses.
(d) Any OTC drug product that is not in compliance with this section
is subject to regulatory action if initially introduced or initially
delivered for introduction into interstate commerce after the dates
specified in paragraphs (d)(1), (d)(2), and (d)(3) of this section.
(3) December 4, 1992, for products subject to paragraph (a)(7) of
this section that contain menthol as an antipruritic in combination with
the antidandruff ingredient coal tar identified in 358.710(a)(1) of
this chapter.
21 CFR 310.545 PART 312 -- INVESTIGATIONAL NEW DRUG APPLICATION
21 CFR 310.545 Subpart A -- General Provisions
Sec.
312.1 Scope.
312.2 Applicability.
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
312.7 Promotion and charging for investigational drugs.
312.10 Waivers.
21 CFR 310.545 Subpart B -- Investigational New Drug Application (IND)
312.20 Requirement for an IND.
312.21 Phases of an investigation.
312.22 General principles of the IND submission.
312.23 IND content and format.
312.30 Protocol amendments.
312.31 Information amendments.
312.32 IND safety reports.
312.33 Annual reports.
312.34 Treatment use of an investigational new drug.
312.35 Submissions for treatment use.
312.36 Emergency use of an investigational new drug.
312.38 Withdrawal of an IND.
21 CFR 310.545 Subpart C -- Administrative Actions
312.40 General requirements for use of an investigational new drug in
a clinical investigation.
312.41 Comment and advice on an IND.
312.42 Clinical holds and requests for modification.
312.44 Termination.
312.45 Inactive status.
312.47 Meetings.
312.48 Dispute resolution.
21 CFR 310.545 Subpart D -- Responsibilities of Sponsors and
Investigators
312.50 General responsibilities of sponsors.
312.52 Transfer of obligations to a contract research organization.
312.53 Selecting investigators and monitors.
312.55 Informing investigators.
312.56 Review of ongoing investigations.
312.57 Recordkeeping and record retention.
312.58 Inspection of sponsor's records and reports.
312.59 Disposition of unused supply of investigational drug.
312.60 General responsibilities of investigators.
312.61 Control of the investigational drug.
312.62 Investigator recordkeeping and record retention.
312.64 Investigator reports.
312.66 Assurance of IRB review.
312.68 Inspection of investigator's records.
312.69 Handling of controlled substances.
312.70 Disqualification of a clinical investigator.
21 CFR 310.545 Subpart E -- Drugs Intended to Treat Life-threatening
and Severely-debilitating Illnesses
312.80 Purpose.
312.81 Scope.
312.82 Early consultation.
312.83 Treatment protocols.
312.84 Risk-benefit analysis in review of marketing applications for
drugs to treat life-threatening and severely-debilitating illnesses.
312.85 Phase 4 studies.
312.86 Focused FDA regulatory research.
312.87 Active monitoring of conduct and evaluation of clinical
trials.
312.88 Safeguards for patient safety.
21 CFR 310.545 Subpart F -- Miscellaneous
312.110 Import and export requirements.
312.120 Foreign clinical studies not conducted under an IND.
312.130 Availability for public disclosure of data and information in
an IND.
312.140 Address for correspondence.
312.145 Guidelines.
21 CFR 310.545 Subpart G -- Drugs for Investigational Use in Laboratory
Research Animals or in Vitro Tests
312.160 Drugs for investigational use in laboratory research animals
or In vitro tests.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353,
355, 356, 357, 371); sec. 351 of the Public Health Service Act (42
U.S.C. 262).
Source: 52 FR 8831, Mar. 19, 1987, unless otherwise noted.
21 CFR 310.545 Subpart A -- General Provisions
21 CFR 312.1 Scope.
(a) This part contains procedures and requirements governing the use
of investigational new drugs, including procedures and requirements for
the submission to, and review by, the Food and Drug Administration of
investigational new drug applications (IND's). An investigational new
drug for which an IND is in effect in accordance with this part is
exempt from the premarketing approval requirements that are otherwise
applicable and may be shipped lawfully for the purpose of conducting
clinical investigations of that drug.
(b) References in this part to regulations in the Code of Federal
Regulations are to Chapter I of Title 21, unless otherwise noted.
21 CFR 312.2 Applicability.
(a) Applicability. Except as provided in this section, this part
applies to all clinical investigations of products that are subject to
section 505 or 507 of the Federal Food, Drug, and Cosmetic Act or to the
licensing provisions of the Public Health Service Act (58 Stat. 632, as
amended (42 U.S.C. 201 et seq.)).
(b) Exemptions. (1) The clinical investigation of a drug product
that is lawfully marketed in the United States is exempt from the
requirements of this part if all the following apply:
(i) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor
intended to be used to support any other significant change in the
labeling for the drug;
(ii) If the drug that is undergoing investigation is lawfully
marketed as a prescription drug product, the investigation is not
intended to support a significant change in the advertising for the
product;
(iii) The investigation does not involve a route of administration or
dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the
requirements for institutional review set forth in Part 56 and with the
requirements for informed consent set forth in Part 50; and
(v) The investigation is conducted in compliance with the
requirements of 312.7.
(2)(i) A clinical investigation involving an in vitro diagnostic
biological product listed in paragraph (b)(2)(ii) of this section is
exempt from the requirements of this part if (a) it is intended to be
used in a diagnostic procedure that confirms the diagnosis made by
another, medically established, diagnostic product or procedure and (b)
it is shipped in compliance with 312.160.
(ii) In accordance with paragraph (b)(2)(i) of this section, the
following products are exempt from the requirements of this part: (a)
blood grouping serum; (b) reagent red blood cells; and (c) anti-human
globulin.
(3) A drug intended solely for tests in vitro or in laboratory
research animals is exempt from the requirements of this part if shipped
in accordance with 312.160.
(4) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1) of this section.
(5) A clinical investigation involving use of a placebo is exempt
from the requirements of this part if the investigation does not
otherwise require submission of an IND.
(c) Bioavailability studies. The applicability of this part to in
vivo bioavailability studies in humans is subject to the provisions of
320.31.
(d) Unlabeled indication. This part does not apply to the use in the
practice of medicine for an unlabeled indication of a new drug or
antibiotic drug product approved under Part 314 or of a licensed
biological product.
(e) Guidance. FDA may, on its own initiative, issue guidance on the
applicability of this part to particular investigational uses of drugs.
On request, FDA will advise on the applicability of this part to a
planned clinical investigation.
21 CFR 312.3 Definitions and interpretations.
(a) The definitions and interpretations of terms contained in section
201 of the act apply to those terms when used in this part:
(b) The following definitions of terms also apply to this part:
Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52
Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).
Clinical investigation means any experiment in which a drug is
administered or dispensed to, or used involving, one or more human
subjects. For the purposes of this part, an experiment is any use of a
drug except for the use of a marketed drug in the course of medical
practice.
Contract research organization means a person that assumes, as an
independent contractor with the sponsor, one or more of the obligations
of a sponsor, e.g., design of a protocol, selection or monitoring of
investigations, evaluation of reports, and preparation of materials to
be submitted to the Food and Drug Administration.
FDA means the Food and Drug Administration.
IND means an investigational new drug application. For purposes of
this part, ''IND'' is synonymous with ''Notice of Claimed
Investigational Exemption for a New Drug.''
Investigational new drug means a new drug, antibiotic drug, or
biological drug that is used in a clinical investigation. The term also
includes a biological product that is used in vitro for diagnostic
purposes. The terms ''investigational drug'' and ''investigational new
drug'' are deemed to be synonymous for purposes of this part.
Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation
is conducted by a team of individuals, the investigator is the
responsible leader of the team. ''Subinvestigator'' includes any other
individual member of that team.
Marketing application means an application for a new drug submitted
under section 505(b) of the act, a request to provide for certification
of an antibiotic submitted under section 507 of the act, or a product
license application for a biological product submitted under the Public
Health Service Act.
Sponsor means a person who takes responsibility for and initiates a
clinical investigation. The sponsor may be an individual or
pharmaceutical company, governmental agency, academic institution,
private organization, or other organization. The sponsor does not
actually conduct the investigation unless the sponsor is a
sponsor-investigator. A person other than an individual that uses one
or more of its own employees to conduct an investigation that it has
initiated is a sponsor, not a sponsor-investigator, and the employees
are investigators.
Sponsor-Investigator means an individual who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. The term does not
include any person other than an individual. The requirements
applicable to a sponsor-investigator under this part include both those
applicable to an investigator and a sponsor.
Subject means a human who participates in an investigation, either as
a recipient of the investigational new drug or as a control. A subject
may be a healthy human or a patient with a disease.
21 CFR 312.6 Labeling of an investigational new drug.
(a) The immediate package of an investigational new drug intended for
human use shall bear a label with the statement ''Caution: New Drug --
Limited by Federal (or United States) law to investigational use.''
(b) The label or labeling of an investigational new drug shall not
bear any statement that is false or misleading in any particular and
shall not represent that the investigational new drug is safe or
effective for the purposes for which it is being investigated.
21 CFR 312.7 Promotion and charging for investigational drugs.
(a) Promotion of an investigational new drug. A sponsor or
investigator, or any person acting on behalf of a sponsor or
investigator, shall not represent in a promotional context that an
investigational new drug is safe or effective for the purposes for which
it is under investigation or otherwise promote the drug. This provision
is not intended to restrict the full exchange of scientific information
concerning the drug, including dissemination of scientific findings in
scientific or lay media. Rather, its intent is to restrict promotional
claims of safety or effectiveness of the drug for a use for which it is
under investigation and to preclude commercialization of the drug before
it is approved for commercial distribution.
(b) Commercial distribution of an investigational new drug. A
sponsor or investigator shall not commercially distribute or test market
an investigational new drug.
(c) Prolonging an investigation. A sponsor shall not unduly prolong
an investigation after finding that the results of the investigation
appear to establish sufficient data to support a marketing application.
(d) Charging for and commercialization of investigational drugs --
(1) Clinical trials under an IND. Charging for an investigational drug
in a clinical trial under an IND is not permitted without the prior
written approval of FDA. In requesting such approval, the sponsor shall
provide a full written explanation of why charging is necessary in order
for the sponsor to undertake or continue the clinical trial, e.g., why
distribution of the drug to test subjects should not be considered part
of the normal cost of doing business.
(2) Treatment protocol or treatment IND. A sponsor or investigator
may charge for an investigational drug for a treatment use under a
treatment protocol or treatment IND provided: (i) There is adequate
enrollment in the ongoing clinical investigations under the authorized
IND; (ii) charging does not constitute commercial marketing of a new
drug for which a marketing application has not been approved; (iii) the
drug is not being commercially promoted or advertised; and (iv) the
sponsor of the drug is actively pursuing marketing approval with due
diligence. FDA must be notified in writing in advance of commencing any
such charges, in an information amendment submitted under 312.31.
Authorization for charging goes into effect automatically 30 days after
receipt by FDA of the information amendment, unless the sponsor is
notified to the contrary.
(3) Noncommercialization of investigational drug. Under this
section, the sponsor may not commercialize an investigational drug by
charging a price larger than that necessary to recover costs of
manufacture, research, development, and handling of the investigational
drug.
(4) Withdrawal of authorization. Authorization to charge for an
investigational drug under this section may be withdrawn by FDA if the
agency finds that the conditions underlying the authorization are no
longer satisfied.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987)
21 CFR 312.10 Waivers.
(a) A sponsor may request FDA to waive applicable requirement under
this part. A waiver request may be submitted either in an IND or in an
information amendment to an IND. In an emergency, a request may be made
by telephone or other rapid communication means. A waiver request is
required to contain at least one of the following:
(1) An explanation why the sponsor's compliance with the requirement
is unnecessary or cannot be achieved;
(2) A description of an alternative submission or course of action
that satisfies the purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds that the sponsor's
noncompliance would not pose a significant and unreasonable risk to
human subjects of the investigation and that one of the following is
met:
(1) The sponsor's compliance with the requirement is unnecessary for
the agency to evaluate the application, or compliance cannot be
achieved;
(2) The sponsor's proposed alternative satisfies the requirement; or
(3) The applicant's submission otherwise justifies a waiver.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.10 Subpart B -- Investigational New Drug Application (IND)
21 CFR 312.20 Requirement for an IND.
(a) A sponsor shall submit an IND to FDA if the sponsor intends to
conduct a clinical investigation with an investigational new drug that
is subject to 312.2(a).
(b) A sponsor shall not begin a clinical investigation subject to
312.2(a) until the investigation is subject to an IND which is in effect
in accordance with 312.40.
21 CFR 312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation.
The clinical investigation of a previously untested drug is generally
divided into three phases. Although in general the phases are conducted
sequentially, they may overlap. These three phases of an investigation
are a follows:
(a) Phase 1. (1) Phase 1 includes the initial introduction of an
investigational new drug into humans. Phase 1 studies are typically
closely monitored and may be conducted in patients or normal volunteer
subjects. These studies are designed to determine the metabolism and
pharmacologic actions of the drug in humans, the side effects associated
with increasing doses, and, if possible, to gain early evidence on
effectiveness. During Phase 1, sufficient information about the drug's
pharmacokinetics and pharmacological effects should be obtained to
permit the design of well-controlled, scientifically valid, Phase 2
studies. The total number of subjects and patients included in Phase 1
studies varies with the drug, but is generally in the range of 20 to 80.
(2) Phase 1 studies also include studies of drug metabolism,
structure-activity relationships, and mechanism of action in humans, as
well as studies in which investigational drugs are used as research
tools to explore biological phenomena or disease processes.
(b) Phase 2. Phase 2 includes the controlled clinical studies
conducted to evaluate the effectiveness of the drug for a particular
indication or indications in patients with the disease or condition
under study and to determine the common short-term side effects and
risks associated with the drug. Phase 2 studies are typically well
controlled, closely monitored, and conducted in a relatively small
number of patients, usually involving no more than several hundred
subjects.
(c) Phase 3. Phase 3 studies are expanded controlled and
uncontrolled trials. They are performed after preliminary evidence
suggesting effectiveness of the drug has been obtained, and are intended
to gather the additional information about effectiveness and safety that
is needed to evaluate the overall benefit-risk relationship of the drug
and to provide an adequate basis for physician labeling. Phase 3
studies usually include from several hundred to several thousand
subjects.
21 CFR 312.22 General principles of the IND submission.
(a) FDA's primary objectives in reviewing an IND are, in all phases
of the investigation, to assure the safety and rights of subjects, and,
in Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the drug's
effectiveness and safety. Therefore, although FDA's review of Phase 1
submissions will focus on assessing the safety of Phase 1
investigations, FDA's review of Phases 2 and 3 submissions will also
include an assessment of the scientific quality of the clinical
investigations and the likelihood that the investigations will yield
data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be
submitted in an IND to assure the accomplishment of the objectives
described in paragraph (a) of this section depends upon such factors as
the novelty of the drug, the extent to which it has been studied
previously, the known or suspected risks, and the developmental phase of
the drug.
(c) The central focus of the initial IND submission should be on the
general investigational plan and the protocols for specific human
studies. Subsequent amendments to the IND that contain new or revised
protocols should build logically on previous submissions and should be
supported by additional information, including the results of animal
toxicology studies or other human studies as appropriate. Annual
reports to the IND should serve as the focus for reporting the status of
studies being conducted under the IND and should update the general
investigational plan for the coming year.
(d) The IND format set forth in 312.23 should be followed routinely
by sponsors in the interest of fostering an efficient review of
applications. Sponsors are expected to exercise considerable
discretion, however, regarding the content of information submitted in
each section, depending upon the kind of drug being studied and the
nature of the available information. Section 312.23 outlines the
information needed for a commercially sponsored IND for a new molecular
entity. A sponsor-investigator who uses, as a research tool, an
investigational new drug that is already subject to a manufacturer's IND
or marketing application should follow the same general format, but
ordinarily may, if authorized by the manufacturer, refer to the
manufacturer's IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A
sponsor-investigator who uses an investigational drug not subject to a
manufacturer's IND or marketing application is ordinarily required to
submit all technical information supporting the IND, unless such
information may be referenced from the scientific literature.
21 CFR 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject
to this part shall submit an ''Investigational New Drug Application''
(IND) including, in the following order:
(1) Cover sheet (Form FDA-1571). A cover sheet for the application
containing the following:
(i) The name, address, and telephone number of the sponsor, the date
of the application, and the name of the investigational new drug.
(ii) Identification of the phase or phases of the clinical
investigation to be conducted.
(iii) A commitment not to begin clinical investigations until an IND
covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that
complies with the requirements set forth in Part 56 will be responsible
for the initial and continuing review and approval of each of the
studies in the proposed clinical investigation and that the investigator
will report to the IRB proposed changes in the research activity in
accordance with the requirements of Part 56.
(v) A commitment to conduct the investigation in accordance with all
other applicable regulatory requirements.
(vi) The name and title of the person responsible for monitoring the
conduct and progress of the clinical investigations.
(vii) The name(s) and title(s) of the person(s) responsible under
312.32 for review and evaluation of information relevant to the safety
of the drug.
(viii) If a sponsor has transferred any obligations for the conduct
of any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer -- in lieu of a
listing of the specific obligations transferred -- may be submitted.
(ix) The signature of the sponsor or the sponsor's authorized
representative. If the person signing the application does not reside
or have a place of business within the United States, the IND is
required to contain the name and address of, and be countersigned by, an
attorney, agent, or other authorized official who resides or maintains a
place of business within the United States.
(2) A table of contents.
(3) Introductory statement and general investigational plan. (i) A
brief introductory statement giving the name of the drug and all active
ingredients, the drug's pharmacological class, the structural formula of
the drug (if known), the formulation of the dosage form(s) to be used,
the route of administration, and the broad objectives and planned
duration of the proposed clinical investigation(s).
(ii) A brief summary of previous human experience with the drug, with
reference to other IND's if pertinent, and to investigational or
marketing experience in other countries that may be relevant to the
safety of the proposed clinical investigation(s).
(iii) If the drug has been withdrawn from investigation or marketing
in any country for any reason related to safety or effectiveness,
identification of the country(ies) where the drug was withdrawn and the
reasons for the withdrawal.
(iv) A brief description of the overall plan for investigating the
drug product for the following year. The plan should include the
following: (a) The rationale for the drug or the research study; (b)
the indication(s) to be studied; (c) the general approach to be
followed in evaluating the drug; (d) the kinds of clinical trials to be
conducted in the first year following the submission (if plans are not
developed for the entire year, the sponsor should so indicate); (e) the
estimated number of patients to be given the drug in those studies; and
(f) any risks of particular severity or seriousness anticipated on the
basis of the toxicological data in animals or prior studies in humans
with the drug or related drugs.
(4) (Reserved)
(5) Investigator's brochure. If required under 312.55, a copy of
the investigator's brochure, containing the following information:
(i) A brief description of the drug substance and the formulation,
including the structural formula, if known.
(ii) A summary of the pharmacological and toxicological effects of
the drug in animals and, to the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition of
the drug in animals and, if known, in humans.
(iv) A summary of information relating to safety and effectiveness in
humans obtained from prior clinical studies. (Reprints of published
articles on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be
anticipated on the basis of prior experience with the drug under
investigation or with related drugs, and of precautions or special
monitoring to be done as part of the investigational use of the drug.
(6) Protocols. (i) A protocol for each planned study. (Protocols
for studies not submitted initially in the IND should be submitted in
accordance with 312.30(a).) In general, protocols for Phase 1 studies
may be less detailed and more flexible than protocols for Phase 2 and 3
studies. Phase 1 protocols should be directed primarily at providing an
outline of the investigation -- an estimate of the number of patients to
be involved, a description of safety exclusions, and a description of
the dosing plan including duration, dose, or method to be used in
determining dose -- and should specify in detail only those elements of
the study that are critical to safety, such as necessary monitoring of
vital signs and blood chemistries. Modifications of the experimental
design of Phase 1 studies that do not affect critical safety assessments
are required to be reported to FDA only in the annual report.
(ii) In Phases 2 and 3, detailed protocols describing all aspects of
the study should be submitted. A protocol for a Phase 2 or 3
investigation should be designed in such a way that, if the sponsor
anticipates that some deviation from the study design may become
necessary as the investigation progresses, alternatives or contingencies
to provide for such deviation are built into the protocols at the
outset. For example, a protocol for a controlled short-term study might
include a plan for an early crossover of nonresponders to an alternative
therapy.
(iii) A protocol is required to contain the following, with the
specific elements and detail of the protocol reflecting the above
distinctions depending on the phase of study:
(a) A statement of the objectives and purpose of the study.
(b) The name and address and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each
investigator, and the name of each subinvestigator (e.g., research
fellow, resident) working under the supervision of the investigator;
the name and address of the research facilities to be used; and the
name and address of each reviewing Institutional Review Board.
(c) The criteria for patient selection and for exclusion of patients
and an estimate of the number of patients to be studied.
(d) A description of the design of the study, including the kind of
control group to be used, if any, and a description of methods to be
used to minimize bias on the part of subjects, investigators, and
analysts.
(e) The method for determining the dose(s) to be administered, the
planned maximum dosage, and the duration of individual patient exposure
to the drug.
(f) A description of the observations and measurements to be made to
fulfill the objectives of the study.
(g) A description of clinical procedures, laboratory tests, or other
measures to be taken to monitor the effects of the drug in human
subjects and to minimize risk.
(7) Chemistry, manufacturing, and control information. (i) As
appropriate for the particular investigations covered by the IND, a
section describing the composition, manufacture, and control of the drug
substance and the drug product. Although in each phase of the
investigation sufficient information is required to be submitted to
assure the proper identification, quality, purity, and strength of the
investigational drug, the amount of information needed to make that
assurance will vary with the phase of the investigation, the proposed
duration of the investigation, the dosage form, and the amount of
information otherwise available. FDA recognizes that modifications to
the method of preparation of the new drug substance and dosage form and
changes in the dosage form itself are likely as the investigation
progresses. Therefore, the emphasis in an initial Phase 1 submission
should generally be placed on the identification and control of the raw
materials and the new drug substance. Final specifications for the drug
substance and drug product are not expected until the end of the
investigational process.
(ii) It should be emphasized that the amount of information to be
submitted depends upon the scope of the proposed clinical investigation.
For example, although stability data are required in all phases of the
IND to demonstrate that the new drug substance and drug product are
within acceptable chemical and physical limits for the planned duration
of the proposed clinical investigation, if very short-term tests are
proposed, the supporting stability data can be correspondingly limited.
(iii) As drug development proceeds and as the scale or production is
changed from the pilot-scale production appropriate for the limited
initial clinical investigations to the larger-scale production needed
for expanded clinical trials, the sponsor should submit information
amendments to supplement the initial information submitted on the
chemistry, manufacturing, and control processes with information
appropriate to the expanded scope of the investigation.
(iv) Reflecting the distinctions described in this paragraph (a)(7),
and based on the phase(s) to be studied, the submission is required to
contain the following:
(a) Drug substance. A description of the drug substance, including
its physical, chemical, or biological characteristics; the name and
address of its manufacturer; the general method of preparation of the
drug substance; the acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the drug
substance; and information sufficient to support stability of the drug
substance during the toxicological studies and the planned clinical
studies. Reference to the current edition of the United States
Pharmacopeia -- National Formulary may satisfy relevant requirements in
this paragraph.
(b) Drug product. A list of all components, which may include
reasonable alternatives for inactive compounds, used in the manufacture
of the investigational drug product, including both those components
intended to appear in the drug product and those which may not appear
but which are used in the manufacturing process, and, where applicable,
the quantitative composition of the investigational drug product,
including any reasonable variations that may be expected during the
investigational stage; the name and address of the drug product
manufacturer; a brief general description of the manufacturing and
packaging procedure as appropriate for the product; the acceptable
limits and analytical methods used to assure the identity, strength,
quality, and purity of the drug product; and information sufficient to
assure the product's stability during the planned clinical studies.
Reference to the current edition of the United States Pharmacopeia --
National Formulary may satisfy certain requirements in this paragraph.
(c) A brief general description of the composition, manufacture, and
control of any placebo used in a controlled clinical trial.
(d) Labeling. A copy of all labels and labeling to be provided to
each investigator.
(e) Environmental analysis requirements. A claim for categorical
exclusion under 25.24 or an environmental assessment under 25.31.
(8) Pharmacology and toxicology information. Adequate information
about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has
concluded that it is reasonably safe to conduct the proposed clinical
investigations. The kind, duration, and scope of animal and other tests
required varies with the duration and nature of the proposed clinical
investigations. Guidelines are available from FDA that describe ways in
which these requirements may be met. Such information is required to
include the identification and qualifications of the individuals who
evaluated the results of such studies and concluded that it is
reasonably safe to begin the proposed investigations and a statement of
where the investigations were conducted and where the records are
available for inspection. As drug development proceeds, the sponsor is
required to submit informational amendments, as appropriate, with
additional information pertinent to safety.
(i) Pharmacology and drug disposition. A section describing the
pharmacological effects and mechanism(s) of action of the drug in
animals, and information on the absorption, distribution, metabolism,
and excretion of the drug, if known.
(ii) Toxicology. (a) An integrated summary of the toxicological
effects of the drug in animals and in vitro. Depending on the nature of
the drug and the phase of the investigation, the description is to
include the results of acute, subacute, and chronic toxicity tests;
tests of the drug's effects on reproduction and the developing fetus;
any special toxicity test related to the drug's particular mode of
administration or conditions of use (e.g., inhalation, dermal, or ocular
toxicology); and any in vitro studies intended to evaluate drug
toxicity.
(b) For each toxicology study that is intended primarily to support
the safety of the proposed clinical investigation, a full tabulation of
data suitable for detailed review.
(iii) For each nonclinical laboratory study subject to the good
laboratory practice regulations under Part 58, a statement that the
study was conducted in compliance with the good laboratory practice
regulations in Part 58, or, if the study was not conducted in compliance
with those regulations, a brief statement of the reason for the
noncompliance.
(9) Previous human experience with the investigational drug. A
summary of previous human experience known to the applicant, if any,
with the investigational drug. The information is required to include
the following:
(i) If the investigational drug has been investigated or marketed
previously, either in the United States or other countries, detailed
information about such experience that is relevant to the safety of the
proposed investigation or to the investigation's rationale. If the durg
has been the subject of controlled trials, detailed information on such
trials that is relevant to an assessment of the drug's effectiveness for
the proposed investigational use(s) should also be provided. Any
published material that is relevant to the safety of the proposed
investigation or to an assessment of the drug's effectiveness for its
proposed investigational use should be provided in full. Published
material that is less directly relevant may be supplied by a
bibliography.
(ii) If the drug is a combination of drugs previously investigated or
marketed, the information required under paragraph (a)(9)(i) of this
section should be provided for each active drug component. However, if
any component in such combination is subject to an approved marketing
application or is otherwise lawfully marketed in the United States, the
sponsor is not required to submit published material concerning that
active drug component unless such material relates directly to the
proposed investigational use (including publications relevant to
component-component interaction).
(iii) If the drug has been marketed outside the United States, a list
of the countries in which the drug has been marketed and a list of the
countries in which the drug has been withdrawn from marketing for
reasons potentially related to safety or effectiveness.
(10) Additional information. In certain applications, as described
below, information on special topics may be needed. Such information
shall be submitted in this section as follows:
(i) Drug dependence and abuse potential. If the drug is a
psychotropic substance or otherwise has abuse potential, a section
describing relevant clinical studies and experience and studies in test
animals.
(ii) Radioactive drugs. If the drug is a radioactive drug,
sufficient data from animal or human studies to allow a reasonable
calculation of radiation-absorbed dose to the whole body and critical
organs upon administration to a human subject. Phase 1 studies of
radioactive drugs must include studies which will obtain sufficient data
for dosimetry calculations.
(iii) Other information. A brief statement of any other information
that would aid evaluation of the proposed clinical investigations with
respect to their safety or their design and potential as controlled
clinical trials to support marketing of the drug.
(11) Relevant information. If requested by FDA, any other relevant
information needed for review of the application.
(b) Information previously submitted. The sponsor ordinarily is not
required to resubmit information previously submitted, but may
incorporate the information by reference. A reference to information
submitted previously must identify the file by name, reference number,
volume, and page number where the information can be found. A reference
to information submitted to the agency by a person other than the
sponsor is required to contain a written statement that authorizes the
reference and that is signed by the person who submitted the
information.
(c) Material in a foreign language. The sponsor shall submit an
accurate and complete English translation of each part of the IND that
is not in English. The sponsor shall also submit a copy of each
original literature publication for which an English translation is
submitted.
(d) Number of copies. The sponsor shall submit an original and two
copies of all submissions to the IND file, including the original
submission and all amendments and reports.
(e) Numbering of IND submissions. Each submission relating to an IND
is required to be numbered serially using a single, three-digit serial
number. The initial IND is required to be numbered 000; each
subsequent submission (e.g., amendment, report, or correspondence) is
required to be numbered chronologically in sequence.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988)
21 CFR 312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to
ensure that the clinical investigations are conducted according to
protocols included in the application. This section sets forth the
provisions under which new protocols may be submitted and changes in
previously submitted protocols may be made.
(a) New protocol. Whenever a sponsor intends to conduct a study that
is not covered by a protocol already contained in the IND, the sponsor
shall submit to FDA a protocol amendment containing the protocol for the
study. Such study may begin provided two conditions are met: (1) The
sponsor has submitted the protocol to FDA for its review; and (2) the
protocol has been approved by the Institutional Review Board (IRB) with
responsibility for review and approval of the study in accordance with
the requirements of Part 56. The sponsor may comply with these two
conditions in either order.
(b) Changes in a protocol. (1) A sponsor shall submit a protocol
amendment describing any change in a Phase 1 protocol that significantly
affects the safety of subjects or any change in a Phase 2 or 3 protocol
that significantly affects the safety of subjects, the scope of the
investigation, or the scientific quality of the study. Examples of
changes requiring an amendment under this paragraph include:
(i) Any increase in drug dosage or duration of exposure of individual
subjects to the drug beyond that in the current protocol, or any
significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse
event; or the dropping of a test intended to monitor safety.
(2)(i) A protocol change under paragraph (b)(1) of this section may
be made provided two conditions are met:
(a) The sponsor has submitted the change to FDA for its review; and
(b) The change has been approved by the IRB with responsibility for
review and approval of the study. The sponsor may comply with these two
conditions in either order.
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing IRB is notified in accordance with
56.104(c).
(c) New investigator. A sponsor shall submit a protocol amendment
when a new investigator is added to carry out a previously submitted
protocol, except that a protocol amendment is not required when a
licensed practitioner is added in the case of a treatment protocol under
312.34. Once the investigator is added to the study, the
investigational drug may be shipped to the investigator and the
investigator may begin participating in the study. The sponsor shall
notify FDA of the new investigator within 30 days of the investigator
being added.
(d) Content and format. A protocol amendment is required to be
prominently identified as such (i.e., ''Protocol Amendment: New
Protocol'', ''Protocol Amendment: Change in Protocol'', or ''Protocol
Amendment: New Investigator''), and to contain the following:
(1)(i) In the case of a new protocol, a copy of the new protocol and
a brief description of the most clinically significant differences
between it and previous protocols.
(ii) In the case of a change in protocol, a brief description of the
change and reference (date and number) to the submission that contained
the protocol.
(iii) In the case of a new investigator, the investigator's name, the
qualifications to conduct the investigation, reference to the previously
submitted protocol, and all additional information about the
investigator's study as is required under 312.23(a)(6)(iii)(b).
(2) Reference, if necessary, to specific technical information in the
IND or in a concurrently submitted information amendment to the IND that
the sponsor relies on to support any clinically significant change in
the new or amended protocol. If the reference is made to supporting
information already in the IND, the sponsor shall identify by name,
reference number, volume, and page number the location of the
information.
(3) If the sponsor desires FDA to comment on the submission, a
request for such comment and the specific questions FDA's response
should address.
(e) When submitted. A sponsor shall submit a protocol amendment for
a new protocol or a change in protocol before its implementation.
Protocol amendments to add a new investigator or to provide additional
information about investigators may be grouped and submitted at 30-day
intervals. When several submissions of new protocols or protocol
changes are anticipated during a short period, the sponsor is
encouraged, to the extent feasible, to include these all in a single
submission.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988)
21 CFR 312.31 Information amendments.
(a) Requirement for information amendment. A sponsor shall report in
an information amendment essential information on the IND that is not
within the scope of a protocol amendment, IND safety reports, or annual
report. Examples of information requiring an information amendment
include:
(1) New toxicology, chemistry, or other technical information; or
(2) A report regarding the discontinuance of a clinical
investigation.
(b) Content and format of an information amendment. An information
amendment is required to bear prominent identification of its contents
(e.g., ''Information Amendment: Chemistry, Manufacturing, and
Control'', ''Information Amendment: Pharmacology-Toxicology'',
''Information Amendment: Clinical''), and to contain the following:
(1) A statement of the nature and purpose of the amendment.
(2) An organized submission of the data in a format appropriate for
scientific review.
(3) If the sponsor desires FDA to comment on an information
amendment, a request for such comment.
(c) When submitted. Information amendments to the IND should be
submitted as necessary but, to the extent feasible, not more than every
30 days.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988)
21 CFR 312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this
section:
Associated with the use of the drug means that there is a reasonable
possibility that the experience may have been caused by the drug.
Serious adverse experience means any experience that suggests a
significant hazard, contraindication, side effect, or precaution. With
respect to human clinical experience, a serious adverse drug experience
includes any experience that is fatal or life-threatening, is
permanently disabling, requires inpatient hospitalization, or is a
congenital anomaly, cancer, or overdose. With respect to results
obtained from tests in laboratory animals, a serious adverse drug
experience includes any experience suggesting a significant risk for
human subjects, including any finding of mutagenicity, teratogenicity,
or carcinogenicity.
Unexpected adverse experience means any adverse experience that is
not identified in nature, severity, or frequency in the current
investigator brochure; or, if an investigator brochure is not required,
that is not identified in nature, severity, or freuquency in the risk
information described in the general investigational plan or elsewhere
in the current application, as amended.
(b) Review of safety information. The sponsor shall promptly review
all information relevant to the safety of the drug obtained or otherwise
received by the sponsor from any source, foreign or domestic, including
information derived from clinical investigations, animal investigations,
commercial marketing experience, reports in the scientific literature,
and unpublished scientific papers.
(c) IND safety reports. (1)(i) Written reports. The sponsor shall
notify FDA and all participating investigators in a written IND safety
report of any adverse experience associated with use of the drug that is
both serious and unexpected. Such notification shall be made as soon as
possible and in no event later than 10 working days after the sponsor's
initial receipt of the information. Each written notification shall
bear prominent identification of its contents, i.e., ''IND Safety
Report.'' Each written notification to FDA shall be transmitted to the
FDA division of the Center for Drug Evaluation and Research or the
Center for Biologics Evaluation and Research which has responsibility
for review of the IND.
(ii) In each written IND safety report, the sponsor shall identify
all safety reports previously filed with the IND concerning a similar
adverse experience, and shall analyze the significance of the adverse
experience in light of the previouos, similar reports.
(2) Telephone report. The sponsor shall also notify FDA by telephone
of any unexpected fatal or life-threatening experience associated with
use of the drug in the clinical studies conducted under the IND no later
than 3 working days after receipt of the information. Each telephone
call to FDA shall be transmitted to the FDA division of the Center for
Drug Evaluation and Research or the Center for Biologics Evaluation and
Research which has responsibility for review of the IND. For purposes
of this section, life-threatening means that the patient was, in the
view of the investigator, at immediate (emphasis added) risk of death
from the reaction as it occurred, i.e., it does not include a reaction
that, had it occurred in a more serious form, might have caused death.
For example, drug-induced hepatitis that resolved without evidence of
hepatic failure would not be considered life-threatening even though
drug-induced hepatitis can be fatal.
(3) Reporting format or frequency. FDA may request a sponsor to
submit IND safety reports in a format or at a frequency different than
that required under this paragraph. The sponsor may also propose and
adopt a different reporting format or frequency if the change is agreed
to in advance by the director of the division in the Center for Drug
Evaluation and Research or the Center for Biologics Evaluation and
Research which is responsible for review of the IND.
(4) A sponsor of a clinical study of a marketed drug is not required
to make a safety report for any adverse experience associated with use
of the drug that is not from the clinical study itself.
(d) Followup. (1) The sponsor shall promptly investigate all safety
information received by it.
(2) Followup information to a safety report shall be submitted as
soon as the relevant information is available.
(3) If the results of a sponsor's investigation show that an adverse
experience not initially determined to be reportable under paragraph (c)
of this section is so reportable, the sponsor shall report such
experience in a safety report as soon as possible after the
determination is made, but in no event longer than 10-working days.
(4) Results of a sponsor's investigation of other safety information
shall be submitted, as appropriate, in an information amendment or
annual report.
(e) Disclaimer. A safety report or other information submitted by a
sponsor under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the sponsor or
FDA that the report or information constitutes an admission that the
drug caused or contributed to an adverse experience. A sponsor need not
admit, and may deny, that the report or information submitted by the
sponsor constitutes an admission that the drug caused or contributed to
an adverse experience.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990)
21 CFR 312.33 Annual reports.
A sponsor shall within 60 days of the anniversary date that the IND
went into effect, submit a brief report of the progress of the
investigation that includes:
(a) Individual study information. A brief summary of the status of
each study in progress and each study completed during the previous
year. The summary is required to include the following information for
each study:
(1) The title of the study (with any appropriate study identifiers
such as protocol number), its purpose, a brief statement identifying the
patient population, and a statement as to whether the study is
completed.
(2) The total number of subjects initially planned for inclusion in
the study, the number entered into the study to date, the number whose
participation in the study was completed as planned, and the number who
dropped out of the study for any reason.
(3) If the study has been completed, or if interim results are known,
a brief description of any available study results.
(b) Summary information. Information obtained during the previous
year's clinical and nonclinical investigations, including:
(1) A narrative or tabular summary showing the most frequent and most
serious adverse experiences by body system.
(2) A summary of all IND safety reports submitted during the past
year.
(3) A list of subjects who died during participation in the
investigation, with the cause of death for each subject.
(4) A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or not
thought to be drug related.
(5) A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug's actions, including, for
example, information about dose response, information from controlled
trails, and information about bioavailability.
(6) A list of the preclinical studies (including animal studies)
completed or in progress during the past year and a summary of the major
preclinical findings.
(7) A summary of any significant manufacturing or microbiological
changes made during the past year.
(c) A description of the general investigational plan for the coming
year to replace that submitted 1 year earlier. The general
investigational plan shall contain the information required under
312.23(a)(3)(iv).
(d) If the investigator brochure has been revised, a description of
the revision and a copy of the new brochure.
(e) A description of any significant Phase 1 protocol modifications
made during the previous year and not previously reported to the IND in
a protocol amendment.
(f) A brief summary of significant foreign marketing developments
with the drug during the past year, such as approval of marketing in any
country or withdrawal or suspension from marketing in any country.
(g) If desired by the sponsor, a log of any outstanding business with
respect to the IND for which the sponsor requests or expects a reply,
comment, or meeting.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.34 Treatment use of an investigational new drug.
(a) General. A drug that is not approved for marketing may be under
clinical investigation for a serious or immediately life-threatening
disease condition in patients for whom no comparable or satisfactory
alternative drug or other therapy is available. During the clinical
investigation of the drug, it may be appropriate to use the drug in the
treatment of patients not in the clinical trials, in accordance with a
treatment protocol or treatment IND. The purpose of this section is to
facilitate the availability of promising new drugs to desperately ill
patients as early in the drug development process as possible, before
general marketing begins, and to obtain additional data on the drug's
safety and effectiveness. In the case of a serious disease, a drug
ordinarily may be made available for treatment use under this section
during Phase 3 investigations or after all clinical trials have been
completed; however, in appropriate circumstances, a drug may be made
available for treatment use during Phase 2. In the case of an
immediately life-threatening disease, a drug may be made available for
treatment use under this section earlier than Phase 3, but ordinarily
not earlier than Phase 2. For purposes of this section, the ''treatment
use'' of a drug includes the use of a drug for diagnostic purposes.
(b) Criteria. (1) FDA shall permit an investigational drug to be
used for a treatment use under a treatment protocol or treatment IND if:
(i) The drug is intended to treat a serious or immediately
life-threatening disease;
(ii) There is no comparable or satisfactory alternative drug or other
therapy available to treat that stage of the disease in the intended
patient population;
(iii) The drug is under investigation in a controlled clinical trial
under an IND in effect for the trial, or all clinical trials have been
completed; and
(iv) The sponsor of the controlled clinical trial is actively
pursuing marketing approval of the investigational drug with due
diligence.
(2) Serious disease. For a drug intended to treat a serious disease,
the Commissioner may deny a request for treatment use under a treatment
protocol or treatment IND if there is insufficient evidence of safety
and effectiveness to support such use.
(3) Immediately life-threatening disease. (i) For a drug intended to
treat an immediately life-threatening disease, the Commissioner may deny
a request for treatment use of an investigational drug under a treatment
protocol or treatment IND if the available scientific evidence, taken as
a whole, fails to provide a reasonable basis for concluding that the
drug:
(A) May be effective for its intended use in its intended patient
population; or
(B) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of
illness or injury.
(ii) For the purpose of this section, an ''immediately
life-threatening'' disease means a stage of a disease in which there is
a reasonable likelihood that death will occur within a matter of months
or in which premature death is likely without early treatment.
(c) Safeguards. Treatment use of an investigational drug is
conditioned on the sponsor and investigators complying with the
safeguards of the IND process, including the regulations governing
informed consent (21 CFR Part 50) and institutional review boards (21
CFR Part 56) and the applicable provisions of Part 312, including
distribution of the drug through qualified experts, maintenance of
adequate manufacturing facilities, and submission of IND safety reports.
(d) Clinical hold. FDA may place on clinical hold a proposed or
ongoing treatment protocol or treatment IND in accordance with 312.42.
(52 FR 19476, May 22, 1987)
21 CFR 312.35 Submissions for treatment use.
(a) Treatment protocol submitted by IND sponsor. A sponsor of a
clinical investigation of a drug who intends to sponsor a treatment use
for the drug under 312.34 shall submit to FDA a treatment protocol. A
treatment use under a treatment protocol may begin 30 days after FDA
receives the protocol or on earlier notification by FDA that the
treatment use described in the protocol may begin.
(1) A treatment protocol is required to contain the following:
(i) The intended use of the drug.
(ii) An explanation of the rationale for use of the drug, including,
as appropriate, either a list of what available regimens ordinarily
should be tried before using the investigational drug or an explanation
of why the use of the investigational drug is preferable to the use of
available marketed treatments.
(iii) A brief description of the criteria for patient selection.
(iv) The method of administration of the drug and the dosages.
(v) A description of clinical procedures, laboratory tests, or other
measures to monitor the effects of the drug and to minimize risk.
(2) A treatment protocol is to be supported by the following:
(i) Informational brochure for supplying to each treating physician.
(ii) The technical information that is relevant to safety and
effectiveness of the drug for the intended treatment purpose.
Information contained in the sponsor's IND may be incorporated by
reference.
(iii) A commitment by the sponsor to assure compliance of all
participating investigators with the informed consent requirements of 21
CFR Part 50.
(3) A licensed practioner who receives an investigational drug for
treatment use under a treatment protocol is an ''investigator'' under
the protocol and is responsible for meeting all applicable investigator
responsibilities under this part and 21 CFR Parts 50 and 56.
(b) Treatment IND submitted by licensed practitioner. (1) If a
licensed medical practitioner wants to obtain an investigational drug
subject to a controlled clinical trial for a treatment use, the
practitioner should first attempt to obtain the drug from the sponsor of
the controlled trial under a treatment protocol. If the sponsor of the
controlled clinical investigation of the drug will not establish a
treatment protocol for the drug under paragraph (a) of this section, the
licensed medical practitioner may seek to obtain the drug from the
sponsor and submit a treatment IND to FDA requesting authorization to
use the investigational drug for treatment use. A treatment use under a
treatment IND may begin 30 days after FDA receives the IND or on earlier
notification by FDA that the treatment use under the IND may begin. A
treatment IND is required to contain the following:
(i) A cover sheet (Form FDA 1571) meeting 312.23(g)(1).
(ii) Information (when not provided by the sponsor) on the drug's
chemistry, manufacturing, and controls, and prior clinical and
nonclinical experience with the drug submitted in accordance with
312.23. A sponsor of a clinical investigation subject to an IND who
supplies an investigational drug to a licensed medical practitioner for
purposes of a separate treatment clinical investigation shall be deemed
to authorize the incorporation-by-reference of the technical information
contained in the sponsor's IND into the medical practitioner's treatment
IND.
(iii) A statement of the steps taken by the practitioner to obtain
the drug under a treatment protocol from the drug sponsor.
(iv) A treatment protocol containing the same information listed in
paragraph (a)(1) of this section.
(v) A statement of the practitioner's qualifications to use the
investigational drug for the intended treatment use.
(vi) The practitioner's statement of familiarity with information on
the drug's safety and effectiveness derived from previous clinical and
nonclinical experience with the drug.
(vii) Agreement to report to FDA safety information in accordance
with 312.32.
(2) A licensed practitioner who submits a treatment IND under this
section is the sponsor-investigator for such IND and is responsible for
meeting all applicable sponsor and investigator responsibilities under
this part and 21 CFR Parts 50 and 56.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 19477, May 22, 1987)
21 CFR 312.36 Emergency use of an investigational new drug.
Need for an investigational drug may arise in an emergency situation
that does not allow time for submission of an IND in accordance with
312.23 or 312.34. In such a case, FDA may authorize shipment of the
drug for a specified use in advance of submission of an IND. A request
for such authorization may be transmitted to FDA by telephone or other
rapid communication means. For investigational biological drugs, the
request should be directed to the Division of Biological Investigational
New Drugs (HFB-230), Center for Biologics Evaluation and Research, 8800
Rockville Pike, Bethesda, MD 20892, 301-443-4864. For all other
investigational drugs, the request for authorization should be directed
to the Document Management and Reporting Branch (HFD-53), Center for
Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857,
301-443-4320. After normal working hours, eastern standard time, the
request should be directed to the FDA Division of Emergency and
Epidemiological Operations, 202-857-8400. Except in extraordinary
circumstances, such authorization will be conditioned on the sponsor
making an appropriate IND submission as soon as practicable after
receiving the authorization.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990)
21 CFR 312.38 Withdrawal of an IND.
(a) At any time a sponsor may withdraw an effective IND without
prejudice.
(b) If an IND is withdrawn, FDA shall be so notified, all clinical
investigations conducted under the IND shall be ended, all current
investigators notified, and all stocks of the drug returned to the
sponsor or otherwise disposed of at the request of the sponsor in
accordance with 312.59.
(c) If an IND is withdrawn because of a safety reason, the sponsor
shall promptly so inform FDA, all participating investigators, and all
reviewing Institutional Review Boards, together with the reasons for
such withdrawal.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.38 Subpart C -- Administrative Actions
21 CFR 312.40 General requirements for use of an investigational new
drug in a clinical investigation.
(a) An investigational new drug may be used in a clinical
investigation if the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to
FDA; the IND is in effect under paragraph (b) of this section; and the
sponsor complies with all applicable requirements in this part and Parts
50 and 56 with respect to the conduct of the clinical investigations;
and
(2) Each participating investigator conducts his or her investigation
in compliance with the requirements of this part and Parts 50 and 56.
(b) An IND goes into effect:
(1) Thirty days after FDA receives the IND, unless FDA notifies the
sponsor that the investigations described in the IND are subject to a
clinical hold under 312.42; or
(2) On earlier notification by FDA that the clinical investigations
in the IND may begin. FDA will notify the sponsor in writing of the
date it receives the IND.
(c) A sponsor may ship an investigational new drug to investigators
named in the IND:
(1) Thirty days after FDA receives the IND; or
(2) On earlier FDA authorization to ship the drug.
(d) An investigator may not administer an investigational new drug to
human subjects until the IND goes into effect under paragraph (b) of
this section.
21 CFR 312.41 Comment and advice on an IND.
(a) FDA may at any time during the course of the investigation
communicate with the sponsor orally or in writing about deficiencies in
the IND or about FDA's need for more data or information.
(b) On the sponsor's request, FDA will provide advice on specific
matters relating to an IND. Examples of such advice may include advice
on the adequacy of technical data to support an investigational plan, on
the design of a clinical trial, and on whether proposed investigations
are likely to produce the data and information that is needed to meet
requirements for a marketing application.
(c) Unless the communication is accompanied by a clinical hold order
under 312.42, FDA communications with a sponsor under this section are
solely advisory and do not require any modification in the planned or
ongoing clinical investigations or response to the agency.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.42 Clinical holds and requests for modification.
(a) General. A clinical hold is an order issued by FDA to the
sponsor to delay a proposed clinical investigation or to suspend an
ongoing investigation. The clinical hold order may apply to one or more
of the investigations covered by an IND. When a proposed study is
placed on clinical hold, subjects may not be given the investigational
drug. When an ongoing study is placed on clinical hold, no new subjects
may be recruited to the study and placed on the investigational drug;
patients already in the study should be taken off therapy involving the
investigational drug unless specifically permitted by FDA in the
interest of patient safety.
(b) Grounds for imposition of clinical hold -- (1) Clinical hold of a
Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1
investigation on clinical hold if it finds that:
(i) Human subjects are or would be exposed to an unreasonable and
significant risk of illness or injury;
(ii) The clinical investigators named in the IND are not qualified by
reason of their scientific training and experience to conduct the
investigation described in the IND;
(iii) The investigator brochure is misleading, erroneous, or
materially incomplete; or
(iv) The IND does not contain sufficient information required under
312.23 to assess the risks to subjects of the proposed studies.
(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may
place a proposed or ongoing Phase 2 or 3 investigation on clinical hold
if it finds that:
(i) Any of the conditions in paragraph (b)(1)(i) through (iv) of this
section apply; or
(ii) The plan or protocol for the investigation is clearly deficient
in design to meet its stated objectives.
(3) Clinical hold of a treatment IND or treatment protocol.
(i) Proposed use. FDA may place a proposed treatment IND or
treatment protocol on clinical hold if it is determined that:
(A) The pertinent criteria in 312.34(b) for permitting the treatment
use to begin are not satisfied; or
(B) The treatment protocol or treatment IND does not contain the
information required under 312.35 (a) or (b) to make the specified
determination under 312.34(b).
(ii) Ongoing use. FDA may place an ongoing treatment protocol or
treatment IND on clinical hold if it is determined that:
(A) There becomes available a comparable or satisfactory alternative
drug or other therapy to treat that stage of the disease in the intended
patient population for which the investigational drug is being used;
(B) The investigational drug is not under investigation in a
controlled clinical trial under an IND in effect for the trial and not
all controlled clinical trials necessary to support a marketing
application have been completed, or a clinical study under the IND has
been placed on clinical hold:
(C) The sponsor of the controlled clinical trial is not pursuing
marketing approval with due diligence;
(D) If the treatment IND or treatment protocol is intended for a
serious disease, there is insufficient evidence of safety and
effectiveness to support such use; or
(E) If the treatment protocol or treatment IND was based on an
immediately life-threatening disease, the available scientific evidence,
taken as a whole, fails to provide a reasonable basis for concluding
that the drug:
(1) May be effective for its intended use in its intended population;
or
(2) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of
illness or injury.
(c) Discussion of deficiency. Whenever FDA concludes that a
deficiency exists in a clinical investigation that may be grounds for
the imposition of clinical hold FDA will, unless patients are exposed to
immediate and serious risk, attempt to discuss and satisfactorily
resolve the matter with the sponsor before issuing the clinical hold
order.
(d) Imposition of clinical hold. The clinical hold order may be made
by telephone or other means of rapid communication or in writing. The
clinical hold order will identify the studies under the IND to which the
hold applies, and will briefly explain the basis for the action. The
clinical hold order will be made by or on behalf of the Division
Director with responsibility for review of the IND. As soon as
possible, and no more than 30 days after imposition of the clinical
hold, the Division Director will provide the sponsor a written
explanation of the basis for the hold.
(e) Resumption of clinical investigations. If, by the terms of the
clinical hold order, resumption of the affected investigation is
permitted without prior notification by FDA once a stated correction or
modification is made, the investigation may proceed as soon as the
correction or modification is made. In all other cases, an
investigation may only resume after the Division Director (or the
Director's designee) with responsibility for review of the IND has
notified the sponsor that the investigation may proceed. In these cases
resumption of the affected investigation(s) will be authorized when the
sponsor corrects the deficiency(ies) previously cited or otherwise
satisfied the agency that the investigation(s) can proceed. Resumption
of a study may be authorized by telephone or other means of rapid
communication.
(f) Appeal. If the sponsor disagrees with the reasons cited for the
clinical hold, the sponsor may request reconsideration of the decision
in accordance with 312.48.
(g) Conversion of IND on clinical hold to inactive status. If all
investigations covered by an IND remain on clinical hold for 1 year or
more, the IND may be placed on inactive status by FDA under 312.45.
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987)
21 CFR 312.44 Termination.
(a) General. This section describes the procedures under which FDA
may terminate an IND. If an IND is terminated, the sponsor shall end
all clinical investigations conducted under the IND and recall or
otherwise provide for the disposition of all unused supplies of the
drug. A termination action may be based on deficiencies in the IND or
in the conduct of an investigation under an IND. Except as provided in
paragraph (d) of this section, a termination shall be preceded by a
proposal to terminate by FDA and an opportunity for the sponsor to
respond. FDA will, in general, only initiate an action under this
section after first attempting to resolve differences informally or,
when appropriate, through the clinical hold procedures described in
312.42.
(b) Grounds for termination -- (1) Phase 1. FDA may propose to
terminate an IND during Phase 1 if it finds that:
(i) Human subjects would be exposed to an unreasonable and
significant risk of illness or unjury.
(ii) The IND does not contain sufficient information required under
312.23 to assess the safety to subjects of the clinical investigations.
(iii) The methods, facilities, and controls used for the
manufacturing, processing, and packing of the investigational drug are
inadequate to establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety.
(iv) The clinical investigations are being conducted in a manner
substantially different than that described in the protocols submitted
in the IND.
(v) The drug is being promoted or distributed for commercial purposes
not justified by the requirements of the investigation or permitted by
312.7.
(vi) The IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material information
required by this part.
(vii) The sponsor fails promptly to investigate and inform the Food
and Drug Administration and all investigators of serious and unexpected
adverse experiences in accordance with 312.32 or fails to make any
other report required under this part.
(viii) The sponsor fails to submit an accurate annual report of the
investigations in accordance with 312.33.
(ix) The sponsor fails to comply with any other applicable
requirement of this part, Part 50, or Part 56.
(x) The IND has remained on inactive status for 5 years or more.
(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2
or Phase 3 if FDA finds that:
(i) Any of the conditions in paragraphs (b)(1) (i) through (x) of
this section apply; or
(ii) The investigational plan or protocol(s) is not reasonable as a
bona fide scientific plan to determine whether or not the drug is safe
and effective for use; or
(iii) There is convincing evidence that the drug is not effective for
the purpose for which it is being investigated.
(3) FDA may propose to terminate a treatment IND if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of this
section apply; or
(ii) Any of the conditions in 312.42(b)(3) apply.
(c) Opportunity for sponsor response. (1) If FDA proposes to
terminate an IND, FDA will notify the sponsor in writing, and invite
correction or explanation within a period of 30 days.
(2) On such notification, the sponsor may provide a written
explanation or correction or may request a conference with FDA to
provide the requested explanation or correction. If the sponsor does
not respond to the notification within the allocated time, the IND shall
be terminated.
(3) If the sponsor responds but FDA does not accept the explanation
or correction submitted, FDA shall inform the sponsor in writing of the
reason for the nonacceptance and provide the sponsor with an opportunity
for a regulatory hearing before FDA under Part 16 on the question of
whether the IND should be terminated. The sponsor's request for a
regulatory hearing must be made within 10 days of the sponsor's receipt
of FDA's notification of nonacceptance.
(d) Immediate termination of IND. Notwithstanding paragraphs (a)
through (c) of this section, if at any time FDA concludes that
continuation of the investigation presents an immediate and substantial
danger to the health of individuals, the agency shall immediately, by
written notice to the sponsor from the Director of the Center for Drug
Evaluation and Research or the Director of the Center for Biologics
Evaluation and Research, terminate the IND. An IND so terminated is
subject to reinstatement by the Director on the basis of additional
submissions that eliminate such danger. If an IND is terminated under
this paragraph, the agency will afford the sponsor an opportunity for a
regulatory hearing under Part 16 on the question of whether the IND
should be reinstated.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990)
21 CFR 312.45 Inactive status.
(a) If no subjects are entered into clinical studies for a period of
2 years or more under an IND, or if all investigations under an IND
remain on clinical hold for 1 year or more, the IND may be placed by FDA
on inactive status. This action may be taken by FDA either on request
of the sponsor or on FDA's own initiative. If FDA seeks to act on its
own initiative under this section, it shall first notify the sponsor in
writing of the proposed inactive status. Upon receipt of such
notification, the sponsor shall have 30 days to respond as to why the
IND should continue to remain active.
(b) If an IND is placed on inactive status, all investigators shall
be so notified and all stocks of the drug shall be returned or otherwise
disposed of in accordance with 312.59.
(c) A sponsor is not required to submit annual reports to an IND on
inactive status. An inactive IND is, however, still in effect for
purposes of the public disclosure of data and information under
312.130.
(d) A sponsor who intends to resume clinical investigation under an
IND placed on inactive status shall submit a protocol amendment under
312.30 containing the proposed general investigational plan for the
coming year and appropriate protocols. If the protocol amendment relies
on information previously submitted, the plan shall reference such
information. Additional information supporting the proposed
investigation, if any, shall be submitted in an information amendment.
Notwithstanding the provisions of 312.30, clinical investigations under
an IND on inactive status may only resume (1) 30 days after FDA receives
the protocol amendment, unless FDA notifies the sponsor that the
investigations described in the amendment are subject to a clinical hold
under 312.42, or (2) on earlier notification by FDA that the clinical
investigations described in the protocol amendment may begin.
(e) An IND that remains on inactive status for 5 years or more may be
terminated under 312.44.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.47 Meetings.
(a) General. Meetings between a sponsor and the agency are
frequently useful in resolving questions and issues raised during the
course of a clinical investigation. FDA encourages such meetings to the
extent that they aid in the evaluation of the drug and in the solution
of scientific problems concerning the drug, to the extent that FDA's
resources permit. The general principle underlying the conduct of such
meetings is that there should be free, full, and open communication
about any scientific or medical question that may arise during the
clinical investigation. These meetings shall be conducted and
documented in accordance with Part 10.
(b) ''End-of-Phase 2'' meetings and meetings held before submission
of a marketing application. At specific times during the drug
investigation process, meetings between FDA and a sponsor can be
especially helpful in minimizing wasteful expenditures of time and money
and thus in speeding the drug development and evaluation process. In
particular, FDA has found that meetings at the end of Phase 2 of an
investigation (end-of-Phase 2 meetings) are of considerable assistance
in planning later studies and that meetings held near completion of
Phase 3 and before submission of a marketing application (''pre-NDA''
meetings) are helpful in developing methods of presentation and
submission of data in the marketing application that facilitate review
and allow timely FDA response.
(1) End-of-Phase 2 meetings -- (i) Purpose. The purpose of an
end-of-Phase 2 meeting is to determine the safety of proceeding to Phase
3, to evaluate the Phase 3 plan and protocols, and to identify any
additional information necessary to support a marketing application for
the uses under investigation.
(ii) Eligibility for meeting. While the end-of-Phase 2 meeting is
designed primarily for IND's involving new molecular entities or major
new uses of marketed drugs, a sponsor of any IND may request and obtain
an end-of-Phase 2 meeting.
(iii) Timing. To be most useful to the sponsor, end-of-Phase 2
meetings should be held before major commitments of effort and resources
to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2
meeting is not, however, intended to delay the transition of an
investigation from Phase 2 to Phase 3.
(iv) Advance information. At least 1 month in advance of an
end-of-Phase 2 meeting, the sponsor should submit background information
on the sponsor's plan for Phase 3, including summaries of the Phase 1
and 2 investigations, the specific protocols for Phase 3 clinical
studies, plans for any additional nonclinical studies, and, if
available, tentative labeling for the drug. The recommended contents of
such a submission are described more fully in FDA Staff Manual Guide
4850.7 that is publicly available under FDA's public information
regulations in Part 20.
(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting
are to be made with the division in FDA's Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research which is
responsible for review of the IND. The meeting will be scheduled by FDA
at a time convenient to both FDA and the sponsor. Both the sponsor and
FDA may bring consultants to the meeting. The meeting should be
directed primarily at establishing agreement between FDA and the sponsor
of the overall plan for Phase 3 and the objectives and design of
particular studies. The adequacy of technical information to support
Phase 3 studies and/or a marketing application may also be discussed.
Agreements reached at the meeting on these matters will be recorded in
minutes of the conference that will be taken by FDA in accordance with
10.65 and provided to the sponsor. The minutes along with any other
written material provided to the sponsor will serve as a permanent
record of any agreements reached. Barring a significant scientific
development that requires otherwise, studies conducted in accordance
with the agreement shall be presumed to be sufficient in objective and
design for the purpose of obtaining marketing approval for the drug.
(2) ''Pre-NDA'' meetings. FDA has found that delays associated with
the initial review of a marketing application may be reduced by
exchanges of information about a proposed marketing application. The
primary purpose of this kind of exchange is to uncover any major
unresolved problems, to identify those studies that the sponsor is
relying on as adequate and well-controlled to establish the drug's
effectiveness, to acquaint FDA reviewers with the general information to
be submitted in the marketing application (including technical
information), to discuss appropriate methods for statistical analysis of
the data, and to discuss the best approach to the presentation and
formatting of data in the marketing application. Arrangements for such
a meeting are to be initiated by the sponsor with the division
responsible for review of the IND. To permit FDA to provide the sponsor
with the most useful advice on preparing a marketing application, the
sponsor should submit to FDA's reviewing division at least 1 month in
advance of the meeting the following information:
(i) A brief summary of the clinical studies to be submitted in the
application.
(ii) A proposed format for organizing the submission, including
methods for presenting the data.
(iii) Any other information for discussion at the meeting.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990)
21 CFR 312.48 Dispute resolution.
(a) General. The Food and Drug Administration is committed to
resolving differences between sponsors and FDA reviewing divisions with
respect to requirements for IND's as quickly and amicably as possible
through the cooperative exchange of information and views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the sponsor should first attempt to resolve
the matter with the division in FDA's Center for Drug Evaluation and
Research or Center for Biologics Evaluation and Research which is
responsible for review of the IND, beginning with the consumer safety
officer assigned to the application. If the dispute is not resolved,
the sponsor may raise the matter with the person designated as
ombudsman, whose function shall be to investigate what has happened and
to facilitate a timely and equitable resolution. Appropriate issues to
raise with the ombudsman include resolving difficulties in scheduling
meetings and obtaining timely replies to inquiries. Further details on
this procedure are contained in FDA Staff Manual Guide 4820.7 that is
publicly available under FDA's public information regulations in Part
20.
(c) Scientific and medical disputes. (1) When scientific or medical
disputes arise during the drug investigation process, sponsors should
discuss the matter directly with the responsible reviewing officials.
If necessary, sponsors may request a meeting with the appropriate
reviewing officials and management representatives in order to seek a
resolution. Requests for such meetings shall be directed to the
director of the division in FDA's Center for Drug Evaluation and
Research or Center for Biologics Evaluation and Research which is
responsible for review of the IND. FDA will make every attempt to grant
requests for meetings that involve important issues and that can be
scheduled at mutually convenient times.
(2) The ''end-of-Phase 2'' and ''pre-NDA'' meetings described in
312.47(b) will also provide a timely forum for discussing and resolving
scientific and medical issues on which the sponsor disagrees with the
agency.
(3) In requesting a meeting designed to resolve a scientific or
medical dispute, applicants may suggest that FDA seek the advice of
outside experts, in which case FDA may, in its discretion, invite to the
meeting one or more of its advisory committee members or other
consultants, as designated by the agency. Applicants may rely on, and
may bring to any meeting, their own consultants. For major scientific
and medical policy issues not resolved by informal meetings, FDA may
refer the matter to one of its standing advisory committees for its
consideration and recommendations.
(52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990)
21 CFR 312.48 Subpart D -- Responsibilities of Sponsors and Investigators
21 CFR 312.50 General responsibilities of sponsors.
Sponsors are responsibile for selecting qualified investigators,
providing them with the information they need to conduct an
investigation properly, ensuring proper monitoring of the
investigation(s), ensuring that the investigation(s) is conducted in
accordance with the general investigational plan and protocols contained
in the IND, maintaining an effective IND with respect to the
investigations, and ensuring that FDA and all participating
investigators are promptly informed of significant new adverse effects
or risks with respect to the drug. Additional specific responsibilities
of sponsors are described elsewhere in this part.
21 CFR 312.52 Transfer of obligations to a contract research
organization.
(a) A sponsor may transfer responsibility for any or all of the
obligations set forth in this part to a contract research organization.
Any such transfer shall be described in writing. If not all obligations
are transferred, the writing is required to describe each of the
obligations being assumed by the contract research organization. If all
obligations are transferred, a general statement that all obligations
have been transferred is acceptable. Any obligation not covered by the
written description shall be deemed not to have been transferred.
(b) A contract research organization that assumes any obligation of a
sponsor shall comply with the specific regulations in this chapter
applicable to this obligation and shall be subject to the same
regulatory action as a sponsor for failure to comply with any obligation
assumed under these regulations. Thus, all references to ''sponsor'' in
this part apply to a contract research organization to the extent that
it assumes one or more obligations of the sponsor.
21 CFR 312.53 Selecting investigators and monitors.
(a) Selecting investigators. A sponsor shall select only
investigators qualified by training and experience as appropriate
experts to investigate the drug.
(b) Control of drug. A sponsor shall ship investigational new drugs
only to investigators participating in the investigation.
(c) Obtaining information from the investigator. Before permitting
an investigator to begin participation in an investigation, the sponsor
shall obtain the following:
(1) A signed investigator statement (Form FDA-1572) containing:
(i) The name and address of the investigator;
(ii) The name and code number, if any, of the protocol(s) in the IND
identifying the study(ies) to be conducted by the investigator;
(iii) The name and address of any medical school, hospital, or other
research facility where the clinical investigation(s) will be conducted;
(iv) The name and address of any clinical laboratory facilities to be
used in the study;
(v) The name and address of the IRB that is responsible for review
and approval of the study(ies);
(vi) A commitment by the investigator that he or she:
(a) Will conduct the study(ies) in accordance with the relevant,
current protocol(s) and will only make changes in a protocol after
notifying the sponsor, except when necessary to protect the safety, the
rights, or welfare of subjects;
(b) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this
part;
(c) Will personally conduct or supervise the described
investigation(s);
(d) Will inform any patients, or any persons used as controls, that
the drugs are being used for investigational purposes and will ensure
that the requirements relating to obtaining informed consent and
institutional review board review and approval are met;
(e) Will report to the sponsor adverse experiences that occur in the
course of the investigation(s) in accordance with 312.64;
(f) Has read and understands the information in the investigator's
brochure, including the potential risks and side effects of the drug;
and
(g) Will ensure that all associates, colleagues, and employees
assisting in the conduct of the study(ies) are informed about their
obligations in meeting the above commitments.
(vii) A commitment by the investigator that, for an investigation
subject to an institutional review requirement under Part 56, an IRB
that complies with the requirements of that part will be responsible for
the initial and continuing review and approval of the clinical
investigation and that the investigator will promptly report to the IRB
all changes in the research activity and all unanticipated problems
involving risks to human subjects or others, and will not make any
changes in the research without IRB approval, except where necessary to
eliminate apparent immediate hazards to the human subjects.
(viii) A list of the names of the subinvestigators (e.g., research
fellows, residents) who will be assisting the investigator in the
conduct of the investigation(s).
(2) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator as an expert in the clinical
investigation of the drug for the use under investigation.
(3) Clinical protocol. (i) For Phase 1 investigations, a general
outline of the planned investigation including the estimated duration of
the study and the maximum number of subjects that will be involved.
(ii) For Phase 2 or 3 investigations, an outline of the study
protocol including an approximation of the number of subjects to be
treated with the drug and the number to be employed as controls, if any;
the clinical uses to be investigated; characteristics of subjects by
age, sex, and condition; the kind of clinical observations and
laboratory tests to be conducted; the estimated duration of the study;
and copies or a description of case report forms to be used.
(d) Selecting monitors. A sponsor shall select a monitor qualified
by training and experience to monitor the progress of the investigation.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.55 Informing investigators.
(a) Before the investigation begins, a sponsor (other than a
sponsor-investigator) shall give each participating clinical
investigator an investigator brochure containing the information
described in 312.23(a)(5).
(b) The sponsor shall, as the overall investigation proceeds, keep
each participating investigator informed of new observations discovered
by or reported to the sponsor on the drug, particularly with respect to
adverse effects and safe use. Such information may be distributed to
investigators by means of periodically revised investigator brochures,
reprints or published studies, reports or letters to clinical
investigators, or other appropriate means. Important safety information
is required to be relayed to investigators in accordance with 312.32.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.56 Review of ongoing investigations.
(a) The sponsor shall monitor the progress of all clinical
investigations being conducted under its IND.
(b) A sponsor who discovers that an investigator is not complying
with the signed agreement (Form FDA-1572), the general investigational
plan, or the requirements of this part or other applicable parts shall
promptly either secure compliance or discontinue shipments of the
investigational new drug to the investigator and end the investigator's
participation in the investigation. If the investigator's participation
in the investigation is ended, the sponsor shall require that the
investigator dispose of or return the investigational drug in accordance
with the requirements of 312.59 and shall notify FDA.
(c) The sponsor shall review and evaluate the evidence relating to
the safety and effectiveness of the drug as it is obtained from the
investigator. The sponsors shall make such reports to FDA regarding
information relevant to the safety of the drug as are required under
312.32. The sponsor shall make annual reports on the progress of the
investigation in accordance with 312.33.
(d) A sponsor who determines that its investigational drug presents
an unreasonable and significant risk to subjects shall discontinue those
investigations that present the risk, notify FDA, all institutional
review boards, and all investigators who have at any time participated
in the investigation of the discontinuance, assure the disposition of
all stocks of the drug outstanding as required by 312.59, and furnish
FDA with a full report of the sponsor's actions. The sponsor shall
discontinue the investigation as soon as possible, and in no event later
than 5 working days after making the determination that the
investigation should be discontinued. Upon request, FDA will confer
with a sponsor on the need to discontinue an investigation.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.57 Recordkeeping and record retention.
(a) A sponsor shall maintain adequate records showing the receipt,
shipment, or other disposition of the investigational drug. These
records are required to include, as appropriate, the name of the
investigator to whom the drug is shipped, and the date, quantity, and
batch or code mark of each such shipment.
(b) A sponsor shall retain the records and reports required by this
part for 2 years after a marketing application is approved for the drug;
or, if an application is not approved for the drug, until 2 years after
shipment and delivery of the drug for investigational use is
discontinued and FDA has been so notified.
(c) A sponsor shall retain reserve samples of any test article and
reference standard used in a bioequivalence or bioavailability study and
release the reserve samples to FDA upon request, in accordance with, and
for the period specified in, 320.32 of this chapter.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 47038, Nov. 8, 1990)
21 CFR 312.58 Inspection of sponsor's records and reports.
(a) FDA inspection. A sponsor shall upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify any records and reports relating to a clinical
investigation conducted under this part. Upon written request by FDA,
the sponsor shall submit the records or reports (or copies of them) to
FDA. The sponsor shall discontinue shipments of the drug to any
investigator who has failed to maintain or make available records or
reports of the investigation as required by this part.
(b) Controlled substances. If an investigational new drug is a
substance listed in any schedule of the Controlled Substances Act (21
U.S.C. 801; 21 CFR Part 1308), records concerning shipment, delivery,
receipt, and disposition of the drug, which are required to be kept
under this part or other applicable parts of this chapter shall, upon
the request of a properly authorized employee of the Drug Enforcement
Administration of the U.S. Department of Justice, be made available by
the investigator or sponsor to whom the request is made, for inspection
and copying. In addition, the sponsor shall assure that adequate
precautions are taken, including storage of the investigational drug in
a securely locked, substantially constructed cabinet, or other securely
locked, substantially constructed enclosure, access to which is limited,
to prevent theft or diversion of the substance into illegal channels of
distribution.
21 CFR 312.59 Disposition of unused supply of investigational drug.
The sponsor shall assure the return of all unused supplies of the
investigational drug from each individual investigator whose
participation in the investigation is discontinued or terminated. The
sponsor may authorize alternative disposition of unused supplies of the
investigational drug provided this alternative disposition does not
expose humans to risks from the drug. The sponsor shall maintain
written records of any disposition of the drug in accordance with
312.57.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.60 General responsibilities of investigators.
An investigator is responsible for ensuring that an investigation is
conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the
rights, safety, and welfare of subjects under the investigator's care;
and for the control of drugs under investigation. An investigator
shall, in accordance with the provisions of Part 50, obtain the informed
consent of each human subject to whom the drug is administered, except
as provided in 50.23. Additional specific responsibilities of clinical
investigators are set forth in this part and in Parts 50 and 56.
21 CFR 312.61 Control of the investigational drug.
An investigator shall administer the drug only to subjects under the
investigator's personal supervision or under the supervision of a
subinvestigator responsible to the investigator. The investigator shall
not supply the investigational drug to any person not authorized under
this part to receive it.
21 CFR 312.62 Investigator recordkeeping and record retention.
(a) Disposition of drug. An investigator is required to maintain
adequate records of the disposition of the drug, including dates,
quantity, and use by subjects. If the investigation is terminated,
suspended, discontinued, or completed, the investigator shall return the
unused supplies of the drug to the sponsor, or otherwise provide for
disposition of the unused supplies of the drug under 312.59.
(b) Case histories. An investigator is required to prepare and
maintain adequate and accurate case histories designed to record all
observations and other data pertinent to the investigation on each
individual treated with the investigational drug or employed as a
control in the investigation.
(c) Record retention. An investigator shall retain records required
to be maintained under this part for a period of 2 years following the
date a marketing application is approved for the drug for the indication
for which it is being investigated; or, if no application is to be
filed or if the application is not approved for such indication, until 2
years after the investigation is discontinued and FDA is notified.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.64 Investigator reports.
(a) Progress reports. The investigator shall furnish all reports to
the sponsor of the drug who is responsible for collecting and evaluating
the results obtained. The sponsor is required under 312.33 to submit
annual reports to FDA on the progress of the clinical investigations.
(b) Safety reports. An investigator shall promptly report to the
sponsor any adverse effect that may reasonably be regarded as caused by,
or probably caused by, the drug. If the adverse effect is alarming, the
investigator shall report the adverse effect immediately.
(c) Final report. An investigator shall provide the sponsor with an
adequate report shortly after completion of the investigator's
participation in the investigation.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.66 Assurance of IRB review.
An investigator shall assure that an IRB that complies with the
requirements set forth in Part 56 will be responsible for the initial
and continuing review and approval of the proposed clinical study. The
investigator shall also assure that he or she will promptly report to
the IRB all changes in the research activity and all unanticipated
problems involving risk to human subjects or others, and that he or she
will not make any changes in the research without IRB approval, except
where necessary to eliminate apparent immediate hazards to human
subjects.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.68 Inspection of investigator's records and reports.
An investigator shall upon request from any properly authorized
officer or employee of FDA, at reasonable times, permit such officer or
employee to have access to, and copy and verify any records or reports
made by the investigator pursuant to 312.62. The investigator is not
required to divulge subject names unless the records of particular
individuals require a more detailed study of the cases, or unless there
is reason to believe that the records do not represent actual case
studies, or do not represent actual results obtained.
21 CFR 312.69 Handling of controlled substances.
If the investigational drug is subject to the Controlled Substances
Act, the investigator shall take adequate precautions, including storage
of the investigational drug in a securely locked, substantially
constructed cabinet, or other securely locked, substantially constructed
enclosure, access to which is limited, to prevent theft or diversion of
the substance into illegal channels of distribution.
21 CFR 312.70 Disqualification of a clinical investigator.
(a) If FDA has information indicating that an investigator has
repeatedly or deliberately failed to comply with the requirements of
this part, Part 50, or Part 56, or has submitted to the sponsor false
information in any required report, the Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research will
furnish the investigator written notice of the matter complained of and
offer the investigator an opportunity to explain the matter in writing,
or, at the option of the investigator, in an informal conference. If an
explanation is offered but not accepted by the Center for Drug
Evaluation and Research or the Center for Biologics Evaluation and
Research, the investigator will be given an opportunity for a regulatory
hearing under Part 16 on the question of whether the investigator is
entitled to receive investigational new drugs.
(b) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the requirements of this part, Part 50, or Part 56, or
has deliberately or repeatedly submitted false information to the
sponsor in any required report, the Commissioner will notify the
investigator and the sponsor of any investigation in which the
investigator has been named as a participant that the investigator is
not entitled to receive investigational drugs. The notification will
provide a statement of basis for such determination.
(c) Each IND and each approved application submitted under Part 314
containing data reported by an investigator who has been determined to
be ineligible to receive investigational drugs will be examined to
determine whether the investigator has submitted unreliable data that
are essential to the continuation of the investigation or essential to
the approval of any marketing application.
(d) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under Part 16. If a danger to the public health exists,
however, the Commissioner shall terminate the IND immediately and notify
the sponsor of the determination. In such case, the sponsor shall have
an opportunity for a regulatory hearing before FDA under Part 16 on the
question of whether the IND should be reinstated.
(e) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued approval of the drug product for which the data were
submitted cannot be justified, the Commissioner will proceed to withdraw
approval of the drug product in accordance with the applicable
provisions of the act.
(f) An investigator who has been determined to be ineligible to
receive investigational drugs may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ investigatioal drugs solely
in compliance with the provisions of this part and of Parts 50 and 56.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990)
21 CFR 312.70 Subpart E -- Drugs Intended to Treat Life Threatening and
Severely-debilitating Illnesses
Authority: Secs. 501, 502, 503, 505, 506, 507, 701, 52 Stat.
1049-1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463
as amended (21 U.S.C. 351, 352, 353, 355, 356, 357, 371); sec. 351, 58
Stat. 702 as amended (42 U.S.C. 262); 21 CFR 5.10, 5.11.
Source: 53 FR 41523, Oct. 21, 1988, unless otherwise noted.
21 CFR 312.80 Purpose.
The purpose of this section is to establish procedures designed to
expedite the development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and
severely-debilitating illnesses, especially where no satisfactory
alternative therapy exists. As stated 314.105(c) of this chapter,
while the statutory standards of safety and effectiveness apply to all
drugs, the many kinds of drugs that are subject to them, and the wide
range of uses for those drugs, demand flexibility in applying the
standards. The Food and Drug Administration (FDA) has determined that
it is appropriate to exercise the broadest flexibility in applying the
statutory standards, while preserving appropriate guarantees for safety
and effectiveness. These procedures reflect the recognition that
physicians and patients are generally willing to accept greater risks or
side effects from products that treat life-threatening and
severely-debilitating illnesses, than they would accept from products
that treat less serious illnesses. These procedures also reflect the
recognition that the benefits of the drug need to be evaluated in light
of the severity of the disease being treated. The procedure outlined in
this section should be interpreted consistent with that purpose.
21 CFR 312.81 Scope.
This section applies to new drug, antibiotic, and biological products
that are being studied for their safety and effectiveness in treating
life-threatening or severely-debilitating diseases.
(a) For purposes of this section, the term ''life-threatening''
means:
(1) Diseases or conditions where the likelihood of death is high
unless the course of the disease is interrupted; and
(2) Diseases or conditions with potentially fatal outcomes, where the
end point of clinical trial analysis is survival.
(b) For purposes of this section, the term ''severely debilitating''
means diseases or conditions that cause major irreversible morbidity.
(c) Sponsors are encouraged to consult with FDA on the applicability
of these procedures to specific products.
21 CFR 312.82 Early consultation.
For products intended to treat life-threatening or
severely-debilitating illnesses, sponsors may request to meet with
FDA-reviewing officials early in the drug development process to review
and reach agreement on the design of necessary preclinical and clinical
studies. Where appropriate, FDA will invite to such meetings one or
more outside expert scientific consultants or advisory committee
members. To the extent FDA resources permit, agency reviewing officials
will honor requests for such meetings
(a) Pre-investigational new drug (IND) meetings. Prior to the
submission of the initial IND, the sponsor may request a meeting with
FDA-reviewing officials. The primary purpose of this meeting is to
review and reach agreement on the design of animal studies needed to
initiate human testing. The meeting may also provide an opportunity for
discussing the scope and design of phase 1 testing, and the best
approach for presentation and formatting of data in the IND.
(b) End-of-phase 1 meetings. When data from phase 1 clinical testing
are available, the sponsor may again request a meeting with
FDA-reviewing officials. The primary purpose of this meeting is to
review and reach agreement on the design of phase 2 controlled clinical
trials, with the goal that such testing will be adequate to provide
sufficient data on the drug's safety and effectiveness to support a
decision on its approvability for marketing. The procedures outlined in
312.47(b)(1) with respect to end-of-phase 2 conferences, including
documentation of agreements reached, would also be used for end-of-phase
1 meetings.
21 CFR 312.83 Treatment protocols.
If the preliminary analysis of phase 2 test results appears
promising, FDA may ask the sponsor to submit a treatment protocol to be
reviewed under the procedures and criteria listed in 312.34 and
312.35. Such a treatment protocol, if requested and granted, would
normally remain in effect while the complete data necessary for a
marketing application are being assembled by the sponsor and reviewed by
FDA (unless grounds exist for clinical hold of ongoing protocols, as
provided in 312.42(b)(3)(ii)).
21 CFR 312.84 Risk-benefit analysis in review of marketing applications
for drugs to treat life-threatening and severely-debilitating illnesses.
(a) FDA's application of the statutory standards for marketing
approval shall recognize the need for a medical risk-benefit judgment in
making the final decision on approvability. As part of this evaluation,
consistent with the statement of purpose in 312.80, FDA will consider
whether the benefits of the drug outweigh the known and potential risks
of the drug and the need to answer remaining questions about risks and
benefits of the drug, taking into consideration the severity of the
disease and the absence of satisfactory alternative therapy.
(b) In making decisions on whether to grant marketing approval for
products that have been the subject of an end-of-phase 1 meeting under
312.82, FDA will usually seek the advice of outside expert scientific
consultants or advisory committees. Upon the filing of such a marketing
application under 314.101 or Part 601 of this chapter, FDA will notify
the members of the relevant standing advisory committee of the
application's filing and its availability for review.
(c) If FDA concludes that the data presented are not sufficient for
marketing approval, FDA will issue (for a drug) a not approvable letter
pursuant to 314.120 of this chapter, or (for a biologic) a deficiencies
letter consistent with the biological product licensing procedures.
Such letter, in describing the deficiencies in the application, will
address why the results of the research design agreed to under 312.82,
or in subsequent meetings, have not provided sufficient evidence for
marketing approval. Such letter will also describe any recommendations
made by the advisory committee regarding the application.
(d) Marketing applications submitted under the procedures contained
in this section will be subject to the requirements and procedures
contained in Part 314 or Part 600 of this chapter, as well as those in
this subpart.
21 CFR 312.85 Phase 4 studies.
Concurrent with marketing approval, FDA may seek agreement from the
sponsor to conduct certain postmarketing (phase 4) studies to delineate
additional information about the drug's risks, benefits, and optimal
use. These studies could include, but would not be limited to, studying
different doses or schedules of administration than were used in phase 2
studies, use of the drug in other patient populations or other stages of
the disease, or use of the drug over a longer period of time.
21 CFR 312.86 Focused FDA regulatory research.
At the discretion of the agency, FDA may undertake focused regulatory
research on critical rate-limiting aspects of the preclinical,
chemical/manufacturing, and clinical phases of drug development and
evaluation. When initiated, FDA will undertake such research efforts as
a means for meeting a public health need in facilitating the development
of therapies to treat life-threatening or severely debilitating
illnesses.
21 CFR 312.87 Active monitoring of conduct and evaluation of clinical
trials.
For drugs covered under this section, the Commissioner and other
agency officials will monitor the progress of the conduct and evaluation
of clinical trials and be involved in facilitating their appropriate
progress.
21 CFR 312.88 Safeguards for patient safety.
All of the safeguards incorporated within Parts 50, 56, 312, 314, and
600 of this chapter designed to ensure the safety of clinical testing
and the safety of products following marketing approval apply to drugs
covered by this section. This includes the requirements for informed
consent (Part 50 of this chapter) and institutional review boards (Part
56 of this chapter). These safeguards further include the review of
animal studies prior to initial human testing ( 312.23), and the
monitoring of adverse drug experiences through the requirements of IND
safety reports ( 312.32), safety update reports during agency review of
a marketing application ( 314.50 of this chapter), and postmarketing
adverse reaction reporting ( 314.80 of this chapter).
21 CFR 312.88 Subpart F -- Miscellaneous
21 CFR 312.110 Import and export requirements.
(a) Imports. An investigational new drug offered for import into the
United States complies with the requirements of this part if it is
subject to an IND that is in effect for it under 312.40 and: (1) The
consignee in the United States is the sponsor of the IND; (2) the
consignee is a qualified investigator named in the IND; or (3) the
consignee is the domestic agent of a foreign sponsor, is responsible for
the control and distribution of the investigational drug, and the IND
identifies the consignee and describes what, if any, actions the
consignee will take with respect to the investigational drug.
(b) Exports. An investigational new drug intended for export from
the United States complies with the requirements of this part as
follows:
(1) If an IND is in effect for the drug under 312.40 and each person
who receives the drug is an investigator named in the application; or
(2) If FDA authorizes shipment of the drug for use in a clinical
investigation. Authorization may be obtained as follows:
(i) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, of a written request from the
person that seeks to export the drug. A request must provide adequate
information about the drug to satisfy FDA that the drug is appropriate
for the proposed investigational use in humans, that the drug will be
used for investigational purposes only, and that the drug may be legally
used by that consignee in the importing country for the proposed
investigational use. The request shall specify the quantity of the drug
to be shipped per shipment and the frequency of expected shipments. If
FDA authorizes exportation under this paragraph, the agency shall
concurrently notify the government of the importing country of such
authorization.
(ii) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, of a formal request from an
authorized official of the government of the country to which the drug
is proposed to be shipped. A request must specify that the foreign
government has adequate information about the drug and the proposed
investigational use, that the drug will be used for investigational
purposes only, and that the foreign government is satisfied that the
drug may legally be used by the intended consignee in that country.
Such a request shall specify the quantity of drug to be shipped per
shipment and the frequency of expected shipments.
(iii) Authorization to export an investigational drug under paragraph
(b)(2)(i) or (ii) of this section may be revoked by FDA if the agency
finds that the conditions underlying its authorization are not longer
met.
(3) This paragraph applies only where the drug is to be used for the
purpose of clinical investigation.
(4) This paragraph does not apply to the export of an antibiotic drug
product shipped in accordance with the provisions of section 801(d) of
the act.
(5) This paragraph does not apply to the export of new drugs
(including biological products) approved for export under section 802 of
the act or section 351(h)(1)(A) of the Public Health Service Act.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987)
21 CFR 312.120 Foreign clinical studies not conducted under an IND.
(a) Introduction. This section describes the criteria for acceptance
by FDA of foreign clinical studies not conducted under an IND. In
general, FDA accepts such studies provided they are well designed, well
conducted, performed by qualified investigators, and conducted in
accordance with ethical principles acceptable to the world community.
Studies meeting these criteria may be utilized to support clinical
investigations in the United States and/or marketing approval.
Marketing approval of a new drug or antibiotic drug based solely on
foreign clinical data is governed by 314.106.
(b) Data submissions. A sponsor who wishes to rely on a foreign
clinical study to support an IND or to support an application for
marketing approval shall submit to FDA the following information:
(1) A description of the investigator's qualifications;
(2) A description of the research facilities;
(3) A detailed summary of the protocol and results of the study, and,
should FDA request, case records maintained by the investigator or
additional background data such as hospital or other institutional
records;
(4) A description of the drug substance and drug product used in the
study, including a description of components, formulation,
specifications, and bioavailability of the specific drug product used in
the clinical study, if available; and
(5) If the study is intended to support the effectiveness of a drug
product, information showing that the study is adequate and well
controlled under 314.126.
(c) Conformance with ethical principles. (1) Foreign clinical
research is required to have been conducted in accordance with the
ethical principles stated in the ''Declaration of Helsinki'' (see
paragraph (c)(4) of this section) or the laws and regulations of the
country in which the research was conducted, whichever represents the
greater protection of the individual.
(2) For each foreign clinical study submitted under this section, the
sponsor shall explain how the research conformed to the ethical
principles contained in the ''Declaration of Helsinki'' or the foreign
country's standards, whichever were used. If the foreign country's
standards were used, the sponsor shall explain in detail how those
standards differ from the ''Declaration of Helsinki'' and how they offer
greater protection.
(3) When the research has been approved by an independent review
committee, the sponsor shall submit to FDA documentation of such review
and approval, including the names and qualifications of the members of
the committee. In this regard, a ''review committee'' means a committee
composed of scientists and, where practicable, individuals who are
otherwise qualified (e.g., other health professionals or laymen). The
investigator may not vote on any aspect of the review of his or her
protocol by a review committee.
(4) The ''Declaration of Helsinki'' states as follows:
It is the mission of the physician to safeguard the health of the
people. His or her knowledge and conscience are dedicated to the
fulfillment of this mission.
The Declaration of Geneva of the World Medical Association binds the
physician with the words, ''The health of my patient will be my first
consideration,'' and the International Code of Medical Ethics declares
that, ''A physician shall act only in the patient's interest when
providing medical care which might have the effect of weakening the
physical and mental condition of the patient.''
The purpose of biomedical research involving human subjects must be
to improve diagnostic, therapeutic and prophylactic procedures and the
understanding of the aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or
prophylactic procedures involve hazards. This applies especially to
biomedical research.
Medical progress is based on research which ultimately must rest in
part on experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be
recognized between medical research in which the aim is essentially
diagnostic or therapeutic for a patient, and medical research, the
essential object of which is purely scientific and without implying
direct diagnostic or therapeutic value to the person subjected to the
research.
Special caution must be exercised in the conduct of research which
may affect the environment, and the welfare of animals used for research
must be respected.
Because it is essential that the results of laboratory experiments be
applied to human beings to further scientific knowledge and to help
suffering humanity, the World Medical Association has prepared the
following recommendations as a guide to every physician in biomedical
research involving human subjects. They should be kept under review in
the future. It must be stressed that the standards as drafted are only
a guide to physicians all over the world. Physicians are not relieved
from criminal, civil and ethical responsibilities under the laws of
their own countries.
1. Biomedical research involving human subjects must conform to
generally accepted scientific principles and should be based on
adequately performed laboratory and animal experimentation and on a
thorough knowledge of the scientific literature.
2. The design and performance of each experimental procedure
involving human subjects should be clearly formulated in an experimental
protocol which should be transmitted for consideration, comment and
guidance to a specially appointed committee independent of the
investigator and the sponsor provided that this independent committee is
in conformity with the laws and regulations of the country in which the
research experiment is performed.
3. Biomedical research involving human subjects should be conducted
only by scientifically qualified persons and under the supervision of a
clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given
his or her consent.
4. Biomedical research involving human subjects cannot legitimately
be carried out unless the importance of the objective is in proportion
to the inherent risk to the subject.
5. Every biomedical research project involving human subjects should
be preceded by careful assessment of predictable risks in comparison
with foreseeable benefits to the subject or to others. Concern for the
interests of the subject must always prevail over the interests of
science and society.
6. The right of the research subject to safeguard his or her
integrity must always be respected. Every precaution should be taken to
respect the privacy of the subject and to minimize the impact of the
study on the subject's physical and mental integrity and on the
personality of the subject.
7. Physicians should abstain from engaging in research projects
involving human subjects unless they are satisfied that the hazards
involved are believed to be predictable. Physicians should cease any
investigation if the hazards are found to outweigh the potential
benefits.
8. In publication of the results of his or her research, the
physician is obliged to preserve the accuracy of the results. Reports
of experimentation not in accordance with the principles laid down in
this Declaration should not be accepted for publication.
9. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, anticipated benefits and
potential hazards of the study and the discomfort it may entail. He or
she should be informed that he or she is at liberty to abstain from
participation in the study and that he or she is free to withdraw his or
her consent to participation at any time. The physician should then
obtain the subject's freely-given informed consent, preferably in
writing.
10. When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a
dependent relationship to him or her or may consent under duress. In
that case the informed consent should be obtained by a physician who is
not engaged in the investigation and who is completely independent of
this official relationship.
11. In case of legal incompetence, informed consent should be
obtained from the legal guardian in accordance with national
legislation. Where physical or mental incapacity makes it impossible to
obtain informed consent, or when the subject is a minor, permission from
the responsible relative replaces that of the subject in accordance with
national legislation.
Whenever the minor child is in fact able to give a consent, the
minor's consent must be obtained in addition to the consent of the
minor's legal guardian.
12. The research protocol should always contain a statement of the
ethical considerations involved and should indicate that the principles
enunciated in the present Declaration are complied with.
1. In the treatment of the sick person, the physician must be free to
use a new diagnostic and therapeutic measure, if in his or her judgment
it offers hope of saving life, reestablishing health or alleviating
suffering.
2. The potential benefits, hazards and discomfort of a new method
should be weighed against the advantages of the best current diagnostic
and therapeutic methods.
3. In any medical study, every patient -- including those of a
control group, if any -- should be assured of the best proven diagnostic
and therapeutic method.
4. The refusal of the patient to participate in a study must never
interfere with the physician-patient relationship.
5. If the physician considers it essential not to obtain informed
consent, the specific reasons for this proposal should be stated in the
experimental protocol for transmission to the independent committee (I,
2).
6. The physician can combine medical research with professional care,
the objective being the acquisition of new medical knowledge, only to
the extent that medical research is justified by its potential
diagnostic or therapeutic value for the patient.
1. In the purely scientific application of medical research carried
out on a human being, it is the duty of the physician to remain the
protector of the life and health of that person on whom biomedical
research is being carried out.
2. The subjects should be volunteers -- either healthy persons or
patients for whom the experimental design is not related to the
patient's illness.
3. The investigator or the investigating team should discontinue the
research if in his/her or their judgment it may, if continued, be
harmful to the individual.
4. In research on man, the interest of science and society should
never take precedence over considerations related to the well-being of
the subject.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
56 FR 22113, May 14, 1991)
21 CFR 312.130 Availability for public disclosure of data and
information in an IND.
(a) The existence of an investigational new drug application will not
be disclosed by FDA unless it has previously been publicly disclosed or
acknowledged.
(b) The availability for public disclosure of all data and
information in an investigational new drug application for a new drug or
antibiotic drug will be handled in accordance with the provisions
established in 314.430 for the confidentiality of data and information
in applications submitted in Part 314. The availability for public
disclosure of all data and information in an investigational new drug
application for a biological product will be governed by the provisions
of 601.50 and 601.51.
(c) Notwithstanding the provisions of 314.430, FDA shall disclose
upon request to an individual to whom an investigational new drug has
been given a copy of any IND safety report relating to the use in the
individual.
(52 FR 8831, Mar. 19, 1987. Redesignated at 53 FR 41523, Oct. 21,
1988)
21 CFR 312.140 Address for correspondence.
(a) Except as provided in paragraph (b) of this section, a sponsor
shall send an initial IND submission to the Central Document Room,
Center for Drug Evaluation and Research, Food and Drug Administration,
Park Bldg., Rm. 214, 12420 Parklawn Dr., Rockville, MD 20852. On
receiving the IND, FDA will inform the sponsor which one of the
divisions in the Center for Drug Evaluation and Research or the Center
for Biologics Evaluation and Research is responsible for the IND.
Amendments, reports, and other correspondence relating to matters
covered by the IND should be directed to the appropriate division. The
outside wrapper of each submission shall state what is contained in the
submission, for example, ''IND Application'', ''Protocol Amendment'',
etc.
(b) Applications for the products listed below should be submitted to
the Division of Biological Investigational New Drugs (HFB-230), Center
for Biologics Evaluation and Research, Food and Drug Administration,
8800 Rockville Pike, Bethesda, MD 20892. (1) Products subject to the
licensing provisions of the Public Health Service Act of July 1, 1944
(58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or subject to Part
600; (2) ingredients packaged together with containers intended for the
collection, processing, or storage of blood or blood components; (3)
urokinase products; (4) plasma volume expanders and hydroxyethyl starch
for leukapheresis; and (5) coupled antibodies, i.e., products that
consist of an antibody component coupled with a drug or radionuclide
component in which both components provide a pharmacological effect but
the biological component determines the site of action.
(c) All correspondence relating to biological products for human use
which are also radioactive drugs shall be submitted to the Division of
Oncology and Radiopharmaceutical Drug Products (HFD-150), Center for
Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, except that applications for coupled
antibodies shall be submitted in accordance with paragraph (b) of this
section.
(d) All correspondence relating to export of an investigational drug
under 312.110(b)(2) shall be submitted to the International Affairs
Staff (HFY-50), Office of Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990)
21 CFR 312.145 Guidelines.
(a) FDA has made available guidelines under 10.90(b) to help persons
to comply with certain requirements of this part.
(b) The Center for Drug Evaluation and Research and the Center for
Biologics Evaluation and Research maintain lists of guidelines that
apply to the Centers' regulations. The lists state how a person can
obtain a copy of each guideline. A request for a copy of the lists
should be directed to the CDER Executive Secretariat Staff (HFD-8),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, for drug products, and the
Congressional, Consumer, and International Affairs Staff (HFB-142),
Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for biological
products.
(52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990;
56 FR 3776, Jan. 31, 1991; 57 FR 10814, Mar. 31, 1992)
21 CFR 312.145 Subpart G -- Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests
21 CFR 312.160 Drugs for investigational use in laboratory research
animals or in vitro tests.
(a) Authorization to ship. (1)(i) A person may ship a drug intended
solely for tests in vitro or in animals used only for laboratory
research purposes if it is labeled as follows:
CAUTION: Contains a new drug for investigational use only in
laboratory research animals, or for tests in vitro. Not for use in
humans.
(ii) A person may ship a biological product for investigational in
vitro diagnostic use that is listed in 312.2(b)(2)(ii) if it is labeled
as follows:
CAUTION: Contains a biological product for investigational in vitro
diagnostic tests only.
(2) A person shipping a drug under paragraph (a) of this section
shall use due diligence to assure that the consignee is regularly
engaged in conducting such tests and that the shipment of the new drug
will actually be used for tests in vitro or in animals used only for
laboratory research.
(3) A person who ships a drug under paragraph (a) of this section
shall maintain adequate records showing the name and post office address
of the expert to whom the drug is shipped and the date, quantity, and
batch or code mark of each shipment and delivery. Records of shipments
under paragraph (a)(1)(i) of this section are to be maintained for a
period of 2 years after the shipment. Records and reports of data and
shipments under paragraph (a)(1)(ii) of this section are to be
maintained in accordance with 312.57(b). The person who ships the drug
shall upon request from any properly authorized officer or employee of
the Food and Drug Administration, at reasonable times, permit such
officer or employee to have access to and copy and verify records
required to be maintained under this section.
(b) Termination of authorization to ship. FDA may terminate
authorization to ship a drug under this section if it finds that:
(1) The sponsor of the investigation has failed to comply with any of
the conditions for shipment established under this section; or
(2) The continuance of the investigation is unsafe or otherwise
contrary to the public interest or the drug is used for purposes other
than bona fide scientific investigation. FDA will notify the person
shipping the drug of its finding and invite immediate correction. If
correction is not immediately made, the person shall have an opportunity
for a regulatory hearing before FDA pursuant to Part 16.
(c) Disposition of unused drug. The person who ships the drug under
paragraph (a) of this section shall assure the return of all unused
supplies of the drug from individual investigators whenever the
investigation discontinues or the investigation is terminated. The
person who ships the drug may authorize in writing alternative
disposition of unused supplies of the drug provided this alternative
disposition does not expose humans to risks from the drug, either
directly or indirectly (e.g., through food-producing animals). The
shipper shall maintain records of any alternative disposition.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
(52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987.
Redesignated at 53 FR 41523, Oct. 21, 1988)
21 CFR 312.160 PART 314 -- APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN ANTIBIOTIC DRUG
21 CFR 312.160 Subpart A -- General Provisions
Sec.
314.1 Scope of this part.
314.2 Purpose.
314.3 Definitions.
21 CFR 312.160 Subpart B -- Applications
314.50 Content and format of an application.
314.55 Abbreviated application.
314.56 Drug products for which abbreviated applications are suitable.
314.60 Amendments to an unapproved application.
314.65 Withdrawal by the applicant of an unapproved application.
314.70 Supplements and other changes to an approved application.
314.71 Procedures for submission of a supplement to an approved
application.
314.72 Change in ownership of an application.
314.80 Postmarketing reporting of adverse drug experiences.
314.81 Other postmarketing reports.
314.90 Waivers.
21 CFR 312.160 Subpart C -- FDA Action on Applications
314.100 Time frames for reviewing applications.
314.101 Filing an application.
314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an application.
314.106 Foreign data.
314.110 Approvable letter to the applicant.
314.120 Not approvable letter to the applicant.
314.125 Refusal to approve an application.
314.126 Adequate and well-controlled studies.
314.150 Withdrawal of approval of an application.
314.152 Notice of withdrawal of approval of an application for a new
drug.
314.160 Approval of an application for which approval was previously
refused, suspended, or withdrawn.
314.170 Adulteration and misbranding of an approved drug.
21 CFR 312.160 Subpart D -- Hearing Procedures for New Drugs
314.200 Notice of opportunity for hearing; notice of participation
and request for hearing; grant or denial of hearing.
314.201 Procedure for hearings.
314.235 Judicial review.
21 CFR 312.160 Subpart E -- Administrative Procedures for Antibiotics
314.300 Procedure for the issuance, amendment, or repeal of
regulations.
21 CFR 312.160 Subpart F -- Miscellaneous Provisions
314.410 Imports and exports of new drugs and antibiotics.
314.420 Drug master files.
314.430 Availability for public disclosure of data and information in
an application.
314.440 Addresses for applications.
314.445 Guidelines.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 706 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352,
353, 355, 356, 357, 371, 376).
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
21 CFR 312.160 Subpart A -- General Provisions
21 CFR 314.1 Scope of this part.
(a) This part sets forth procedures and requirements for the
submission to, and the review by, the Food and Drug Administration of
applications and abbreviated applications, as well as amendments,
supplements, and postmarketing reports to them, by persons seeking or
holding approval from FDA of the following:
(1) An application under section 505 of the Federal Food, Drug, and
Cosmetic Act to market a new drug.
(2) An application under section 507 of the Federal Food, Drug, and
Cosmetic Act to market an antibiotic drug.
(b) This part does not apply to drug products subject to licensing by
FDA under the Public Health Service Act (58 Stat. 632 as amended (42
U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the
Code of Federal Regulations.
(c) References in this part to regulations in the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.
21 CFR 314.2 Purpose.
The purpose of this part is to establish an efficient and thorough
drug review process in order to: (a) Facilitate the approval of drugs
shown to be safe and effective; and (b) ensure the disapproval of drugs
not shown to be safe and effective. These regulations are also intended
to establish an effective system for FDA's surveillance of marketed
drugs. These regulations shall be construed in light of these
objectives.
21 CFR 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the act apply to those terms when used in this part.
(b) The following definitions of terms apply to this part:
Act means the Federal Food, Drug, and Cosmetic Act (sections 201-901,
52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).
Applicant means any person who submits an application or abbreviated
application or an amendment or supplement to them under this part to
obtain Food and Drug Administration approval of a new drug or an
antibiotic drug and any person who owns an approved application.
Application means both the application described under 314.50 and
the abbreviated application under 314.55, including all amendments and
supplements.
Approvable letter means a written communication to an applicant from
FDA stating that the agency will approve the application if specific
additional information or material is submitted or specific conditions
are met. An approvable letter does not constitute approval of any part
of an application and does not permit marketing of the drug that is the
subject of the application.
Approval letter means a written communication to an applicant from
FDA approving an application. An approval letter permits marketing of
the drug product that is the subject of the application.
Drug product means a finished dosage form, for example, tablet,
capsule, or solution, that contains a drug substance, generally, but not
necessarily, in association with one or more other ingredients.
Drug substance means an active ingredient that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease or to affect the
structure of any function of the human body, but does not include
intermediates used in the synthesis of such ingredient.
FDA means the Food and Drug Administration.
Not approvable letter means a written communication to an applicant
from FDA stating that the agency does not consider the application
approvable because one or more deficiencies in the application preclude
the agency from approving it.
21 CFR 314.3 Subpart B -- Applications
21 CFR 314.50 Content and format of an application.
Applications, including abbreviated applications, and supplements to
approved applications are required to be submitted in the form and
contain the information, as appropriate for the particular submission,
required under this section. Two copies of the application are
required, an archival copy and a review copy. An application for a new
chemical entity will generally contain an application form, an index, a
summary, five or six technical sections, case report tabulations of
patient data, case report forms, drug samples, and labeling. Other
applications will generally contain only some of those items, and
information will be limited to that needed to support the particular
submission. These include an application for a duplicate of a marketed
drug product (such as a ''paper NDA,'' which relies primarily on
published literature to provide substantial evidence of effectiveness
and adequate scientific evidence of safety for the claimed indications),
an abbreviated application, an amendment, and a supplement. The
application is required to contain reports of all investigations of the
drug product sponsored by the applicant, and all other information about
the drug pertinent to an evaluation of the application that is received
or otherwise obtained by the applicant from any source. The Food and
Drug Administration will maintain guidelines on the format and content
of applications to assist applicants in their preparation.
(a) Application form. The applicant shall submit a completed and
signed application form that contains the following:
(1) The name and address of the applicant; the date of the
application; the application number if previously issued (for example,
if the application is a resubmission, an amendment, or a supplement);
the name of the drug product, including its established, proprietary,
code, and chemical names; the dosage form and strength; the route of
administration; the identification numbers of all investigational new
drug applications that are referenced in the application; the
identification numbers of all drug master files and other applications
under this part that are referenced in the application; and the drug
product's proposed indications for use.
(2) A statement whether the submission is an original submission, a
resubmission, an abbreviated application under 314.55, or a supplement
to an application under 314.70.
(3) A statement whether the applicant proposes to market the drug
product as a prescription or an over-the-counter product.
(4) A check-list identifying what enclosures required under this
section the applicant is submitting.
(5) The applicant, or the applicant's attorney, agent, or other
authorized official shall sign the application. If the person signing
the application does not reside or have a place of business within the
United States, the application is required to contain the name and
address of, and be countersigned by, an attorney, agent, or other
authorized official who resides or maintains a place of business within
the United States.
(b) Index. The archival copy of the application is required to
contain a comprehensive index by volume number and page number to the
summary under paragraph (c) of this section, the technical sections
under paragraph (d) of this section, and the supporting information
under paragraph (f) of this section.
(c) Summary. (1) An application is required to contain a summary of
the application in enough detail that the reader may gain a good general
understanding of the data and information in the application, including
an understanding of the quantitative aspects of the data. The summary
is not required for abbreviated applications under 314.55 and
supplements under 314.70. Resubmissions of an application should
contain an updated summary, as appropriate. The summary should discuss
all aspects of the application, and synthesize the information into a
well-structured and unified document. The summary should be written at
approximately the level of detail required for publication in, and meet
the editorial standards generally applied by, refereed scientific and
medical journals. In addition to the agency personnel reviewing the
summary in the context of their review of the application, FDA may
furnish the summary to FDA advisory committee members and agency
officials whose duties require an understanding of the application. To
the extent possible, data in the summary should be presented in tabular
and graphic forms. FDA has prepared a guideline under 10.90(b) that
provides information about how to prepare a summary. The summary
required under this paragraph may be used by FDA or the applicant to
prepare the Summary Basis of Approval document for public disclosure
(under 314.430(e)(2)(ii)) when the application is approved.
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling for the drug, with annotations
to the information in the summary and technical sections of the
application that support the inclusion of each statement in the
labeling, and, if the application is for a prescription drug, statements
describing the reasons for omitting a section or subsection of the
labeling format in 201.57.
(ii) A statement identifying the pharmacologic class of the drug and
a discussion of the scientific rationale for the drug, its intended use,
and the potential clinical benefits of the drug product.
(iii) A brief description of the marketing history, if any, of the
drug outside the United States, including a list of the countries in
which the drug has been marketed, a list of any countries in which the
drug has been withdrawn from marketing for any reason related to safety
or effectiveness, and a list of countries in which applications for
marketing are pending. The description is required to describe both
marketing by the applicant and, if known, the marketing history of other
persons.
(iv) A summary of the chemistry, manufacturing, and controls section
of the application.
(v) A summary of the nonclinical pharmacology and toxicology section
of the application.
(vi) A summary of the human pharmacokinetics and bioavailability
section of the application.
(vii) A summary of the microbiology section of the application (for
anti-infective drugs only).
(viii) A summary of the clinical data section of the application,
including the results of statistical analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk
considerations related to the drug, including a discussion of any
proposed additional studies or surveillance the applicant intends to
conduct postmarketing.
(d) Technical sections. The application is required to contain the
technical sections described below. Each technical section is required
to contain data and information in sufficient detail to permit the
agency to make a knowledgeable judgment about whether to approve the
application or whether grounds exist under section 505(d) or 507 of the
act to refuse to approve the application. The required technical
sections are as follows:
(1) Chemistry, manufacturing, and controls section. A section
describing the composition, manufacture, and specification of the drug
substance and the drug product, including the following:
(i) Drug substance. A full description of the drug substance
including its physical and chemical characteristics and stability; the
name and address of its manufacturer; the method of synthesis (or
isolation) and purification of the drug substance; the process controls
used during manufacture and packaging; and such specifications and
analytical methods as are necessary to assure the identity, strength,
quality, and purity of the drug substance and the bioavailability of the
drug products made from the substance, including, for example,
specifications relating to stability, sterility, particle size, and
crystalline form. The application may provide additionally for the use
of alternatives to meet any of these requirements, including alternative
sources, process controls, methods, and specifications. Reference to
the current edition of the U.S. Pharmacopeia and the National Formulary
may satisfy relevant requirements in this paragraph.
(ii) Drug product. A list of all components used in the manufacture
of the drug product (regardless of whether they appear in the drug
product); and a statement of the composition of the drug product; a
statement of the specifications and analytical methods for each
component; the name and address of each manufacturer the drug product;
a description of the manufacturing and packaging procedures and
in-process controls for the drug product; such specifications and
analytical methods as are necessary to assure the identity, strength,
quality, purity, and bioavailability of the drug product, including, for
example, specifications relating to sterility, dissolution rate,
containers and closure systems; and stability data with proposed
expiration dating. The application may provide additionally for the use
of alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process controls,
methods, and specifications. Reference to the current edition of the
U.S. Pharmacopeia and the National Formulary may satisfy relevant
requirements in this paragraph.
(iii) Environmental impact. The application is required to contain
either a claim for categorical exclusion under 25.24 of this chapter or
an environmental assessment under 25.31 of this chapter.
(iv) The applicant may, at its option, submit a complete chemistry,
manufacturing, and controls section 90 to 120 days before the
anticipated submission of the remainder of the application. FDA will
review such early submissions as resources permit.
(2) Nonclinical pharmacology and toxicology section. A section
describing, with the aid of graphs and tables, animal and in vitro
studies with drug, including the following:
(i) Studies of the pharmacological actions of the drug in relation to
its proposed therapeutic indication and studies that otherwise define
the pharmacologic properties of the drug or are pertinent to possible
adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate
to the drug's intended clinical uses, including, as appropriate, studies
assessing the drug's acute, subacute, and chronic toxicity;
carcinogenicity; and studies of toxicities related to the drug's
particular mode of administration or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on
reproduction and on the developing fetus.
(iv) Any studies of the absorption, distribution, metabolism, and
excretion of the drug in animals.
(v) For each nonclinical laboratory study subject to the good
laboratory practice regulations under Part 58 a statement that it was
conducted in compliance with the good laboratory practice regulations in
Part 58, or, if the study was not conducted in compliance with those
regulations, a brief statement of the reason for the noncompliance.
(3) Human pharmacokinetics and bioavailability section. A section
describing the human pharmacokinetic data and human bioavailability
data, or information supporting a waiver of the submission of in vivo
bioavailability data under Subpart B of Part 320, including the
following:
(i) A description of each of the bioavailability and pharmacokinetic
studies of the drug in humans performed by or on behalf of the applicant
that includes a description of the analytical and statistical methods
used in each study and a statement with respect to each study that it
either was conducted in compliance with the institutional review board
regulations in Part 56, or was not subject to the regulations under
56.104 or 56.105, and that it was conducted in compliance with the
informed consent regulations in Part 50.
(ii) If the application describes in the chemistry, manufacturing,
and controls section specifications or analytical methods needed to
assure the bioavailability of the drug product or drug substance, or
both, a statement in this section of the rationale for establishing the
specification or analytical methods, including data and information
supporting the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics
and metabolism of the active ingredients and the bioavailability or
bioequivalence, or both, of the drug product.
(4) Microbiology section. If the drug is an anti-infective drug, a
section describing the microbiology data, including the following:
(i) A description of the biochemical basis of the drug's action on
microbial physiology.
(ii) A description of the antimicrobial spectra of the drug,
including results of in vitro preclinical studies to demonstrate
concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the
drug, including results of any known epidemiologic studies to
demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory methods (for
example, in vitro sensitivity discs) needed for effective use of the
drug.
(5) Clinical data section. A section describing the clinical
investigations of the drug, including the following:
(i) A description and analysis of each clinical pharmacology study of
the drug, including a brief comparison of the results of the human
studies with the animal pharmacology and toxicology data.
(ii) A description and analysis of each controlled clinical study
pertinent to a proposed use of the drug, including the protocol and a
description of the statistical analyses used to evaluate the study. If
the study report is an interim analysis, this is to be noted and a
projected completion date provided. Controlled clinical studies that
have not been analyzed in detail for any reason (e.g., because they have
been discontinued or are incomplete) are to be included in this section,
including a copy of the protocol and a brief description of the results
and status of the study.
(iii) A description of each uncontrolled clinical study, a summary of
the results, and a brief statement explaining why the study is
classified as uncontrolled.
(iv) A description and analysis of any other data or information
relevant to an evaluation of the safety and effectiveness of the drug
product obtained or otherwise received by the applicant from any source,
foreign or domestic, including information derived from clinical
investigations, including controlled and uncontrolled studies of uses of
the drug other than those proposed in the application, commercial
marketing experience, reports in the scientific literature, and
unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial
evidence of effectiveness for the claimed indications. Evidence is also
required to support the dosage and administration section of the
labeling, including support for the dosage and dose interval
recommended, and modifications for specific subgroups (for example,
pediatrics, geriatrics, patients with renal failure).
(vi) A summary and updates of safety information, as follows:
(a) The applicant shall submit an integrated summary of all available
information about the safety of the drug product, including pertinent
animal data, demonstrated or potential adverse effects of the drug,
clinically significant drug/drug interactions, and other safety
considerations, such as data from epidemiological studies of related
drugs. A description of any statistical analyses performed in analyzing
safety data should also be included, unless already included under
paragraph (a)(5)(ii) of this section.
(b) The applicant shall, under section 505(i) of the act, update
periodically its pending application with new safety information learned
about the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
draft labeling. These ''safety update reports'' are required to include
the same kinds of information (from clinical studies, animal studies,
and other sources) and are required to be submitted in the same format
as the integrated summary in paragraph (d)(5)(vi)(a) of this section.
In addition, the reports are required to include the case report forms
for each patient who died during a clinical study or who did not
complete the study because of an adverse event (unless this requirement
is waived). The applicant shall submit these reports (1) 4 months after
the initial submission; (2) following receipt of an approvable letter;
and (3) at other times as requested by FDA. Prior to the submission of
the first such report, applicants are encouraged to consult with FDA
regarding further details on its form and content.
(vii) If the drug has a potential for abuse, a description and
analysis of studies or information related to abuse of the drug,
including a proposal for scheduling under the Controlled Substances Act.
A description of any studies related to overdosage is also required,
including information on dialysis, antidotes, or other treatments, if
known.
(viii) An integrated summary of the benefits and risks of the drug,
including a discussion of why the benefits exceed the risks under the
conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human
subjects that it either was conducted in compliance with the
institutional review board regulations in Part 56, or was not subject to
the regulations under 56.104 or 56.105, and that it was conducted in
compliance with the informed consent regulations in Part 50.
(x) If a sponsor has transferred any obligations for the conduct of
any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer -- in lieu of a
listing of the specific obligations transferred -- may be submitted.
(xi) If original subject records were audited or reviewed by the
sponsor in the course of monitoring any clinical study to verify the
accuracy of the case reports submitted to the sponsor, a list
identifying each clinical study so audited or reviewed.
(6) Statistical section. A section describing the statistical
evaluation of clinical data, including the following:
(i) A copy of the information submitted under paragraph (d)(5)(ii) of
this section concerning the description and analysis of each controlled
clinical study, and the documentation and supporting statistical
analyses used in evaluating the controlled clinical studies.
(ii) A copy of the information submitted under paragraph
(d)(5)(vi)(a) of this section concerning a summary of information about
the safety of the drug product, and the documentation and supporting
statistical analyses used in evaluating the safety information.
(e) Samples and labeling. (1) Upon request from FDA, the applicant
shall submit the samples described below to the places identified in the
agency's request. FDA will generally ask applicants to submit samples
directly to two or more agency laboratories that will perform all
necessary tests on the samples and validate the applicant's analytical
methods.
(i) Four representative samples of the following, each sample in
sufficient quantity to permit FDA to perform three times each test
described in the application to determine whether the drug substance and
the drug product meet the specifications given in the application:
(a) The drug product proposed for marketing;
(b) The drug substance used in the drug product from which the
samples of the drug product were taken; and
(c) Reference standards and blanks (except that reference standards
recognized in an official compendium need not be submitted).
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant shall submit the following in the archival copy of
the application:
(i) Three copies of the analytical methods and related descriptive
information contained in the chemistry, manufacturing, and controls
section under paragraph (d)(1) of this section for the drug substance
and the drug product that are necessary for FDA's laboratories to
perform all necessary tests on the samples and to validate the
applicant's analytical methods. The related descriptive information
includes a description of each sample; the proposed regulatory
specifications for the drug; a detailed description of the methods of
analysis; supporting data for accuracy, specificity, precision and
ruggedness; and complete results of the applicant's tests on each
sample.
(ii) Copies of the label and all labeling for the drug product (4
copies of draft labeling or 12 copies of final printed labeling).
(f) Case report forms and tabulations. The archival copy of the
application is required to contain the following case report tabulations
and case report forms:
(1) Case report tabulations. The application is required to contain
tabulations of the data from each adequate and well-controlled study
under 314.126 (Phase 2 and Phase 3 studies as described in 312.21 (b)
and (c) of this chapter), tabulations of the data from the earliest
clinical pharmacology studies (Phase 1 studies as described in
312.21(a) of this chapter), and tabulations of the safety data from
other clinical studies. Routine submission of other patient data from
uncontrolled studies is not required. The tabulations are required to
include the data on each patient in each study, except that the
applicant may delete those tabulations which the agency agrees, in
advance, are not pertinent to a review of the drug's safety or
effectiveness. Upon request, FDA will discuss with the applicant in a
''pre-NDA'' conference those tabulations that may be appropriate for
such deletion. Barring unforeseen circumstances, tabulations agreed to
be deleted at such a conference will not be requested during the conduct
of FDA's review of the application. If such unforeseen circumstances do
occur, any request for deleted tabulations will be made by the director
of the FDA division responsible for reviewing the application, in
accordance with paragraph (f)(3) of this section.
(2) Case report forms. The application is required to contain copies
of individual case report forms for each patient who died during a
clinical study or who did not complete the study because of an adverse
event, whether believed to be drug related or not, including patients
receiving reference drugs or placebo. This requirement may be waived by
FDA for specific studies if the case report forms are unnecessary for a
proper review of the study.
(3) Additional data. The applicant shall submit to FDA additional
case report forms and tabulations needed to conduct a proper review of
the application, as requested by the director of the FDA division
responsible for reviewing the application. The applicant's failure to
submit information requested by FDA within 30 days after receipt of the
request may result in the agency viewing any eventual submission as a
major amendment under 314.60 and extending the review period as
necessary. If desired by the applicant, the FDA division director will
verify in writing any request for additional data that was made orally.
(4) Applicants are invited to meet with FDA before submitting an
application to discuss the presentation and format of supporting
information. If the applicant and FDA agree, the applicant may submit
tabulations of patient data and case report forms in a form other than
hard copy, for example, on microfiche or computer tapes.
(g) Other. The following general requirements apply to the
submission of information within the summary under paragraph (c) of this
section and within the technical sections under paragraph (d) of this
section.
(1) The applicant ordinarily is not required to resubmit information
previously submitted, but may incorporate the information by reference.
A reference to information submitted previously is required to identify
the file by name, reference number, volume, and page number in the
agency's records where the information can be found. A reference to
information submitted to the agency by a person other than the applicant
is required to contain a written statement that authorizes the reference
and that is signed by the person who submitted the information.
(2) The applicant shall submit an accurate and complete English
translation of each part of the application that is not in English. The
applicant shall submit a copy of each original literature publication
for which an English translation is submitted.
(h) Format of an original application. (1) The applicant shall
submit a complete archival copy of the application that contains the
information required under paragraphs (a) through (f) of this section.
FDA will maintain the archival copy during the review of the application
to permit individual reviewers to refer to information that is not
contained in their particular technical sections of the application, to
give other agency personnel access to the application for official
business, and to maintain in one place a complete copy of the
application. An applicant may submit on microfiche the portions of the
archival copy of the application described in paragraphs (b) through (d)
of this section. Information relating to samples and labeling,
described in paragraph (e) of this section, is required to be submitted
in hard copy. Tabulations of patient data and case report forms,
described in paragraph (f) of this section, may be submitted on
microfiche only if the applicant and FDA agree. If FDA agrees, the
applicant may use another suitable microform system.
(2) The applicant shall submit a review copy of the application.
Each of the technical sections (described in paragraphs (d) (1) through
(6) of this section) in the review copy is required to be separately
bound with a copy of the application form required under paragraph (a)
of this section and a copy of the summary required under paragraph (c)
of this section. The applicant may obtain from FDA sufficient folders
to bind the archival and review copies of the application.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 16668, Apr. 26, 1985; 50 FR 21238, May 23, 1985; 52 FR 8847,
Mar. 19, 1987; 55 FR 11580, Mar. 29, 1990)
21 CFR 314.55 Abbreviated application.
(a) An abbreviated application is an application in which reports of
nonclinical laboratory studies and reports of clinical investigations
(except those pertaining to in vivo bioavailability of the drug product)
may be omitted. The information may be omitted when the Food and Drug
Administration has determined that the information already available to
it is adequate to establish that a particular dosage form of a drug
meets the statutory standards for safety and effectiveness. An
abbreviated application will usually be reserved for duplicates of drug
products previously approved under a full application under 314.50. An
abbreviated application is not required to comply with the requirements
in 314.50 (c), (d)(2), (4), (5), (6), and (f).
(b) FDA will file an abbreviated application only if it has made a
finding that an abbreviated application is suitable for a drug product.
If FDA finds that a drug product may be approved for marketing on the
basis of an abbreviated application, it will make that finding publicly
available, as follows:
(1) If the finding applies to a broad category of drug products, the
agency will amend 314.56 to identify the category in that section.
(2) If the finding applies to a drug product because it is so closely
related to a product for which an abbreviated application is suitable
that the same conclusions about safety and effectiveness apply to it,
the agency will make the finding public by updating its list of drug
products for which abbreviated applications are suitable. The list is
available from the National Technical Information Service, Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161.
(3) If the finding applies to duplicates of a drug product that is
subject to FDA's Drug Efficacy Study Implementation program (a review of
drug products approved as safe between 1938 and 1962), the agency will
make that finding public through a notice published in the Federal
Register.
(c)(1) A finding by FDA that an abbreviated application is suitable
for a drug product applies only to a product that is the same in active
ingredient, dosage form and strength, route of administration, and
conditions of use as the drug product that was the subject of the
finding. For a drug product that is similar but different in one or
more of these characteristics, an abbreviated application will be
accepted only if FDA has made a separate finding of suitability.
However, filing of an abbreviated application for a drug product does
not signify that the product is safe and effective until the application
is approved.
(2) A finding that a drug product is a new drug because it is similar
to a product that is a new drug, and is therefore subject to the
requirements of this part, does not include a finding that an
abbreviated application is suitable for the similar product.
(3) A finding that a single-active-entity drug product is safe and
effective and that an abbreviated application is suitable is not a basis
for determining that a combination drug product containing that entity
as one of its ingredients is either safe or effective or that an
abbreviated application is suitable. The finding also is not a basis
for determining that the combination drug product meets all of the
requirements for combination drugs as described in 300.50.
(d) (1) A person may seek a determination of the suitability of an
abbreviated application for a product that the person believes is
similar or related to a drug product that has been declared to be
suitable for an abbreviated application. Extension of the finding that
a drug product is safe and effective to another product will ordinarily
be limited to other dosage forms for the same route of administration or
to closely related ingredients. If preclinical or clinical evidence is
needed to support the safety, or if clinical evidence is needed to
support the effectiveness, of the proposed product, then an abbreviated
application is not appropriate for the similar or related drug product.
(2) A person seeking a determination that an abbreviated application
is suitable for a similar or related drug product shall use the petition
procedures established in 10.30. The petitioner shall set forth the
reasons that justify extending the finding that an abbreviated
application is suitable for one product to the similar or related
product proposed to be marketed.
(3) An application submitted in the form of an abbreviated
application for a drug product that has not been the subject of a
finding that allows an abbreviated application for the product will be
considered to be a petition under 10.30 and will be processed as such.
(e) Each abbreviated application is required to contain a reference
to FDA's finding that an abbreviated application is suitable for the
specific product that is the subject of the application and to contain
both an archival and a review copy of the application.
(1) The applicant shall submit a complete archival copy of the
application that contains the information required under 314.50 (a),
(b), (d)(1) and (3), (e), and (g). An applicant may submit the archival
copy of the application on microfiche or, if FDA agrees, another
suitable microform system.
(2) The applicant shall submit a review copy that contains the
technical sections described in 314.50(d)(1) and (3). Each of the
technical sections in the review copy is required to be separately bound
with a copy of the application form required under 314.50(a).
(3) The applicant may obtain from FDA sufficient folders to bind the
archival and the review copies of the application.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985)
21 CFR 314.56 Drug products for which abbreviated applications are
suitable.
Abbreviated applications are suitable for the following drugs within
the limits set forth in 314.55(c):
(a) Duplicates of drug products that were first approved before
October 10, 1962, and reformulations of these products, if the original
or reformulated product has been evaluated as part of the drug efficacy
study and announced by notice in the Federal Register as effective for
one or more indications, and if the Food and Drug Administration has
made a finding that an abbreviated application is suitable.
(b) (Reserved)
(c) Drug products that are very closely related to a product
described in paragraph (a) of this section and that are subject to a
separate finding of suitability for marketing under an abbreviated
application.
(d) Drug products that contain a chlorofluorocarbon determined to be
an essential use and identified in 2.125(h)(2) as suitable for an
abbreviated application.
(e) Duplicates of an antibiotic drug for which FDA has approved an
application.
21 CFR 314.60 Amendments to an unapproved application.
The applicant may submit an amendment to an application that is filed
under 314.100, but not yet approved. The submission of a major
amendment (for example, an amendment that contains significant new data
from a previously unreported study or detailed newnalyses of previously
submitted data), whether on the applicant's own initiative or at the
invitation of the agency, constitutes an agreement by the applicant
under section 505(c) of the act to extend the date by which the agency
is required to reach a decision on the application. Ordinarily, the
agency will extend the review period for a major amendment but only for
the time necessary to review the new information. However, the agency
may not extend the review period more than 180 days. If the agency
extends the review period for the application, the director of the
division responsible for reviewing the application will notify the
applicant of the length of the extension. The submission of an
amendment that is not a major amendment will not extend the review
period.
21 CFR 314.65 Withdrawal by the applicant of an unapproved application.
An applicant may at any time withdraw an application that is not yet
approved by notifying the Food and Drug Administration in writing. The
agency will consider an applicant's failure to respond within 10 days to
an approvable letter under 314.110 or a not approvable letter under
314.120 to be a request by the applicant to withdraw the application. A
decision to withdraw the application is without prejudice to refiling.
The agency will retain the application and will provide a copy to the
applicant on request under the fee schedule in 20.42 of FDA's public
information regulations.
21 CFR 314.70 Supplements and other changes to an approved application.
(a) Changes to an approved application. The applicant shall notify
the Food and Drug Administration about each change in each condition
established in an approved application beyond the variations already
provided for in the application. The notice is required to describe the
change fully. Depending on the type of change, the applicant shall
notify FDA about it in a supplemental application under paragraph (b) or
(c) of this section or by inclusion of the information in the annual
report to the application under paragraph (d) of this section.
Notwithstanding the requirements of paragraphs (b) and (c) of this
section, an applicant shall make a change provided for in those
paragraphs (for example, the deletion of an ingredient common to many
drug products) in accordance with a guideline, notice, or regulation
published in the Federal Register that provides for a less burdensome
notification of the change (for example, by notification at the time a
supplement is submitted or in the next annual report).
(b) Supplements requiring FDA approval before the change is made. An
applicant shall submit a supplement, and obtain FDA approval of it,
before making the changes listed below in the conditions in an approved
application, unless the change is made to comply with an official
compendium. An applicant may ask FDA to expedite its review of a
supplement if a delay in making the change described in it would impose
an extraordinary hardship on the applicant. Such a supplement and its
mailing cover should be plainly marked: ''Supplement -- Expedited
Review Requested.''
(1) Drug substance. A change affecting the drug substance to
accomplish any of the following:
(i) To relax the limits for a specification;
(ii) To establish a new regulatory analytical method;
(iii) To delete a specification or regulatory analytical method;
(iv) To change the synthesis of the drug substance, including a
change in solvents and a change in the route of synthesis.
(v) To use a different facility or establishment to manufacture the
drug substance, where: (a) the manufacturing process in the new
facility or establishment differs materially from that in the former
facility or establishment, or (b) the new facility or establishment has
not received a satisfactory current good manufacturing practice (CGMP)
inspection within the previous 2 years covering that manufacturing
process.
(2) Drug product. A change affecting the drug product to accomplish
any of the following:
(i) To add or delete an ingredient, or otherwise to change the
composition of the drug product, other than deletion of an ingredient
intended only to affect the color of the drug product;
(ii) To relax the limits for a specification;
(iii) To establish a new regulatory analytical method;
(iv) To delete a specification or regulatory analytical method;
(v) To change the method of manufacture of the drug product,
including changing or relaxing an in-process control;
(vi) To use a different facility or establishment, including a
different contract laboratory or labeler, to manufacture, process, or
pack the drug product;
(vii) To change the container and closure system for the drug product
(for example, glass to high density polyethylene (HDPE), or HDPE to
polyvinyl chloride) or change a specification or regulatory analytical
method for the container and closure system;
(viii) To change the size of the container, except for solid dosage
forms, without a change in the container and closure system.
(ix) To extend the expiration date of the drug product based on data
obtained under a new or revised stability testing protocol that has not
been approved in the application.
(x) To establish a new procedure for reprocessing a batch of the drug
product that fails to meet specifications.
(3) Labeling. Any change in labeling, except one described in
paragraph (c)(2) or (d) of this section.
(c) Supplements for changes that may be made before FDA approval. An
applicant shall submit a supplement at the time the applicant makes any
kind of change listed below in the conditions in an approved
application, unless the change is made to comply with an official
compendium. A supplement under this paragraph is required to give a
full explanation of the basis for the change, identify the date on which
the change is made, and, if the change concerns labeling, include 12
copies of final printed labeling. The applicant shall promptly revise
all promotional labeling and drug advertising to make it consistent with
any change in the labeling. The supplement and its mailing cover should
be plainly marked: ''Special Supplement -- Changes Being Effected.''
(1) Adds a new specification or test method or changes in the
methods, facilities (except a change to a new facility), or controls to
provide increased assurance that the drug will have the characteristics
of identity, strength, quality, and purity which it purports or is
represented to possess;
(2) Changes labeling to accomplish any of the following:
(i) To add or strengthen a contraindication, warning, precaution, or
adverse reaction;
(ii) To add or strengthen a statement about drug abuse, dependence,
or overdosage; or
(iii) To add or strengthen an instruction about dosage and
administration that is intended to increase the safe use of the product.
(iv) To delete false, misleading, or unsupported indications for use
or claims for effectiveness.
(3) To use a different facility or establishment to manufacture the
drug substance, where: (i) The manufacturing process in the new
facility or establishment does not differ materially from that in the
former facility or establishment, and (ii) the new facility or
establishment has received a satisfactory current good manufacturing
practice (CGMP) inspection within the previous 2 years covering that
manufacturing process.
(d) Changes described in the annual report. An applicant shall not
submit a supplement to make any change in the conditions in an approved
application, unless otherwise required under paragraph (b) or (c) of
this section, but shall describe the change in the next annual report
required under 314.81. Some examples of changes that can be described
in the annual report are the following:
(1) Any change made to comply with an official compendium.
(2) A change in the labeling concerning the description of the drug
product or in the information about how the drug product is supplied,
that does not involve a change in the dosage strength or dosage form.
(3) An editorial or similar minor change in labeling.
(4) The deletion of an ingredient intended only to affect the color
of the drug product.
(5) An extension of the expiration date based upon full shelf-life
data obtained from a protocol approved in the application.
(6) A change within the container and closure system for the drug
product (for example, a change from one high density polyethylene (HDPE)
to another HDPE), except a change in container size for nonsolid dosage
forms, based upon a showing of equivalency to the approved system under
a protocol approved in the application or published in an official
compendium.
(7) The addition or deletion of an alternate analytical method.
(8) A change in the size of a container for a solid dosage form,
without a change from one container and closure system to another.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985)
21 CFR 314.71 Procedures for submission of a supplement to an approved
application.
(a) Only the applicant may submit a supplement to an application.
(b) All procedures and actions that apply to an application under
314.50 and an abbreviated application under 314.55 also apply to
supplements, except that the information required in the supplement is
limited to that needed to support the change. A supplement is required
to contain an archival copy and a review copy that include an
application form and appropriate technical sections, samples, and
labeling.
(c) All procedures and actions that apply to applications under this
part, including actions by applicants and the Food and Drug
Administration, also apply to supplements.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985)
21 CFR 314.72 Change in ownership of an application.
(a) An applicant may transfer ownership of its application. At the
time of transfer the new and former owners are required to submit
information to the Food and Drug Administration as follows:
(1) The former owner shall submit a letter or other document that
states that all rights to the application have been transferred to the
new owner.
(2) The new owner shall submit an application form signed by the new
owner and a letter or other document containing the following:
(i) The new owner's commitment to agreements, promises, and
conditions made by the former owner and contained in the application;
(ii) The date that the change in ownership is effective; and
(iii) Either a statement that the new owner has a complete copy of
the approved application, including supplements and records that are
required to be kept under 314.81, or a request for a copy of the
application from FDA's files. FDA will provide a copy of the
application to the new owner under the fee schedule in 20.42 of FDA's
public information regulations.
(b) The new owner shall advise FDA about any change in the conditions
in the approved application under 314.70, except the new owner may
advise FDA in the next annual report about a change in the drug
product's label or labeling to change the product's brand or the name of
its manufacturer, packer, or distributor.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985)
21 CFR 314.80 Postmarketing reporting of adverse drug experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience means any adverse event associated with the
use of a drug in humans, whether or not considered drug related,
including the following: an adverse event occurring in the course of
the use of a drug product in professional practice; an adverse event
occurring from drug overdose, whether accidental or intentional; an
adverse event occurring from drug abuse; an adverse event occurring
from drug withdrawal; and any significant failure of expected
pharmacological action.
Increased frequency means an increase in the rate of occurrence of a
particular adverse drug experience, e.g., an increased number of reports
of a particular adverse drug experience after appropriate adjustment for
drug exposure.
Serious means an adverse drug experience that is fatal or
life-threatening, is permanently disabling, requires inpatient
hospitalization, or is a congenital anomaly, cancer, or overdose.
Unexpected means an adverse drug experience that is not listed in the
current labeling for the drug and includes an event that may be
symptomatically and pathophysiologically related to an event listed in
the labeling, but differs from the event because of greater severity or
specificity. For example, under this definition, hepatic necrosis would
be unexpected (by virtue of greater severity) if the labeling only
referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the labeling only listed cerebral vascular
accidents.
(b) Review of adverse drug experiences. Each applicant having an
approved application under 314.50 or 314.55 shall promptly review all
adverse drug experience information obtained or otherwise received by
the applicant from any source, foreign or domestic, including
information derived from commercial marketing experience, postmarketing
clinical investigations, postmarketing epidemiological/surveillance
studies, reports in the scientific literature, and unpublished
scientific papers.
(c) Reporting requirements. The applicant shall report to FDA
adverse drug experience information, as described in this section. The
applicant shall submit two copies of each report described in this
section to the Central Document Room, Park Bldg., Rm. 214, 12420
Parklawn Dr., Rockville, MD 20852. FDA may waive the requirement for
the second copy in appropriate instances.
(1) Fifteen-day ''Alert reports.'' (i) The applicant shall report
each adverse drug experience that is both serious and unexpected,
regardless of source, as soon as possible but in any case within 15
working days of initial receipt of the information. These reports are
required to be submitted on Form FDA-1639 (Adverse Reaction Report).
The applicant shall promptly investigate all adverse drug experiences
that are the subject of these 15-day Alert reports and shall submit
followup reports within 15 working days of receipt of new information or
as requested by FDA. If additional information is not obtainable, a
followup report may be required that describes briefly the steps taken
to seek additional information and the reasons why it could not be
obtained. These 15-day Alert reports and followups to them are required
to be submitted under separate cover and may not be included, except for
summary or tabular purposes, in a periodic report.
(ii) The applicant shall review periodically (at least as often as
the periodic reporting cycle) the frequency of reports of adverse drug
experiences that are both serious and expected, regardless of source,
and report any significant increase in frequency as soon as possible but
in any case within 15 working days of determining that a significant
increase in frequency exists. Upon written notice, FDA may require that
applicants review the frequency of reports of serious, expected adverse
drug experiences at intervals different than the periodic reporting
cycle. Reports of a significant increase in frequency are required to
be submitted in narrative form (including the time period on which the
increased frequency is based, the method of analysis, and the
interpretation of the results), rather than using Form FDA-1639.
Fifteen-day Alert reports based on increased frequency are required to
be submitted under separate cover and may not be included, except for
summary purposes, in a periodic report.
(iii) The requirements of paragraphs (c)(1) (i) and (ii) of this
section, concerning the submission of 15-day alert reports, shall also
apply to any person (other than the applicant) whose name appears on the
label of an approved drug product as a manufacturer, packer, or
distributor. However, in order to avoid unnecessary duplication in the
submission to FDA, and followup to, reports required by paragraph (c)(1)
(i) and (ii) of this section, obligations of a nonapplicant may be met
by submission of all reports of serious adverse drug experiences to the
applicant. If a nonapplicant elects to submit adverse drug experience
reports to the applicant rather than to FDA, it shall submit each report
to the applicant within 3 working days of its receipt by the
nonapplicant, and the applicant shall then comply with the requirements
of this section. Under this circumstance, the nonapplicant shall
maintain a record of this action which shall include:
(a) A copy of the drug experience report.
(b) Date the report was received by the nonapplicant.
(c) Date the report was submitted to the applicant.
(d) Name and address of the applicant.
(iv) Each report submitted under this paragraph shall bear prominent
identification as to its contents, i.e., ''15-day Alert report'' or
''15-day Alert report -- followup.''
(2) Periodic adverse drug experience reports. (i) The applicant
shall report each adverse drug experience not reported under paragraph
(c)(1)(i) of this section at quarterly intervals, for 3 years from the
date of approval of the application, and then at annual intervals. The
applicant shall submit each quarterly report within 30 days of the close
of the quarter (the first quarter beginning on the date of approval of
the application) and each annual report within 60 days of the
anniversary date of approval of the application. Upon written notice,
FDA may extend or reestablish the requirement that an applicant submit
quarterly reports, or require that the applicant submit reports under
this section at different times than those stated. For example, the
agency may reestablish a quarterly reporting requirement following the
approval of a major supplement. Followup information to adverse drug
experiences submitted in a periodic report may be submitted in the next
periodic report.
(ii) Each periodic report is required to contain: (a) a narrative
summary and analysis of the information in the report and an analysis of
the 15-day Alert reports submitted during the reporting interval (all
15-day Alert reports being appropriately referenced by the applicant's
patient identification number, adverse reaction term(s), and date of
submission to FDA); (b) a Form FDA-1639 (Adverse Reaction Report) for
each adverse drug experience not reported under paragraph (c)(1)(i) of
this section (with an index consisting of a line listing of the
applicant's patient identification number and adverse reaction term(s));
and (c) a history of actions taken since the last report because of
adverse drug experiences (for example, labeling changes or studies
initiated).
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse drug experience information
obtained from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. (1) A 15-day Alert report based on
information from the scientific literature is required to be accompanied
by a copy of the published article. The 15-day reporting requirements
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected
adverse drug experiences) apply only to reports found in scientific and
medical journals either as case reports or as the result of a formal
clinical trial. The 15-day reporting requirements in paragraph
(c)(1)(ii) of this section (i.e., a significant increase in frequency of
a serious, expected adverse drug experience) apply only to reports found
in scientific and medical journals either as the result of a formal
clinical trial, or from epidemiologic studies or analyses of experience
in a monitored series of patients.
(2) As with all reports submitted under paragraph (c)(1)(i) of this
section, reports based on the scientific literature shall be submitted
on Form FDA-1639 or comparable format as prescribed by paragraph (f) of
this section. In cases where the applicant believes that preparing the
Form FDA-1639 constitutes an undue hardship, the applicant may arrange
with the Division of Epidemiology and Surveillance for an acceptable
alternative reporting format.
(e) Postmarketing studies. (1) An applicant is not required to
submit a 15-day Alert report under paragraph (c) of this section for an
adverse drug experience obtained from a postmarketing study (whether or
not conducted under an investigational new drug application) unless the
applicant concludes that there is a reasonable possibility that the drug
caused the adverse experience.
(2) The applicant shall separate and clearly mark reports of adverse
drug experiences that occur during a postmarketing study as being
distinct from those experiences that are being reported spontaneously to
the applicant.
(f) Reporting Form FDA-1639. (1) Except as provided in paragraphs
(c)(1)(ii) and (f)(3) of this section, the applicant shall complete a
Form FDA-1639 (Adverse Reaction Report) for each report of an adverse
drug experience.
(2) Each completed Form FDA-1639 should refer only to an individual
patient or a single attached publication.
(3) Instead of using Form FDA-1639, an applicant may use a
computer-generated FDA-1639 or other alternative format (e.g., a
computer-generated tape or tabular listing) provided that: (i) The
content of the alternative format is equivalent in all elements of
information to those specified in Form FDA-1639; and (ii) the format is
agreed to in advance by the Division of Epidemiology and Surveillance
(HFD-730).
(4) Single copies of Form FDA-1639 may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the
PHS Forms and Publications Distribution Center, 12100 Parklawn Dr.,
Rockville, MD 20857.
(g) Multiple reports. An applicant should not include in reports
under this section any adverse drug experiences that occurred in
clinical trials if they were previously submitted as part of the
approved application. If a report applies to a drug for which an
applicant holds more than one approved application, the applicant should
submit the report to the application that was first approved. If a
report refers to more than one drug marketed by an applicant, the
applicant should submit the report to the application for the drug
listed first in the report.
(h) Patient privacy. An applicant should not include in reports
under this section the names and addresses of individual patients;
instead, the applicant should assign a unique code number to each
report, preferably not more than eight characters in length. The
applicant should include the name of the reporter from whom the
information was received. Names of patients, health care professionals,
hospitals, and geographical identifiers in adverse drug experience
reports are not releasable to the public under FDA's public information
regulations in Part 20.
(i) Recordkeeping. The applicant shall maintain for a period of 10
years records of all adverse drug experiences known to the applicant,
including raw data and any correspondence relating to adverse drug
experiences.
(j) Guideline. FDA has prepared under 10.90(b) a guideline for the
submission of reports of adverse drug experiences and suggested followup
investigation of reports.
(k) Withdrawal of approval. If an applicant fails to establish and
maintain records and make reports required under this section, FDA may
withdraw approval of the application and, thus, prohibit continued
marketing of the drug product that is the subject of the application.
(l) Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the applicant
or FDA that the report or information constitutes an admission that the
drug caused or contributed to an adverse effect. An applicant need not
admit, and may deny, that the report or information submitted under this
section constitutes an admission that the drug caused or contributed to
an adverse effect. For purposes of this provision, the term
''applicant'' also includes any person reporting under paragraph
(c)(1)(iii) of this section.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985; 51 FR 24481, July 3, 1986; 52 FR 37936,
Oct. 13, 1987; 55 FR 11580, Mar. 29, 1990)
21 CFR 314.81 Other postmarketing reports.
(a) Applicability. Each applicant shall make the reports for each of
its approved applications and abbreviated applications required under
this section and sections 505(k) and 507(g) of the act.
(b) Reporting requirements. The applicant shall submit to the Food
and Drug Administration at the specified times two copies of the
following reports:
(1) NDA -- Field alert report. The applicant shall submit
information of the following kinds about distributed drug products and
articles to the FDA district office that is responsible for the facility
involved within 3 working days of receipt by the applicant. The
information may be provided by telephone or other rapid communication
means, with prompt written followup. The report and its mailing cover
should be plainly marked: ''NDA -- Field Alert Report.''
(i) Information concerning any incident that causes the drug product
or its labeling to be mistaken for, or applied to, another article.
(ii) Information concerning any bacteriological contn, or any
significant chemical, physical, or other change or deterioration in the
distributed drug product, or any failure of one or more distributed
batches of the drug product to meet the specifications established for
it in the application.
(2) Annual report. The applicant shall submit the following
information in the order listed each year within 60 days of the
anniversary date of approval of the application. The applicant shall
submit the report to the FDA division responsible for reviewing the
application. Each annual report is required to be accompanied by a
completed transmittal Form FDA-2252 (Transmittal of Periodic Reports for
Drugs for Human Use) which may be obtained from the PHS Forms and
Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD
20857, and is required to include all the information required under
this section that the applicant received or otherwise obtained during
the annual reporting interval which ends on the anniversary date. The
report is required to contain the following:
(i) Summary. A brief summary of significant new information from the
previous year that might affect the safety, effectiveness, or labeling
of the drug product. The report is also required to contain a brief
description of actions the applicant has taken or intends to take as a
result of this new information, for example, submit a labeling
supplement, add a warning to the labeling, or initiate a new study.
(ii) Distribution data. Information about the quantity of the drug
product distributed under the approved application, including that
distributed to distributors. The information is required to include the
National Drug Code (NDC) number, the total number of dosage units of
each strength or potency distributed (e.g., 100,000/5 milligram tablets,
50,000/10 milliliter vials), and the quantities distributed for domestic
use and the quantities distributed for foreign use. Disclosure of
financial or pricing data is not required.
(iii) Labeling. Currently used professional labeling, patient
brochures or package inserts (if any), a representative sample of the
package labels, and a summary of any changes in labeling that have been
made since the last report listed by date in the order in which they
were implemented, or if no changes, a statement of that fact.
(iv) Chemistry, manufacturing, and controls changes. (a) Reports of
experiences, investigations, studies, or tests involving chemical or
physical properties, or any other properties of the drug (such as the
drug's behavior or properties in relation to microorganisms, including
both the effects of the drug on microorganisms and the effects of
microorganisms on the drug). These reports are only required for new
information that may affect FDA's previous conclusions about the safety
or effectiveness of the drug product.
(b) A full description of the manufacturing and controls changes not
requiring a supplemental application under 314.70 (b) and (c), listed
by date in the order in which they were implemented.
(v) Nonclinical laboratory studies. Copies of unpublished reports
and summaries of published reports of new toxicological findings in
animal studies and in vitro studies (e.g., mutagenicity) conducted by,
or otherwise obtained by, the applicant concerning the ingredients in
the drug product. The applicant shall submit a copy of a published
report if requested by FDA.
(vi) Clinical data. (a) Published clinical trials of the drug (or
abstracts of them), including clinical trials on safety and
effectiveness; clinical trials on new uses; biopharmaceutic,
pharmacokinetic, and clinical pharmacology studies; and reports of
clinical experience pertinent to safety (for example, epidemiologic
studies or analyses of experience in a monitored series of patients)
conducted by or otherwise obtained by the applicant. Review articles,
papers describing the use of the drug product in medical practice,
papers and abstracts in which the drug is used as a research tool,
promotional articles, press clippings, and papers that do not contain
tabulations or summaries of original data should not be reported.
(b) Summaries of completed unpublished clinical trials, or
prepublication manuscripts if available, conducted by, or otherwise
obtained by, the applicant. Supporting information should not be
reported. (A study is considered completed 1 year after it is
concluded.)
(vii) Status reports. A statement on the current status of any
postmarketing studies performed by, or on behalf of, the applicant. To
facilitate communications between FDA and the applicant, the report may,
at the applicant's discretion, also contain a list of any open
regulatory business with FDA concerning the drug product subject to the
application.
(3) Other reporting -- (i) Advertisements and promotional labeling. .
The applicant shall submit specimens of mailing pieces and any other
labeling or advertising devised for promotion of the drug product at the
time of initial dissemination of the labeling and at the time of initial
publication of the advertisement for a prescription drug product.
Mailing pieces and labeling that are designed to contain samples of a
drug product are required to be complete, except the sample of the drug
product may be omitted. Each submission is required to be accompanied
by a completed transmittal Form FDA-2253 (Transmittal of Advertisements
and Promotional Labeling for Drugs for Human Use) and is required to
include a copy of the product's current professional labeling. Form
FDA-2253 may be obtained from the PHS Forms and Publications
Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857.
(ii) Special reports. Upon written request the agency may require
that the applicant submit the reports under this section at different
times than those stated.
(c) General requirements -- (1) Multiple applications. For all
reports required by this section, the applicant shall submit the
information common to more than one application only to the application
first approved, and shall not report separately on each application.
The submission is required to identify all the applications to which the
report applies.
(2) Patient identification. Applicants should not include in reports
under this section the names and addresses of individual patients;
instead, the applicant should code the patient names whenever possible
and retain the code in the applicant's files. The applicant shall
maintain sufficient patient identification information to permit FDA, by
using that information alone or along with records maintained by the
investigator of a study, to identify the name and address of individual
patients; this will ordinarily occur only when the agency needs to
investigate the reports further or when there is reason to believe that
the reports do not represent actual results obtained.
(d) Withdrawal of approval. If an applicant fails to make reports
required under this section, FDA may withdraw approval of the
application and, thus, prohibit continued marketing of the drug product
that is the subject of the application.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990)
21 CFR 314.90 Waivers.
(a) An applicant may ask the Food and Drug Administration to waive
under this section any requirement that applies to the applicant under
314.50 through 314.81. An applicant may ask FDA to waive under
314.126(c) any criteria of an adequate and well-controlled study
described in 314.126(b). A waiver request under this section is
required to be submitted with supporting documentation in an
application, or in an amendment or supplement to an application. The
waiver request is required to contain one of the following:
(1) An explanation why the applicant's compliance with the
requirement is unnecessary or cannot be achieved;
(2) A description of an alternative submission that satisfies the
purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The applicant's compliance with the requirement is unnecessary
for the agency to evaluate the application or compliance cannot be
achieved;
(2) The applicant's alternative submission satisfies the requirement;
or
(3) The applicant's submission otherwise justifies a waiver.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985)
21 CFR 314.90 Subpart C -- FDA Action on Applications
21 CFR 314.100 Time frames for reviewing applications.
(a) Within 180 days of receipt of an application, the Food and Drug
Administration will review it and send the applicant either an approval
letter under 314.105, an approvable letter under 314.110, or a not
approvable letter under 314.120. This 180-day period is called the
''review clock.''
(b) During the review period an applicant may withdraw an application
under 314.65 and later resubmit it. FDA will then follow the same
procedure as if a new application were submitted.
(c) The time period may be extended by mutual agreement between FDA
and an applicant or, as provided in 314.60, as the result of a major
amendment.
21 CFR 314.101 Filing an application.
(a) Within 60 days after the Food and Drug Administration receives an
application, the agency will determine whether the application may be
filed. The filing of an application means that FDA has made a threshold
determination that the application is sufficiently complete to permit a
substantive review.
(b) If FDA finds that none of the reasons in paragraphs (d) and (e)
of this section for refusing to file the application apply, the agency
will file the application and notify the applicant in writing. The date
of filing will be the date 60 days after the date FDA received the
application. The date of filing begins the 180-day period described in
section 505(c) of the act. This 180-day period is called the ''filing
clock.''
(c) If FDA refuses to file the application, the agency will notify
the applicant in writing and state the reason under paragraph (d) or (e)
of this section for the refusal. If FDA refuses to file the application
under paragraph (d) of this section, the applicant may request in
writing within 30 days of the date of the agency's notification an
informal conference with the agency about whether the agency should file
the application. If following the informal conference the applicant
requests that FDA file the application (with or without amendments to
correct the deficiencies), the agency will file the application over
protest under paragraph (b) of this section, notify the applicant in
writing, and review it as filed. If the application is filed over
protest, the date of filing will be the date 60 days after the date the
applicant requested the informal conference. The applicant need not
resubmit a copy of an application that is filed over protest. If FDA
refuses to file the application under paragraph (e) of this section, the
applicant may amend the application and resubmit it and the agency will
make a determination under this section whether it may be filed.
(d) FDA may refuse to file an application if any of the following
applies.
(1) The application does not contain a completed application form.
(2) The application is not submitted in the form required under
314.50 or 314.55.
(3) The application is incomplete because it does not on its face
contain information required under section 505(b) (1), (2), (3), (4),
(5), and (6) or section 507 of the act and 314.50 or 314.55.
(4) The applicant fails to submit a complete environmental assessment
which addresses each of the items specified in the applicable format
under 25.31 of this chapter or fails to provide sufficient information
to establish that the requested action is subject to categorical
exclusion under 25.24 of this chapter.
(5) The application does not contain an accurate and complete English
translation of each part of the application that is not in English.
(6) The application does not contain a statement for each nonclinical
laboratory study that it was conducted in compliance with the
requirements set forth in Part 58, or, for each study not conducted in
compliance with Part 58, a brief statement of the reason for the
noncompliance.
(7) The application does not contain a statement for each clinical
study that it was conducted in compliance with the institutional review
board regulations in Part 56, or was not subject to those regulations,
and that it was conducted in compliance with the informed consent
regulations in Part 50; or, if the study was subject to but was not
conducted in compliance with those regulations, the application does not
contain a brief statement of the reason for the noncompliance.
(e) The agency will refuse to file an application if any of the
following applies:
(1) The drug product that is the subject of the submission is already
covered by an approved application.
(2) The submission purports to be an abbreviated application under
314.55, but the drug product is not one for which FDA has made a finding
that an abbreviated application is acceptable under 314.55(b). FDA will
file a copy of the application as a citizen petition under 10.30
seeking a finding under 314.55 that an abbreviated application is
acceptable for the drug product, and so notify the applicant in writing.
(3) The drug product is subject to licensing by FDA under the Public
Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and
Subchapter F of Chapter I of Title 21 of the Code of Federal
Regulations.
(f) (1) Within 180 days after the date of filing, plus the period of
time the review period was extended (if any), FDA will either (i)
approve the application or (ii) issue a notice of opportunity for
hearing if the applicant asked FDA to provide it an opportunity for a
hearing on an application in response to an approvable letter or a not
approvable letter.
(2) This paragraph does not apply to applications that have been
withdrawn from FDA review by the applicant.
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 16668, Apr. 26, 1985)
21 CFR 314.102 Communication between FDA and applicants.
(a) General principles. During the course of reviewing an
application, FDA shall communicate with applicants about scientific,
medical, and procedural issues that arise during the review process.
Such communication may take the form of telephone conversations,
letters, or meetings, whichever is most appropriate to discuss the
particular issue at hand. Communications shall be appropriately
documented in the application in accordance with 10.65. Further details
on the procedures for communication between FDA and applicants are
contained in a staff manual guide that is publicly available.
(b) Notification of easily correctable deficiencies. FDA reviewers
shall make every reasonable effort to communicate promptly to applicants
easily correctable deficiencies found in an application when those
deficiencies are discovered, particularly deficiencies concerning
chemistry, manufacturing, and controls issues. The agency will also
inform applicants promptly of its need for more data or information or
for technical changes in the application needed to facilitate the
agency's review. This early communication is intended to permit
applicants to correct such readily identified deficiencies relatively
early in the review process and to submit an amendment before the review
period has elapsed. Such early communication would not ordinarily apply
to major scientific issues, which require consideration of the entire
pending application by agency managers as well as reviewing staff.
Instead, these major scientific issues will ordinarily be addressed in
an action letter.
(c) Ninety-day conference. Approximately 90 days after the agency
receives the application, FDA will provide applicants with an
opportunity to meet with agency reviewing officials. The purpose of the
meeting will be to inform applicants of the general progress and status
of their applications, and to advise applicants of deficiencies which
have been identified by that time and which have not already been
communicated. This meeting will be available on applications for all
new chemical entities and major new indications of marketed drugs. Such
meetings will be held at the applicant's option, and may be held by
telephone if mutually agreed upon.
(d) End-of-review conference. At the conclusion of FDA's review of
an application, as designated by the issuance of an approvable or not
approvable letter, FDA will provide applicants with an opportunity to
meet with agency reviewing officials. The purpose of the meeting will
be to discuss what further steps need to be taken by the applicant
before the application can be approved. This meeting will be available
on all applications, with priority given to applications for new
chemical entities and major new indications for marketed drugs.
Requests for such meetings shall be directed to the director of the
division responsible for reviewing the application.
(e) Other meetings. Other meetings between FDA and applicants may be
held, with advance notice, to discuss scientific, medical, and other
issues that arise during the review process. Requests for meetings
shall be directed to the director of the division responsible for
reviewing the application. FDA will make every attempt to grant
requests for meetings that involve important issues and that can be
scheduled at mutually convenient times. However, ''drop-in'' visits
(i.e., an unannounced and unscheduled visit by a company representative)
are discouraged except for urgent matters, such as to discuss an
important new safety issue.
21 CFR 314.103 Dispute resolution.
(a) General. The Food and Drug Administration is committed to
resolving differences between applicants and FDA reviewing divisions
with respect to technical requirements for applications as quickly and
amicably as possible through the cooperative exchange of information and
views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the applicant should first attempt to resolve
the matter with the division responsible for reviewing the application,
beginning with the consumer safety officer assigned to the application.
If resolution is not achieved, the applicant may raise the matter with
the person designated as ombudsman, whose function shall be to
investigate what has happened and to facilitate a timely and equitable
resolution. Appropriate issues to raise with the ombudsman include
resolving difficulties in scheduling meetings, obtaining timely replies
to inquiries, and obtaining timely completion of pending reviews.
Further details on this procedure are contained in a staff manual guide
that is publicly available under FDA's public information regulations in
part 20.
(c) Scientific and medical disputes. (1) Because major scientific
issues are ordinarily communicated to applicants in an approvable or not
approvable letter pursuant to 314.110 or 314.120, respectively, the
''end-of-review conference'' described in 314.102(d) will provide a
timely forum for discussing and resolving, if possible, scientific and
medical issues on which the applicant disagrees with the agency. In
addition, the ''ninety-day conference'' described in 314.102(c) will
provide a timely forum for discussing and resolving, if possible, issues
identified by that date.
(2) When scientific or medical disputes arise at other times during
the review process, applicants should discuss the matter directly with
the responsible reviewing officials. If necessary, applicants may
request a meeting with the appropriate reviewing officials and
management representatives in order to seek a resolution. Ordinarily,
such meetings would be held first with the Division Director, then with
the Office Director, and finally with the Center Director if the matter
is still unresolved. Requests for such meetings shall be directed to
the director of the division responsible for reviewing the application.
FDA will make every attempt to grant requests for meetings that involve
important issues and that can be scheduled at mutually convenient times.
(3) In requesting a meeting designed to resolve a scientific or
medical dispute, applicants may suggest that FDA seek the advice of
outside experts, in which case FDA may, in its discretion, invite to the
meeting one or more of its advisory committee members or other
consultants, as designated by the agency. Applicants may also bring
their own consultants. For major scientific and medical policy issues
not resolved by informal meetings, FDA may refer the matter to one of
its standing advisory committees for its consideration and
recommendations.
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985)
21 CFR 314.104 Drugs with potential for abuse.
The Food and Drug Administration will inform the Drug Enforcement
Administration under section 201(f) of the Controlled Substances Act (21
U.S.C. 801) when an application is submitted for a drug that appears to
have an abuse potential.
21 CFR 314.105 Approval of an application.
(a) The Food and Drug Administration will approve an application and
send the applicant an approval letter if none of the reasons in 314.125
for refusing to approve the application apply. The date of the agency's
approval letter is the date of approval of the application. When FDA
sends an applicant an approval letter for an antibiotic, it will
promulgate a regulation under 314.300 providing for certification of
the drug, if necessary. A new drug product or antibiotic may not be
marketed until an approval letter is issued. Marketing of an antibiotic
need not await the promulgation of a regulation under 314.300.
(b) FDA will approve an application and issue the applicant an
approval letter (rather than an approvable letter under 314.110) on the
basis of draft labeling if the only deficiencies in the application
concern editorial or similar minor deficiencies in the draft labeling.
Such approval will be conditioned upon the applicant incorporating the
specified labeling changes exactly as directed, and upon the applicant
submitting to FDA a copy of the final printed labeling prior to
marketing.
(c) FDA will approve an application after it determines that the drug
meets the statutory standards for safety and effectiveness,
manufacturing and controls, and labeling. While the statutory standards
apply to all drugs, the many kinds of drugs that are subject to them and
the wide range of uses for those drugs demand flexibility in applying
the standards. Thus FDA is required to exercise its scientific judgment
to determine the kind and quantity of data and information an applicant
is required to provide for a particular drug to meet them. FDA makes
its views on drug products and classes of drugs available through
guidelines, recommendations, and other statements of policy.
21 CFR 314.106 Foreign data.
(a) General. The acceptance of foreign data in an application
generally is governed by 312.120 of this chapter.
(b) As sole basis for marketing approval. An application based
solely on foreign clinical data meeting U.S. criteria for marketing
approval may be approved if: (1) The foreign data are applicable to the
U.S. population and U.S. medical practice; (2) the studies have been
performed by clinical investigators of recognized competence; and (3)
the data may be considered valid without the need for an on-site
inspection by FDA or, if FDA considers such an inspection to be
necessary, FDA is able to validate the data through an on-site
inspection or other appropriate means. Failure of an application to
meet any of these criteria will result in the application not being
approvable based on the foreign data alone. FDA will apply this policy
in a flexible manner according to the nature of the drug and the data
being considered.
(c) Consultation between FDA and applicants. Applicants are
encouraged to meet with agency officials in a ''presubmission'' meeting
when approval based solely on foreign data will be sought.
(50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11580, Mar. 29, 1990)
21 CFR 314.110 Approvable letter to the applicant.
In selected circumstances it is useful at the end of the review
period for the Food and Drug Administration to indicate to the applicant
that the application is basically approvable providing certain issues
are resolved. An approvable letter may be issued in such circumstances.
FDA will send the applicant an approvable letter if the application
substantially meets the requirements of this part and the agency
believes that it can approve the application if specific additional
information or material is submitted or specific conditions (for
example, certain changes in labeling) are agreed to by the applicant.
The approvable letter will describe the information or material FDA
requires or the conditions the applicant is asked to meet. As a
practical matter, the approvable letter will serve in most instances as
a mechanism for resolving outstanding issues on drugs that are about to
be approved and marketed. Within 10 days after the date of the
approvable letter, the applicant shall either:
(a) Amend the application or notify FDA of an intent to file an
amendment. The filing of an amendment or notice of intent to file an
amendment constitutes an agreement by the applicant to extend the review
period for 45 days after the date FDA receives the amendment. The
extension is to permit the agency to review the amendment.
(b) Withdraw the application. FDA will consider the applicant's
failure to respond within 10 days to an approvable letter to be a
request by the applicant to withdraw the application under 314.65. A
decision to withdraw an application is without prejudice to a refiling.
(c) For a new drug, ask the agency to provide the applicant an
opportunity for a hearing on the question of whether there are grounds
for denying approval of the application under section 505(d) of the act.
The applicant shall submit the request to the Division of Regulatory
Affairs (HFD-360), Center for Drug Evaluation and Research, Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60
days of the date of the approvable letter, or within a different time
period to which FDA and the applicant agree, the agency will either
approve the application under 314.105 or refuse to approve the
application under 314.125 and give the applicant written notice of an
opportunity for a hearing under 314.200 and section 505(c)(2) of the
act on the question of whether there are grounds for denying approval of
the application under section 505(d) of the act.
(d) For an antibiotic, file a petition or notify FDA of an intent to
file a petition proposing the issuance, amendment, or repeal of a
regulation under 314.300 and section 507(f) of the act.
(e) Notify FDA that the applicant agrees to an extension of the
review period under section 505(c) of the act, so that the applicant can
determine whether to respond further under paragraph (a), (b), (c), or
(d) of this section. The applicant's notice is required to state the
length of the extension. FDA will honor any reasonable request for such
an extension. FDA will consider the applicant's failure to respond
further within the extended review period to be a request to withdraw
the application under 314.65. A decision to withdraw an application is
without prejudice to a refiling.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
55 FR 11580, Mar. 29, 1990)
21 CFR 314.120 Not approvable letter to the applicant.
The Food and Drug Administration will send the applicant a not
approvable letter if the agency believes that the application may not be
approved for one of the reasons given in 314.125. The not approvable
letter will describe the deficiencies in the application. Within 10
days after the date of the not approvable letter, the applicant shall
either:
(a) Amend the application or notify FDA of an intent to file an
amendment. The filing of an amendment or a notice of intent to file an
amendment constitutes an agreement by the applicant to extend the review
period under 314.60.
(b) Withdraw the application. FDA will consider the applicant's
failure to respond within 10 days to a not approvable letter to be a
request by the applicant to withdraw the application under 314.65. A
decision to withdraw the application is without prejudice to refiling.
(c) For a new drug, ask the agency to provide the applicant an
opportunity for a hearing on the question of whether there are grounds
for denying approval of the application under section 505(d) of the act.
The applicant shall submit the request to the Division of Regulatory
Affairs (HFD-360), Center for Drug Evaluation and Research, Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60
days of the date of the not approvable letter, or within a different
time period to which FDA and the applicant agree, the agency will either
approve the application under 314.105 or refuse to approve the
application under 314.125 and give the applicant written notice of an
opportunity for a hearing under 314.200 and section 505(c)(2) of the
act on the question of whether there are grounds for denying approval of
the application under section 505(d) of the act.
(d) For an antibiotic, file a petition or notify FDA of an intent to
file a petition proposing the issuance, amendment, or repeal of a
regulation under 314.300 and section 507(f) of the act.
(e) Notify FDA that the applicant agrees to an extension of the
review period under section 505(c) of the act, so that the applicant can
determine whether to respond further under paragraph (a), (b), (c), or
(d) of this section. The applicant's notice is required to state the
length of the extension. FDA will honor any reasonable request for such
an extension. FDA will consider the applicant's failure to respond
further within the extended review period to be a request to withdraw
the application under 314.65. A decision to withdraw an application is
without prejudice to a refiling.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
55 FR 11580, Mar. 29, 1990)
21 CFR 314.125 Refusal to approve an application.
(a) The Food and Drug Administration will refuse to approve the
application and for a new drug give the applicant written notice of an
opportunity for a hearing under 314.200 on the question of whether
there are grounds for denying approval of the application under section
505(d) of the act, or for an antibiotic publish a proposed regulation
based on an acceptable petition under 314.300, if:
(1) FDA sends the applicant an approvable or a not approvable letter
under 314.110 or 314.120;
(2) The applicant requests an opportunity for hearing for a new drug
on the question of whether the application is approvable or files a
petition for an antibiotic proposing the issuance, amendment, or repeal
of a regulation; and
(3) FDA finds that any of the reasons given in paragraph (b) of this
section apply.
(b) FDA may refuse to approve an application for any of the following
reasons:
(1) The methods to be used in, and the facilities and controls used
for, the manufacture, processing, packing, or holding of the drug
substance or the drug product are inadequate to preserve its identity,
strength, quality, purity, stability, and bioavailability.
(2) The investigations required under section 505(b) or 507 of the
act do not include adequate tests by all methods reasonably applicable
to show whether or not the drug is safe for use under the conditions
prescribed, recommended, or suggested in its proposed labeling.
(3) The results of the tests show that the drug is unsafe for use
under the conditions prescribed, recommended, or suggested in its
proposed labeling or the results do not show that the drug product is
safe for use under those conditions.
(4) There is insufficient information about the drug to determine
whether the product is safe for use under the conditions prescribed,
recommended, or suggested in its proposed labeling.
(5) There is a lack of substantial evidence consisting of adequate
and well-controlled investigations, as defined in 314.126, that the
drug product will have the effect it purports or is represented to have
under the conditions of use prescribed, recommended, or suggested in its
proposed labeling.
(6) The proposed labeling is false or misleading in any particular.
(7) The application contains an untrue statement of a material fact.
(8) The drug product's proposed labeling does not comply with the
requirements for labels and labeling in Part 201.
(9) The application does not contain bioavailability or
bioequivalence data required under Part 320.
(10) A reason given in a letter refusing to file the application
under 314.101(d), if the deficiency is not corrected.
(11) The drug will be manufactured or processed in whole or in part
in an establishment that is not registered and not exempt from
registration under section 510 of the act and Part 207.
(12) The applicant does not permit a properly authorized officer or
employee of the Department of Health and Human Services an adequate
opportunity to inspect the facilities, controls, and any records
relevant to the application.
(13) The methods to be used in, and the facilities and controls used
for, the manufacture, processing, packing, or holding of the drug
substance or the drug product do not comply with the current good
manufacturing practice regulations in Parts 210 and 211.
(14) The application does not contain an explanation of the omission
of a report of any investigation of the drug product sponsored by the
applicant, or an explanation of the omission of other information about
the drug pertinent to an evaluation of the application that is received
or otherwise obtained by the applicant from any source.
(15) A nonclinical laboratory study that is described in the
application and that is essential to show that the drug is safe for use
under the conditions prescribed, recommended, or suggested in its
proposed labeling, was not conducted in compliance with the good
laboratory practice regulations in Part 58 and no reason for the
noncompliance is provided or, if it is, the differences between the
practices used in conducting the study and the good laboratory practice
regulations do not support the validity of the study.
(16) Any clinical investigation involving human subjects described in
the application, subject to the institutional review board regulations
in Part 56 or informed consent regulations in Part 50, was not conducted
in compliance with those regulations such that the rights or safety of
human subjects were not adequately protected.
(17) The applicant or contract research organization that conducted a
bioavailability or bioequivalence study contained in the application
refuses to permit an inspection of facilities or records relevant to the
study by a properly authorized officer or employee of the Department of
Health and Human Services or refuses to submit reserve samples of the
drug products used in the study when requested by FDA.
(c) For drugs intended to treat life-threatening or
severely-debilitating illnesses that are developed in accordance with
312.80 through 312.88 of this chapter, the criteria contained in
paragraphs (b) (3), (4), and (5) of this section shall be applied
according to the considerations contained in 312.84 of this chapter.
(50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988;
55 FR 47038, Nov. 8, 1990)
21 CFR 314.126 Adequate and well-controlled studies.
(a) The purpose of conducting clinical investigations of a drug is to
distinguish the effect of a drug from other influences, such as
spontaneous change in the course of the disease, placebo effect, or
biased observation. The characteristics described in paragraph (b) of
this section have been developed over a period of years and are
recognized by the scientific community as the essentials of an adequate
and well-controlled clinical investigation. The Food and Drug
Administration considers these characteristics in determining whether an
investigation is adequate and well-controlled for purposes of sections
505 and 507 of the act. Reports of adequate and well-controlled
investigations provide the primary basis for determining whether there
is ''substantial evidence'' to support the claims of effectiveness for
new drugs and antibiotics. Therefore, the study report should provide
sufficient details of study design, conduct, and analysis to allow
critical evaluation and a determination of whether the characteristics
of an adequate and well-controlled study are present.
(b) An adequate and well-controlled study has the following
characteristics:
(1) There is a clear statement of the objectives of the investigation
and a summary of the proposed or actual methods of analysis in the
protocol for the study and in the report of its results. In addition,
the protocol should contain a description of the proposed methods of
analysis, and the study report should contain a description of the
methods of analysis ultimately used. If the protocol does not contain a
description of the proposed methods of analysis, the study report should
describe how the methods used were selected.
(2) The study uses a design that permits a valid comparison with a
control to provide a quantitative assessment of drug effect. The
protocol for the study and report of results should describe the study
design precisely; for example, duration of treatment periods, whether
treatments are parallel, sequential, or crossover, and whether the
sample size is predetermined or based upon some interim analysis.
Generally, the following types of control are recognized:
(i) Placebo concurrent control. The test drug is compared with an
inactive preparation designed to resemble the test drug as far as
possible. A placebo-controlled study may include additional treatment
groups, such as an active treatment control or a dose-comparison
control, and usually includes randomization and blinding of patients or
investigators, or both.
(ii) Dose-comparison concurrent control. At least two doses of the
drug are compared. A dose-comparison study may include additional
treatment groups, such as placebo control or active control.
Dose-comparison trials usually include randomization and blinding of
patients or investigators, or both.
(iii) No treatment concurrent control. Where objective measurements
of effectiveness are available and placebo effect is negligible, the
test drug is compared with no treatment. No treatment concurrent
control trials usually include randomization.
(iv) Active treatment concurrent control. The test drug is compared
with known effective therapy; for example, where the condition treated
is such that administration of placebo or no treatment would be contrary
to the interest of the patient. An active treatment study may include
additional treatment groups, however, such as a placebo control or a
dose-comparison control. Active treatment trials usually include
randomization and blinding of patients or investigators, or both. If
the intent of the trial is to show similarity of the test and control
drugs, the report of the study should assess the ability of the study to
have detected a difference between treatments. Similarity of test drug
and active control can mean either that both drugs were effective or
that neither was effective. The analysis of the study should explain
why the drugs should be considered effective in the study, for example,
by reference to results in previous placebo-controlled studies of the
active control drug.
(v) Historical control. The results of treatment with the test drug
are compared with experience historically derived from the adequately
documented natural history of the disease or condition, or from the
results of active treatment, in comparable patients or populations.
Because historical control populations usually cannot be as well
assessed with respect to pertinent variables as can concurrent control
populations, historical control designs are usually reserved for special
circumstances. Examples include studies of diseases with high and
predictable mortality (for example, certain malignancies) and studies in
which the effect of the drug is self-evident (general anesthetics, drug
metabolism).
(3) The method of selection of subjects provides adequate assurance
that they have the disease or condition being studied, or evidence of
susceptibility and exposure to the condition against which prophylaxis
is directed.
(4) The method of assigning patients to treatment and control groups
minimizes bias and is intended to assure comparability of the groups
with respect to pertinent variables such as age, sex, severity of
disease, duration of disease, and use of drugs or therapy other than the
test drug. The protocol for the study and the report of its results
should describe how subjects were assigned to groups. Ordinarily, in a
concurrently controlled study, assignment is by randomization, with or
without stratification.
(5) Adequate measures are taken to minimize bias on the part of the
subjects, observers, and analysts of the data. The protocol and report
of the study should describe the procedures used to accomplish this,
such as blinding.
(6) The methods of assessment of subjects' response are well-defined
and reliable. The protocol for the study and the report of results
should explain the variables measured, the methods of observation, and
criteria used to assess response.
(7) There is an analysis of the results of the study adequate to
assess the effects of the drug. The report of the study should describe
the results and the analytic methods used to evaluate them, including
any appropriate statistical methods. The analysis should assess, among
other things, the comparability of test and control groups with respect
to pertinent variables, and the effects of any interim data analyses
performed.
(c) The Director of the Center for Drug Evaluation and Research may,
on the Director's own initiative or on the petition of an interested
person, waive in whole or in part any of the criteria in paragraph (b)
of this section with respect to a specific clinical investigation,
either prior to the investigation or in the evaluation of a completed
study. A petition for a waiver is required to set forth clearly and
concisely the specific criteria from which waiver is sought, why the
criteria are not reasonably applicable to the particular clinical
investigation, what alternative procedures, if any, are to be, or have
been employed, and what results have been obtained. The petition is
also required to state why the clinical investigations so conducted will
yield, or have yielded, substantial evidence of effectiveness,
notwithstanding nonconformance with the criteria for which waiver is
requested.
(d) For an investigation to be considered adequate for approval of a
new drug, it is required that the test drug be standardized as to
identity, strength, quality, purity, and dosage form to give
significance to the results of the investigation.
(e) Uncontrolled studies or partially controlled studies are not
acceptable as the sole basis for the approval of claims of
effectiveness. Such studies carefully conducted and documented, may
provide corroborative support of well-controlled studies regarding
efficacy and may yield valuable data regarding safety of the test drug.
Such studies will be considered on their merits in the light of the
principles listed here, with the exception of the requirement for the
comparison of the treated subjects with controls. Isolated case
reports, random experience, and reports lacking the details which permit
scientific evaluation will not be considered.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
55 FR 11580, Mar. 29, 1990)
21 CFR 314.150 Withdrawal of approval of an application.
(a) The Food and Drug Administration will notify the applicant, and,
if appropriate, all other persons who manufacture or distribute
identical, related, or similar drug products as defined in 310.6, and
for a new drug afford an opportunity for a hearing on a proposal to
withdraw approval of the application under section 505(e) of the act and
under the procedure in 314.200, or, for an antibiotic, rescind a
certification or release, or amend or repeal a regulation providing for
certification under section 507 of the act and under the procedure in
314.300, if any of the following applies:
(1) The Secretary of Health and Human Services has suspended the
approval of the application for a new drug on a finding that there is an
imminent hazard to the public health. FDA will promptly afford the
applicant an expedited hearing following summary suspension on a finding
of imminent hazard to health.
(2) FDA finds:
(i) That clinical or other experience, tests, or other scientific
data show that the drug is unsafe for use under the conditions of use
upon the basis of which the application was approved; or
(ii) That new evidence of clinical experience, not contained in the
application or not available to FDA until after the application was
approved, or tests by new methods, or tests by methods not deemed
reasonably applicable when the application was approved, evaluated
together with the evidence available when the application was approved,
reveal that the drug is not shown to be safe for use under the
conditions of use upon the basis of which the application was approved;
or
(iii) Upon the basis of new information before FDA with respect to
the drug, evaluated together with the evidence available when the
application was approved, that there is a lack of substantial evidence
from adequate and well-controlled investigations as defined in 314.126,
that the drug will have the effect it is purported or is represented to
have under the conditions of use prescribed, recommended, or suggested
in its labeling; or
(iv) That the application contains any untrue statement of a material
fact.
(b) FDA may notify the applicant, and, if appropriate, all other
persons who manufacture or distribute identical, related, or similar
drug products as defined in 310.6, and for a new drug afford an
opportunity for a hearing on a proposal to withdraw approval of the
application under section 505(e) of the act and under the procedure in
314.200, or, for an antibiotic, rescind a certification or release, or
amend or repeal a regulation providing for certification under section
507 of the act and the procedure in 314.300, if the agency finds:
(1) That the applicant has failed to establish a system for
maintaining required records, or has repeatedly or deliberately failed
to maintain required records or to make required reports under section
505(k) or 507(g) of the act and 314.80 and 314.81, or that the
applicant has refused to permit access to, or copying or verification
of, its records.
(2) That on the basis of new information before FDA, evaluated
together with the evidence available when the application was approved,
the methods used in, or the facilities and controls used for, the
manufacture, processing, and packing of the drug are inadequate to
assure and preserve its identity, strength, quality, and purity and were
not made adequate within a reasonable time after receipt of written
notice from the agency.
(3) That on the basis of new information before FDA, evaluated
together with the evidence available when the application was approved,
the labeling of the drug, based on a fair evaluation of all material
facts, is false or misleading in any particular; and the labeling was
not corrected by the applicant within a reasonable time after receipt of
written notice from the agency.
(4) That the applicant has failed to comply with the notice
requirements of section 510(j)(2) of the act.
(5) That the applicant has failed to submit bioavailability or
bioequivalence data required under Part 320.
(6) The application does not contain an explanation of the omission
of a report of any investigation of the drug product sponsored by the
applicant, or an explanation of the omission of other information about
the drug pertinent to an evaluation of the application that is received
or otherwise obtained by the applicant from any source.
(7) That any nonclinical laboratory study that is described in the
application and that is essential to show that the drug is safe for use
under the conditions prescribed, recommended, or suggested in its
labeling was not conducted in compliance with the good laboratory
practice regulations in Part 58 and no reason for the noncompliance was
provided or, if it was, the differences between the practices used in
conducting the study and the good laboratory practice regulations do not
support the validity of the study.
(8) Any clinical investigation involving human subjects described in
the application, subject to the institutional review board regulations
in Part 56 or informed consent regulations in Part 50, was not conducted
in compliance with those regulations such that the rights or safety of
human subjects were not adequately protected.
(9) That the applicant or contract research organization that
conducted a bioavailability or bioequivalence study contained in the
application refuses to permit an inspection of facilities or records
relevant to the study by a properly authorized officer or employee of
the Department of Health and Human Services or refuses to submit reserve
samples of the drug products used in the study when requested by FDA.
(c) FDA will withdraw approval of an application if the applicant
requests its withdrawal because the drug subject to the application is
no longer being marketed, provided none of the conditions listed in
paragraphs (a) and (b) of this section apply to the drug. FDA will
consider a written request for withdrawal under this paragraph to be a
waiver of an opportunity for hearing otherwise provided for in this
section. Withdrawal of approval of an application under this paragraph
is without prejudice to refiling.
(d) FDA may notify an applicant that it believes a potential problem
associated with a drug is sufficiently serious that the drug should be
removed from the market and may ask the applicant to waive the
opportunity for hearing otherwise provided for under this section, to
permit FDA to withdraw approval of the application for the product, and
to remove voluntarily the product from the market. If the applicant
agrees, the agency will not make a finding under paragraph (b) of this
section, but will withdraw approval of the application in a notice
published in the Federal Register that contains a brief summary of the
agency's and the applicant's views of the reasons for withdrawal.
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 55 FR 11580, Mar. 29, 1990; 55 FR 47038, Nov. 8, 1990)
21 CFR 314.152 Notice of withdrawal of approval of an application for a
new drug.
If the Food and Drug Administration withdraws approval of an
application for a new drug, FDA will publish a notice in the Federal
Register announcing the withdrawal of approval.
21 CFR 314.160 Approval of an application for which approval was
previously refused, suspended, or withdrawn.
Upon the Food and Drug Administration's own initiative or upon
request of an applicant, FDA may, on the basis of new data, approve an
application which it had previously refused, suspended, or withdrawn
approval. FDA will publish a notice in the Federal Register announcing
the approval.
21 CFR 314.170 Adulteration and misbranding of an approved drug.
All drugs, including those the Food and Drug Administration approves,
or provides for certification of, under sections 505, 506, and 507 of
the act and this part, are subject to the adulteration and misbranding
provisions in sections 501, 502, and 503 of the act. FDA is authorized
to regulate approved new drugs and approved antibiotic drugs by
regulations issued through informal rulemaking under sections 501, 502,
and 503 of the act.
21 CFR 314.170 Subpart D -- Hearing Procedures for New Drugs
21 CFR 314.200 Notice of opportunity for hearing; notice of
participation and request for hearing; grant or denial of hearing.
(a) Notice of opportunity for hearing. The Director of the Center
for Drug Evaluation and Research, Food and Drug Administration, will
give the applicant, and all other persons who manufacture or distribute
identical, related, or similar drug products as defined in 310.6,
notice and an opportunity for a hearing on the Center's proposal to
refuse to approve an application or to withdraw the approval of an
application. The notice will state the reasons for the action and the
proposed grounds for the order.
(1) The notice may be general (that is, simply summarizing in a
general way the information resulting in the notice) or specific (that
is, either referring to specific requirements in the statute and
regulations with which there is a lack of compliance, or providing a
detailed description and analysis of the specific facts resulting in the
notice).
(2) FDA will publish the notice in the Federal Register and will
state that the applicant, and other persons subject to the notice under
310.6, who wishes to participate in a hearing, has 30 days after the
date of publication of the notice to file a written notice of
participation and request for hearing. The applicant, or other persons
subject to the notice under 310.6, who fails to file a written notice
of participation and request for hearing within 30 days, waives the
opportunity for a hearing.
(3) It is the responsibility of every manufacturer and distributor of
a drug product to review every notice of opportunity for a hearing
published in the Federal Register to determine whether it covers any
drug product that person manufactures or distributes. Any person may
request an opinion of the applicability of a notice to a specific
product that may be identical, related, or similar to a product listed
in a notice by writing to the Division of Drug Labeling Compliance
(HFD-310), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857. A person shall
request an opinion within 30 days of the date of publication of the
notice to be eligible for an opportunity for a hearing under the notice.
If a person requests an opinion, that person's time for filing an
appearance and request for a hearing and supporting studies and analyses
begins on the date the person receives the opinion from FDA.
(b) FDA will provide the notice of opportunity for a hearing to
applicants and to other persons subject to the notice under 310.6, as
follows:
(1) To any person who has submitted an application, by delivering the
notice in person or by sending it by registered or certified mail to the
last address shown in the application.
(2) To any person who has not submitted an application but who is
subject to the notice under 310.6, by publication of the notice in the
Federal Register.
(c) (1) Notice of participation and request for a hearing, and
submission of studies and comments. The applicant, or any other person
subject to the notice under 310.6, who wishes to participate in a
hearing, shall file with the Dockets Management Branch (HFA-305), Food
and Drug Administration, Rm. 4-62, Rockville, MD 20857, (i) within 30
days after the date of the publication of the notice (or of the date of
receipt of an opinion requested under paragraph (a)(3) of this section)
a written notice of participation and request for a hearing and (ii)
within 60 days after the date of publication of the notice, unless a
different period of time is specified in the notice of opportunity for a
hearing, the studies on which the person relies to justify a hearing as
specified in paragraph (d) of this section. The applicant, or other
person, may incorporate by reference the raw data underlying a study if
the data were previously submitted to FDA as part of an application or
other report.
(2) FDA will not consider data or analyses submitted after 60 days in
determining whether a hearing is warranted unless they are derived from
well-controlled studies begun before the date of the notice of
opportunity for hearing and the results of the studies were not
available within 60 days after the date of publication of the notice.
Nevertheless, FDA may consider other studies on the basis of a showing
by the person requesting a hearing of inadvertent omission and hardship.
The person requesting a hearing shall list in the request for hearing
all studies in progress, the results of which the person intends later
to submit in support of the request for a hearing. The person shall
submit under paragraph (c)(1)(ii) of this section a copy of the complete
protocol, a list of the participating investigators, and a brief status
report of the studies.
(3) Any other interested person who is not subject to the notice of
opportunity for a hearing may also submit comments on the proposal to
withdraw approval of the application. The comments are required to be
submitted within the time and under the conditions specified in this
section.
(d) The person requesting a hearing is required to submit under
paragraph (c)(1)(ii) of this section the studies (including all
protocols and underlying raw data) on which the person relies to justify
a hearing with respect to the drug product. Except, a person who
requests a hearing on the refusal to approve an application is not
required to submit additional studies and analyses if the studies upon
which the person relies have been submitted in the application and in
the format and containing the summaries required under 314.50.
(1) If the grounds for FDA's proposed action concern the
effectiveness of the drug, each request for hearing is required to be
supported only by adequate and well-controlled clinical studies meeting
all of the precise requirements of 314.126 and, for combination drug
products, 300.50, or by other studies not meeting those requirements
for which a waiver has been previously granted by FDA under 314.126.
Each person requesting a hearing shall submit all adequate and
well-controlled clinical studies on the drug product, including any
unfavorable analyses, views, or judgments with respect to the studies.
No other data, information, or studies may be submitted.
(2) The submission is required to include a factual analysis of all
the studies submitted. If the grounds for FDA's proposed action concern
the effectiveness of the drug, the analysis is required to specify how
each study accords, on a point-by-point basis, with each criterion
required for an adequate well-controlled clinical investigation
established under 314.126 and, if the product is a combination drug
product, with each of the requirements for a combination drug
established in 300.50, or the study is required to be accompanied by an
appropriate waiver previously granted by FDA. If a study concerns a
drug or dosage form or condition of use or mode of administration other
than the one in question, that fact is required to be clearly stated.
Any study conducted on the final marketed form of the drug product is
required to be clearly identified.
(3) Each person requesting a hearing shall submit an analysis of the
data upon which the person relies, except that the required information
relating either to safety or to effectiveness may be omitted if the
notice of opportunity for hearing does not raise any issue with respect
to that aspect of the drug; information on compliance with 300.50 may
be omitted if the drug product is not a combination drug product. FDA
can most efficiently consider submissions made in the following format.
I. Safety data.
A. Animal safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
B. Human safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination
about the safety of each individual active component.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination
about the safety of each individual active component.
II. Effectiveness data.
A. Individual active components: Controlled studies, with an
analysis showing clearly how each study satisfies, on a point-by-point
basis, each of the criteria required by 314.126.
B. Combinations of individual active components.
1. Controlled studies with an analysis showing clearly how each study
satisfies on a point-by-point basis, each of the criteria required by
314.126.
2. An analysis showing clearly how each requirement of 300.50 has
been satisfied.
III. A summary of the data and views setting forth the medical
rationale and purpose for the drug and its ingredients and the
scientific basis for the conclusion that the drug and its ingredients
have been proven safe and/or effective for the intended use. If there
is an absence of controlled studies in the material submitted or the
requirements of any element of 300.50 or 314.126 have not been fully
met, that fact is required to be stated clearly and a waiver obtained
under 314.126 is required to be submitted.
IV. A statement signed by the person responsible for such submission
that it includes in full (or incorporates by reference as permitted in
314.200(c)(2)) all studies and information specified in 314.200(d).
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(e) Contentions that a drug product is not subject to the new drug
requirements. A notice of opportunity for a hearing encompasses all
issues relating to the legal status of each drug product subject to it,
including identical, related, and similar drug products as defined in
310.6. A notice of appearance and request for a hearing under paragraph
(c)(1)(i) of this section is required to contain any contention that the
product is not a new drug because it is generally recognized as safe and
effective within the meaning of section 201(p) of the act, or because it
is exempt from part or all of the new drug provisions of the act under
the exemption for products marketed before June 25, 1938, contained in
section 201(p) of the act or under section 107(c) of the Drug Amendments
of 1962, or for any other reason. Each contention is required to be
supported by a submission under paragraph (c)(1)(ii) of this section and
the Commissioner of Food and Drugs will make an administrative
determination on each contention. The failure of any person subject to
a notice of opportunity for a hearing, including any person who
manufactures or distributes an identical, related, or similar drug
product as defined in 310.6, to submit a notice of participation and
request for hearing or to raise all such contentions constitutes a
waiver of any contentions not raised.
(1) A contention that a drug product is generally recognized as safe
and effective within the meaning of section 201(p) of the act is
required to be supported by submission of the same quantity and quality
of scientific evidence that is required to obtain approval of an
application for the product, unless FDA has waived a requirement for
effectiveness (under 314.126) or safety, or both. The submission
should be in the format and with the analyses required under paragraph
(d) of this section. A person who fails to submit the required
scientific evidence required under paragraph (d) waives the contention.
General recognition of safety and effectiveness shall ordinarily be
based upon published studies which may be corroborated by unpublished
studies and other data and information.
(2) A contention that a drug product is exempt from part or all of
the new drug provisions of the act under the exemption for products
marketed before June 25, 1938, contained in section 201(p) of the act,
or under section 107(c) of the Drug Amendments of 1962, is required to
be supported by evidence of past and present quantitative formulas,
labeling, and evidence of marketing. A person who makes such a
contention should submit the formulas, labeling, and evidence of
marketing in the following format.
I. Formulation.
A. A copy of each pertinent document or record to establish the exact
quantitative formulation of the drug (both active and inactive
ingredients) on the date of initial marketing of the drug.
B. A statement whether such formulation has at any subsequent time
been changed in any manner. If any such change has been made, the exact
date, nature, and rationale for each change in formulation, including
any deletion or change in the concentration of any active ingredient
and/or inactive ingredient, should be stated, together with a copy of
each pertinent document or record to establish the date and nature of
each such change, including, but not limited to, the formula which
resulted from each such change. If no such change has been made, a copy
of representative documents or records showing the formula at
representative points in time should be submitted to support the
statement.
II. Labeling.
A. A copy of each pertinent document or record to establish the
identity of each item of written, printed, or graphic matter used as
labeling on the date the drug was initially marketed.
B. A statement whether such labeling has at any subsequent time been
discontinued or changed in any manner. If such discontinuance or change
has been made, the exact date, nature, and rationale for each
discontinuance or change and a copy of each pertinent document or record
to establish each such discontinuance or change should be submitted,
including, but not limited to, the labeling which resulted from each
such discontinuance or change. If no such discontinuance or change has
been made, a copy of representative documents or records showing
labeling at representative points in time should be submitted to support
the statement.
III. Marketing.
A. A copy of each pertinent document or record to establish the exact
date the drug was initially marketed.
B. A statement whether such marketing has at any subsequent time been
discontinued. If such marketing has been discontinued, the exact date
of each such discontinuance should be submitted, together with a copy of
each pertinent document or record to establish each such date.
IV. Verification.
A statement signed by the person responsible for such submission,
that all appropriate records have been searched and to the best of that
person's knowledge and belief it includes a true and accurate
presentation of the facts.
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(3) The Food and Drug Administration will not find a drug product,
including any active ingredient, which is identical, related, or
similar, as described in 310.6, to a drug product, including any active
ingredient for which an application is or at any time has been effective
or deemed approved, or approved under section 505 of the act, to be
exempt from part or all of the new drug provisions of the act.
(4) A contention that a drug product is not a new drug for any other
reason is required to be supported by submission of the factual records,
data, and information that are necessary and appropriate to support the
contention.
(5) It is the responsibility of every person who manufactures or
distributes a drug product in reliance upon a ''grandfather'' provision
of the act to maintain files that contain the data and information
necessary fully to document and support that status.
(f) Separation of functions. Separation of functions commences upon
receipt of a request for hearing. The Director of the Center for Drug
Evaluation and Research, Food and Drug Administration, will prepare an
analysis of the request and a proposed order ruling on the matter. The
analysis and proposed order, the request for hearing, and any proposed
order denying a hearing and response under paragraph (g) (2) or (3) of
this section will be submitted to the Office of the Commissioner of Food
and Drugs for review and decision. When the Center for Drug Evaluation
and Research recommends denial of a hearing on all issues on which a
hearing is requested, no representative of the Center will participate
or advise in the review and decision by the Commissioner. When the
Center for Drug Evaluation and Research recommends that a hearing be
granted on one or more issues on which a hearing is requested,
separation of functions terminates as to those issues, and
representatives of the Center may participate or advise in the review
and decision by the Commissioner on those issues. The Commissioner may
modify the text of the issues, but may not deny a hearing on those
issues. Separation of functions continues with respect to issues on
which the Center for Drug Evaluation and Research has recommended denial
of a hearing. The Commissioner will neither evaluate nor rule on the
Center's recommendation on such issues and such issues will not be
included in the notice of hearing. Participants in the hearing may make
a motion to the presiding officer for the inclusion of any such issue in
the hearing. The ruling on such a motion is subject to review in
accordance with 12.35(b). Failure to so move constitutes a waiver of
the right to a hearing on such an issue. Separation of functions on all
issues resumes upon issuance of a notice of hearing. The Office of the
General Counsel, Department of Health and Human Services, will observe
the same separation of functions.
(g) Summary judgment. A person who requests a hearing may not rely
upon allegations or denials but is required to set forth specific facts
showing that there is a genuine and substantial issue of fact that
requires a hearing with respect to a particular drug product specified
in the request for hearing.
(1) Where a specific notice of opportunity for hearing (as defined in
paragraph (a)(1) of this section) is used, the Commissioner will enter
summary judgment against a person who requests a hearing, making
findings and conclusions, denying a hearing, if it conclusively appears
from the face of the data, information, and factual analyses in the
request for the hearing that there is no genuine and substantial issue
of fact which precludes the refusal to approve the application or the
withdrawal of approval of the application; for example, no adequate and
well-controlled clinical investigations meeting each of the precise
elements of 314.126 and, for a combination drug product, 300.50,
showing effectiveness have been identified. Any order entering summary
judgment is required to set forth the Commissioner's findings and
conclusions in detail and is required to specify why each study
submitted fails to meet the requirements of the statute and regulations
or why the request for hearing does not raise a genuine and substantial
issue of fact.
(2) When following a general notice of opportunity for a hearing (as
defined in paragraph (a)(1) of this section) the Director of the Center
for Drug Evaluation and Research concludes that summary judgment against
a person requesting a hearing should be considered, the Director will
serve upon the person requesting a hearing by registered mail a proposed
order denying a hearing. This person has 60 days after receipt of the
proposed order to respond with sufficient data, information, and
analyses to demonstrate that there is a genuine and substantial issue of
fact which justifies a hearing.
(3) When following a general or specific notice of opportunity for a
hearing a person requesting a hearing submits data or information of a
type required by the statute and regulations, and the Director of the
Center for Drug Evaluation and Research concludes that summary judgment
against the person should be considered, the Director will serve upon
the person by registered mail a proposed order denying a hearing. The
person has 60 days after receipt of the proposed order to respond with
sufficient data, information, and analyses to demonstrate that there is
a genuine and substantial issue of fact which justifies a hearing.
(4) If review of the data, information, and analyses submitted show
that the grounds cited in the notice are not valid, for example, that
substantial evidence of effectiveness exists, the Commissioner will
enter summary judgment for the person requesting the hearing, and
rescind the notice of opportunity for hearing.
(5) If the Commissioner grants a hearing, it will begin within 90
days after the expiration of the time for requesting the hearing unless
the parties otherwise agree in the case of denial of approval, and as
soon as practicable in the case of withdrawal of approval.
(6) The Commissioner will grant a hearing if there exists a genuine
and substantial issue of fact or if the Commissioner concludes that a
hearing would otherwise be in the public interest.
(7) If the manufacturer or distributor of an identical, related, or
similar drug product requests and is granted a hearing, the hearing may
consider whether the product is in fact identical, related, or similar
to the drug product named in the notice of opportunity for a hearing.
(8) A request for a hearing, and any subsequent grant or denial of a
hearing, applies only to the drug products named in such documents.
(h) FDA will issue a notice withdrawing approval and declaring all
products unlawful for drug products subject to a notice of opportunity
for a hearing, including any identical, related, or similar drug product
under 310.6, for which an opportunity for a hearing is waived or for
which a hearing is denied. The Commissioner may defer or stay the
action pending a ruling on any related request for a hearing or pending
any related hearing or other administrative or judicial proceeding.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990)
21 CFR 314.201 Procedure for hearings.
Parts 10 through 16 apply to hearings relating to new drugs under
section 505 (d) and (e) of the act.
21 CFR 314.235 Judicial review.
(a) The Commissioner of Food and Drugs will certify the transcript
and record. In any case in which the Commissioner enters an order
without a hearing under 314.200(g), the record certified by the
Commissioner is required to include the requests for hearing together
with the data and information submitted and the Commissioner's findings
and conclusion.
(b) A manufacturer or distributor of an identical, related, or
similar drug product under 310.6 may seek judicial review of an order
withdrawing approval of a new drug application, whether or not a hearing
has been held, in a United States court of appeals under section 505(h)
of the act.
21 CFR 314.235 Subpart E -- Administrative Procedures for Antibiotics
21 CFR 314.300 Procedure for the issuance, amendment, or repeal of
regulations.
(a) The procedures in Part 10 apply to the issuance, amendment, or
repeal of regulations under section 507 of the act.
(b) (1) The Commissioner of Food and Drugs, on his or her own
initiative or on the application or request of any interested person,
may publish in the Federal Register a notice of proposed rulemaking and
order to issue, amend, or repeal any regulation contemplated by section
507 of the act. The notice and order may be general (that is, simply
summarizing in a general way the information resulting in the notice and
order) or specific (that is, either referring to specific requirements
in the statute and regulations with which there is a lack of compliance,
or providing a detailed description and analysis of the specific facts
resulting in the notice and order).
(2) The Food and Drug Administration will give interested persons an
opportunity to submit written comments and to request an informal
conference on the proposal, unless the notice and opportunity for
comment and informal conference have already been provided in connection
with the announcement of the reports of the National Academy of
Sciences/National Research Council, Drug Efficacy Study Group, to
persons who will be adversely affected, or as provided in 10.40(e) and
12.20(c)(2). A person is required to request an informal conference
within 30 days of the notice of proposed rulemaking unless otherwise
specified in the notice. If an informal conference is requested and
granted, those persons participating in the conference may submit
comments, within 30 days of the conference, unless otherwise specified
in the proposal.
(3) It is the responsibility of every manufacturer and distributor of
an antibiotic drug product to review every proposal published in the
Federal Register to determine whether it covers any drug product that
person manufactures or distributes.
(4) After considering the written comments, the results of any
conference, and the data available, the Commissioner will publish an
order in the Federal Register acting on the proposal, with an
opportunity for any person who will be adversely affected to file
objections, to request a hearing, and to show reasonable grounds for the
hearing. Any person who wishes to participate in a hearing, shall file
with the Dockets Management Branch (HFA-305), Food and Drug
Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857, (i)
within 30 days after the date of the publication of the order a written
notice of participation and request for a hearing and (ii) within 60
days after the date of publication of the order, unless a different
period of time is specified in the order, the studies on which the
person relies to justify a hearing as specified in paragraph (b)(6) of
this section. The person may incorporate by reference the raw data
underlying a study if the data were previously submitted to FDA as part
of an application or other report.
(5) FDA will not consider data or analysis submitted after 60 days in
determining whether a hearing is warranted unless they are derived from
well-controlled studies begun before the date of the order and the
results of the studies were not available within 60 days after the date
of publication of the order. Nevertheless, FDA may consider other
studies on the basis of a showing by the person requesting a hearing of
inadvertent omission and hardship. The person requesting a hearing
shall list in the request for hearing all studies in progress, the
results of which the person intends later to submit in support of the
request for hearing. The person shall submit under paragraph (b)(4)(ii)
of this section a copy of the complete protocol, a list of the
participating investigators, and a brief status report of the studies.
(6) The person requesting a hearing is required to submit as required
under 314.200(c)(1)(ii) the studies (including all protocols and
underlying raw data) on which the person relies to justify a hearing
with respect to the drug product. Except, a person who requests a
hearing on a proposal is not required to submit additional studies and
analyses if the studies upon which the person relies have been submitted
in an application and in the format and containing the summaries
required under 314.50.
(i) If the grounds for FDA proposed action concern the effectiveness
of the drug, each request for hearing is required to be supported only
by adequate and well-controlled clinical studies meeting all of the
precise requirements of 314.126 and, for combination drug products,
300.50, or by other studies not meeting those requirements for which a
waiver has been previously granted by FDA under 314.126. Each person
requesting a hearing shall submit all adequate and well-controlled
clinical studies on the drug product, any unfavorable analyses, views,
or judgments with respect to the studies. No other data, information,
or studies may be submitted.
(ii) The submission is required to include a factual analysis of all
the studies submitted. If the grounds for FDA proposed action concern
the effectiveness of the drug, the analysis is required to specify how
each study accords, on a point-by-point basis, with each criterion
required for an adequate well-controlled clinical investigation
established under 314.126 and, if the product is a combination drug
product, with each of the requirements for a combination drug
established in 300.50, or the study is required to be accompanied by an
appropriate waiver previously granted by FDA. If a study concerns a
drug entity or dosage form or condition of use or mode of administration
other than the one in question, that fact is required to be clearly
stated. Any study conducted on the final marketed form of the drug
product is required to be clearly identified.
(iii) Each person requesting a hearing shall submit an analysis of
the data upon which the person relies, except that the required
information relating either to safety or to effectiveness may be omitted
if the notice of opportunity for hearing does not raise any issue with
respect to that aspect of the drug; information on compliance with
300.50 may be omitted if the drug product is not a combination drug
product. FDA can most efficiently consider submissions made in the
following format.
I. Safety data.
A. Animal safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
B. Human safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination
about the safety of each individual active component.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination
about the safety of each individual active component.
II. Effectiveness data.
A. Individual active components: Controlled studies, with an
analysis showing clearly how each study satisfies, on a point-by-point
basis, each of the criteria required by 314.126.
B. Combinations of individual active components.
1. Controlled studies with an analysis showing clearly how each study
satisfies on a point-by-point basis, each of the criteria required by
314.126.
2. An analysis showing clearly how each requirement of 300.50 has
been satisfied.
III. A summary of the data and views setting forth the medical
rationale and purpose for the drug and its ingredients and the
scientific basis for the conclusion that the drug and its ingredients
have been proven safe and/or effective for the intended use. If there
is an absence of controlled studies in the material submitted or the
requirements of any element of 300.50 or 314.126 have not been fully
met, that fact is required to be stated clearly and a waiver obtained
under 314.126 is required to be submitted.
IV. A statement signed by the person responsible for such submission
that it includes in full (or incorporates by reference as permitted in
314.200(c)(2)) all studies and information specified in 314.200(d).
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(7) Separation of functions. Separation of functions commences upon
receipt of a request for hearing. The Director of the Center for Drug
Evaluation and Research will prepare an analysis of the request and a
proposed order ruling on the matter. The analysis and proposed order,
the request for hearing, and any proposed order denying a hearing and
response under paragraph (b)(8) (ii) or (iii) of this section will be
submitted to the Office of the Commissioner for review and decision.
When the Center for Drug Evaluation and Research recommends denial of a
hearing on all issues on which a hearing is requested, no representative
of the Center will participate or advise in the review and decision by
the Commissioner. When the Center for Drug Evaluation and Research
recommends that a hearing be granted on one or more issues on which a
hearing is requested, separation of functions terminates as to those
issues, and representatives of the Center may participate or advise in
the review and decision by the Commissioner on those issues. The
Commissioner may modify the text of the issues, but may not deny a
hearing on those issues. Separation of functions continues with respect
to issues on which the Center for Drug Evaluatioon and Research has
recommended denial of a hearing. The Commissioner will neither evaluate
nor rule on the Center's recommendation on such issues and such issues
will not be included in the notice of hearing. Participants in the
hearing may make a motion to the presiding officer for the inclusion of
any such issue in the hearing. The ruling on such a motion is subject
to review in accordance with 12.35(b). Failure to so move constitutes a
waiver of the right to a hearing on such an issue. Separation of
functions on all issues resumes upon issuance of a notice of hearing.
The Office of the General Counsel, Department of Health and Human
Services, will observe the same separation of functions.
(8) Summary judgment. A person who requests a hearing may not rely
upon allegations or denials but is required to set forth specific facts
showing that there is a genuine and substantial issue of fact that
requires a hearing with respect to a particular drug product specified
in the request for hearing.
(i) Where a specific notice of opportunity for hearing (as defined in
paragraph (b)(1) of this section) is used, the Commissioner will enter
summary judgment against a person who requests a hearing, making
findings and conclusions, denying a hearing, if it conclusively appears
from the face of the data, information, and factual analyses in the
request for the hearing that there is no genuine and substantial issue
of fact which precludes the refusal to approve the application or the
withdrawal of approval of the application; for example, no adequate and
well-controlled clinical investigations meeting each of the precise
elements of 314.126 and, for a combination drug product, 300.50,
showing effectiveness have been identified. Any order entering summary
judgment is required to set forth the Commissioner's findings and
conclusions in detail and is required to specify why each study
submitted fails to meet the requirements of the statute and regulations
or why the request for hearing does not raise a genuine and substantial
issue of fact.
(ii) When following a general notice of opportunity for a hearing (as
defined in paragraph (b)(1) of this section) the Director of the Center
for Drug Evaluation and Research concludes that summary judgment against
a person requesting a hearing should be considered, the Director will
serve upon the person requesting a hearing by registered mail a proposed
order denying a hearing. This person has 60 days after receipt of the
proposed order to respond with sufficient data, information, and
analyses to demonstrate that there is a genuine and substantial issue of
fact which justifies a hearing.
(iii) When following a general or specific notice of opportunity for
a hearing a person requesting a hearing submits data or information of a
type required by the statute and regulations, and the Director of the
Center for Drug Evaluation and Research concludes that summary judgment
against the person should be considered, the Director will serve upon
the person by registered mail a proposed order denying a hearing. The
person has 60 days after receipt of the proposed order to respond with
sufficient data, information, and analyses to demonstrate that there is
a genuine and substantial issue of fact which justifies a hearing.
(iv) If review of the data, information, and analyses submitted show
that the basis for the order is not valid, for example, that substantial
evidence of effectiveness exists, the Commissioner will enter summary
judgment for the person requesting the hearing, and revoke the order.
If a hearing is not requested, the order will become effective as
published.
(v) If the Commissioner grants a hearing, it will be conducted under
Part 12.
(vi) The Commissioner will grant a hearing if there exists a genuine
and substantial issue of fact or if the Commissioner concludes that a
hearing would otherwise be in the public interest.
(9) The repeal of any regulation constitutes a revocation of all
outstanding certificates based upon such regulation. However, the
Commissioner may, in his or her discretion, defer or stay such action
pending a ruling on any related request for a hearing or pending any
related hearing or other administrative or judicial proceeding.
(c) Whenever any interested person submits an application or request
under section 507 of the act and Part 314 and FDA sends the person an
approvable letter under 314.110 or a not approvable letter under
314.120, the person may file a petition proposing the issuance,
amendment, or repeal of the regulation under the provisions of section
507(f) of the act and Part 10. The Commissioner shall cause the
regulation proposed in the petition to be published in the Federal
Register within 60 days of the receipt of an acceptable petition and
further proceedings shall be in accord with the provisions of sections
507(f) and 701 (f) and (g) of the act and Part 10.
(d) (1) FDA will not promulgate a regulation providing for the
certification of any batch of any drug composed wholly or in part of any
kind of penicillin, streptomycin, chlortetracycline, chloramphenicol,
bacitracin, or any other antibiotic drug, or any derivative thereof,
intended for human use and no existing regulation will be continued in
effect unless it is established by substantial evidence that the drug
will have such characteristics of identity, strength, quality, and
purity necessary to adequately ensure safety and efficacy of use.
''Substantial evidence'' has been defined by Congress to mean ''evidence
consisting of adequate and well-controlled investigations, including
clinical investigations, by experts qualified by scientific training and
experience to evaluate the effectiveness of the drug involved, on the
basis of which it could fairly and responsibly be concluded by such
experts that the drug will have the effect it purports or is represented
to have under the conditions prescribed, recommended, or suggested in
the labeling or proposed labeling thereof.'' This definition is made
applicable to a number of antibiotic drugs by section 507(h) of the act
and it is the test of efficacy that FDA will apply in promulgating,
amending, or repealing regulations for all antibiotics under section
507(a) of the act as well.
(2) The scientific essentials of an adequate and well-controlled
clinical investigation are described in 314.126.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended
at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990)
21 CFR 314.300 Subpart F -- Miscellaneous Provisions
21 CFR 314.410 Imports and exports of new drugs and antibiotics.
(a) Imports. (1) A new drug or an antibiotic may be imported into
the United States if: (i) It is the subject of an approved application
under this part or, in the case of an antibiotic not exempt from
certification under Part 433, it is also certified or released; or (ii)
it complies with the regulations pertaining to investigational new drugs
under Part 312; and it complies with the general regulations pertaining
to imports under Subpart E of Part 1.
(2) A drug substance intended for use in the manufacture, processing,
or repacking of a new drug may be imported into the United States if it
complies with the labeling exemption in 201.122 pertaining to shipments
of drug substances in domestic commerce.
(b) Exports. (1) A new drug or an antibiotic may be exported if it
is the subject of an approved application under this part, and, in the
case of an antibiotic, it is certified or released, or it complies with
the regulations pertaining to investigational new drugs under Part 312.
(2) A new drug substance that is covered by an application approved
under this part for use in the manufacture of an approved drug product
may be exported by the applicant or any person listed as a supplier in
the approved application, provided the drug substance intended for
export meets the specifications of, and is shipped with a copy of the
labeling required for, the approved drug product.
(3) An antibiotic drug product or drug substance that is subject to
certification under section 507 of the act, but which has not been
certified or released, may be exported under section 801(d) of the act
if it meets the following conditions:
(i) It meets the specifications of the foreign purchaser;
(ii) It is not in conflict with the laws of the country to which it
is intended for export;
(iii) It is labeled on the outside of the shipping package that it is
intended for export; and
(iv) It is not sold or offered for sale in the United States.
21 CFR 314.420 Drug master files.
(a) A drug master file is a submission of information to the Food and
Drug Administration by a person (the drug master file holder) who
intends it to be used for one of the following purposes: To permit the
holder to incorporate the information by reference when the holder
submits an investigational new drug application under Part 312 or
submits an application or an abbreviated application or an amendment or
supplement to them under this part, or to permit the holder to authorize
other persons to rely on the information to support a submission to FDA
without the holder having to disclose the information to the person.
FDA ordinarily neither independently reviews drug master files nor
approves or disapproves submissions to a drug master file. Instead, the
agency customarily reviews the information only in the context of an
application under Part 312 or this part. A drug master file may contain
information of the kind required for any submission to the agency,
including information about the following:
(1) Manufacturing site, facilities, operating procedures, and
personnel (because an FDA on-site inspection of a foreign drug
manufacturing facility presents unique problems of planning and travel
not presented by an inspection of a domestic manufacturing facility,
this information is only recommended for foreign manufacturing
establishments);
(2) Drug substance, drug substance intermediate, and materials used
in their preparation, or drug product;
(3) Packaging materials;
(4) Excipient, colorant, flavor, essence, or materials used in their
preparation;
(5) FDA-accepted reference information. (A person wishing to submit
information and supporting data in a drug master file (DMF) that is not
covered by Types I through IV DMF's must first submit a letter of intent
to the Drug Master File Staff, Food and Drug Administration, 12420
Parklawn Dr., Rm. 2-14, Rockville, MD 20852. FDA will then contact the
person to discuss the proposed submission.)
(b) An investigational new drug application or an application,
abbreviated application, amendment, or supplement may incorporate by
reference all or part of the contents of any drug master file in support
of the submission if the holder authorizes the incorporation in writing.
Each incorporation by reference is required to describe the
incorporated material by name, reference number, volume, and page number
of the drug master file.
(c) A drug master file is required to be submitted in two copies.
The agency has prepared under 10.90(b) a guideline that provides
information about how to prepare a well-organized drug master file. If
the drug master file holder adds, changes, or deletes any information in
the file, the holder shall notify in writing, each person authorized to
reference that information. Any addition, change, or deletion of
information in a drug master file (except the list required under
paragraph (d) of this section) is required to be submitted in two copies
and to describe by name, reference number, volume, and page number the
information affected in the drug master file.
(d) The drug master file is required to contain a complete list of
each person currently authorized to incorporate by reference any
information in the file, identifying by name, reference number, volume,
and page number the information that each person is authorized to
incorporate. If the holder restricts the authorization to particular
drug products, the list is required to include the name of each drug
product and the application number, if known, to which the authorization
applies.
(e) The public availability of data and information in a drug master
file, including the availability of data and information in the file to
a person authorized to reference the file, is determined under Part 20
and 314.430.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
53 FR 33122, Aug. 30, 1988; 55 FR 28380, July 11, 1990)
21 CFR 314.430 Availability for public disclosure of data and
information in an application.
(a) The Food and Drug Administration will determine the public
availability of any part of an application under this section and Part
20. For purposes of this section, the application includes all data and
information submitted with or incorporated by reference in the
application, including investigational new drug applications, drug
master files under 314.420, supplements submitted under 314.70,
reports under 314.80, and other submissions. For purposes of this
section, safety and effectiveness data include all studies and tests of
a drug on animals and humans and all studies and tests of the drug for
identity, stability, purity, potency, and bioavailability.
(b) FDA will not publicly disclose the existence of an application
before an approvable letter is sent to the applicant under 314.110,
unless the existence of the application has been previously publicly
disclosed or acknowledged. The Center for Drug Evaluation and Research
will maintain and make available for public disclosure a list of
applications for which the agency has sent an approvable letter to the
applicant.
(c) If the existence of an unapproved application has not been
publicly disclosed or acknowledged, no data or information in the
application is available for public disclosure.
(d) If the existence of an application has been publicly disclosed or
acknowledged before the agency sends an approval letter to the
applicant, no data or information contained in the application is
available for public disclosure before the agency sends an approval
letter, but the Commissioner may, in his or her discretion, disclose a
summary of selected portions of the safety and effectiveness data that
are appropriate for public consideration of a specific pending issue,
for example, for consideration of an issue at an open session of an FDA
advisory committee.
(e) After FDA sends an approval letter to the applicant, the
following data and information in the application are immediately
available for public disclosure, unless the applicant shows that
extraordinary circumstances exist. A list of approved applications,
entitled ''Approved Prescription Drug Products with Therapeutic
Equivalence Evaluations (list ID APDP),'' is available from the
Government Printing Office, Washington, DC 20402. The list is updated
monthly.
(1) (Reserved)
(2) If the application applies to a new drug, all safety and
effectiveness data previously disclosed to the public as set forth in
20.81 and a summary or summaries of the safety and effectiveness data
and information submitted with or incorporated by reference in the
application. The summaries do not constitute the full reports of
investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1))
on which the safety or effectiveness of the drug may be approved. The
summaries consist of the following:
(i) For an application approved before July 1, 1975, internal agency
records that describe safety and effectiveness data and information, for
example, a summary of the basis for approval or internal reviews of the
data and information, after deletion of the following:
(a) Names and any information that would identify patients or test
subjects or investigators.
(b) Any inappropriate gratuitous comments unnecessary to an objective
analysis of the data and information.
(ii) For an application approved on or after July 1, 1975, a Summary
Basis of Approval (SBA) document that contains a summary of the safety
and effectiveness data and information evaluated by FDA during the drug
approval process. The SBA is prepared in one of the following ways:
(a) Before approval of the application, the applicant may prepare a
draft SBA which the Center for Drug Evaluation and Research will review
and may revise. The draft may be submitted with the application or as
an amendment.
(b) The Center for Drug Evaluation and Research may prepare the SBA.
(3) A protocol for a test or study, unless it is shown to fall within
the exemption established for trade secrets and confidential commercial
information in 20.61.
(4) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information after deletion of the
following:
(i) Names and any information that would identify the person using
the product.
(ii) Names and any information that would identify any third party
involved with the report, such as a physician or hospital or other
institution.
(5) A list of all active ingredients and any inactive ingredients
previously disclosed to the public as set forth in 20.81.
(6) An assay method or other analytical method, unless it serves no
regulatory or compliance purpose and is shown to fall within the
exemption established for trade secrets and confidential commercial
information in 20.61.
(7) All correspondence and written summaries of oral discussions
between FDA and the applicant relating to the application, under the
provisions of Part 20.
(8) All records showing the testing of an action on a particular lot
of a certifiable antibiotic by FDA.
(f) All safety and effectiveness data and information which have been
submitted in an application and which have not previously been disclosed
to the public are available to the public, upon request, at the time any
one of the following events occurs unless extraordinary circumstances
are shown:
(1) No work is being or will be undertaken to have the application
approved.
(2) A final determination is made that the application is not
approvable and all legal appeals have been exhausted.
(3) Approval of the application is withdrawn and all legal appeals
have been exhausted.
(4) A final determination has been made that the drug is not a new
drug.
(5) For applications submitted under section 505(b) of the act, the
effective date of the approval of the first application submitted under
section 505(k) of the act which refers to such drug, or the date on
which the approval of an application under section 505(k) which refers
to such drug could be made effective if such an application had been
submitted.
(6) For applications submitted under sections 505(k), 506, and 507 of
the act, when FDA sends an approval letter to the applicant.
(g) The following data and information in an application are not
available for public disclosure unless they have been previously
disclosed to the public as set forth in 20.81 or they relate to a
product or ingredient that has been abandoned and they do not represent
a trade secret or confidential commercial or financial information under
20.61:
(1) Manufacturing methods or processes, including quality control
procedures.
(2) Production, sales distribution, and similar data and information,
except that any compilation of that data and information aggregated and
prepared in a way that does not reveal data or information which is not
available for public disclosure under this provision is available for
public disclosure.
(3) Quantitative or semiquantitative formulas.
(h) The compilations of information specified in 20.117 are
available for public disclosure.
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
55 FR 11580, Mar. 29, 1990)
21 CFR 314.440 Addresses for applications.
(a) Applicants shall send applications and other correspondence
relating to matters covered by this part, except for products listed in
paragraph (b) of this section or as otherwise directed, to the Center
for Drug Evaluation and Research, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, and directed to the appropriate
office identified below:
(1) An application under 314.50 submitted for filing should be
directed to the Document and Records Section, 12420 Parklawn Drive,
Rockville, MD 20852. Applicants may obtain folders for binding
applications from the Forms and Publications Warehouse, 12100 Parklawn
Drive, Rockville, MD 20852. After FDA has filed the application, the
agency will inform the applicant which division is responsible for the
application. Amendments, supplements, resubmissions, requests for
waivers, and other correspondence about an application that has been
filed should be directed to the appropriate division.
(2) An abbreviated application under 314.55, and amendments,
supplements, resubmissions, and other correspondence about an
abbreviated application should be directed to the Office of Generic
Drugs (HFD-230). Applicants may obtain folders for binding abbreviated
applications from that office.
(3) A request for an opportunity for a hearing under 314.110 or
314.120 on the question of whether there are grounds for denying
approval of an application, except an application under paragraph (b) of
this section, should be directed to the Division of Regulatory Affairs
(HFD-360).
(b) Applicants shall send applications and other correspondence
relating to matters covered by this part for the drug products listed
below to the Division of Product Certification (HFB-240), Center for
Biologics Evaluation and Research, Food and Drug Administration, 8800
Rockville Pike, Bethesda, MD 20892, except applicants shall send a
request for an opportunity for a hearing under 314.110 or 314.120 on
the question of whether there are grounds for denying approval of an
application to the Director, Center for Biologics Evaluation and
Research (HFB-1), at the same address.
(1) Ingredients packaged together with containers intended for the
collection, processing, or storage of blood and blood components.
(2) Urokinase products.
(3) Plasma volume expanders and hydroxyethyl starch for
leukapheresis.
(50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985;
55 FR 11581, Mar. 29, 1990)
21 CFR 314.445 Guidelines.
(a) The Food and Drug Administration prepares guidelines under
10.90(b) to help persons comply with requirements in this part.
(b) The Center for Drug Evaluation and Research will maintain and
make publicly available a list of guidelines that apply to the Center's
regulations. The list states how a person can obtain a copy of each
guideline. A request for a copy of the list should be directed to the
CDER Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857.
(50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11581, Mar. 29, 1990;
56 FR 3776, Jan. 31, 1991)
21 CFR 314.445 PART 320 -- BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
21 CFR 314.445 Subpart A -- General Provisions
Sec.
320.1 Definitions.
21 CFR 314.445 Subpart B -- Procedures for Determining the
Bioavailability of Drug Products
320.21 Requirements for submission of in vivo bioavailability data.
320.22 Criteria for waiver of evidence of in vivo bioavailability.
320.23 Basis for demonstrating bioavailability.
320.24 General approaches for determining bioavailability.
320.25 Guidelines for the conduct of an in vivo bioavailability
study.
320.26 Guidelines on the design of a single-dose in vivo
bioavailability study.
320.27 Guidelines on the design of a multiple-dose in vivo
bioavailability study.
320.28 Correlation of bioavailability with an acute pharmacological
effect or clinical evidence.
320.29 Analytical methods for an in vivo bioavailability study.
320.30 Inquiries regarding bioavailability requirements and review of
protocols by the Food and Drug Administration.
320.31 Applicability of requirements regarding an ''Investigational
New Drug Application.''
320.32 Retention of bioavailability samples.
21 CFR 314.445 Subpart C -- Bioequivalence Requirements
320.50 Purpose.
320.51 Procedures for establishing or amending a bioequivalence
requirement.
320.52 Criteria and evidence to establish a bioequivalence
requirement.
320.53 Types of bioequivalence requirements.
320.54 Contents of a petition to establish a bioequivalence
requirement.
320.55 Requirements for batch testing and certification by the Food
and Drug Administration.
320.56 Requirements for in vitro testing of each batch.
320.57 Requirements for the conduct of in vivo bioequivalence testing
in humans.
320.58 Requirements for marketing a drug product subject to a
bioequivalence requirement.
320.59 Bioequivalence requirements based on data voluntarily
submitted.
320.60 Bioequivalence requirements for a drug product subject to an
old drug monograph.
320.61 Requirements for in vivo testing of a drug product not meeting
an in vitro bioequivalence standard.
320.62 Requirements for maintenance of records of bioequivalence
testing.
320.63 Retention of bioequivalence samples.
Authority: Secs. 201, 501, 502, 505, 507, 701 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, 357, 371).
21 CFR 314.445 Subpart A -- General Provisions
21 CFR 320.1 Definitions.
(a) Bioavailability means the rate and extent to which the active
drug ingredient or therapeutic moiety is absorbed from a drug product
and becomes available at the site of drug action.
(b) Drug product means a finished dosage form, e.g., tablet, capsule,
or solution, that contains the active drug ingredient, generally, but
not necessarily, in association with inactive ingredients.
(c) Pharmaceutical equivalents means drug products that contain
identical amounts of the identical active drug ingredient, i.e., the
same sat or ester of the same therapeutic moiety, in identical dosage
forms, but not necessarily containing the same inactive ingredients, and
that meet the identical compendial or other applicable standard of
identity, strength, quality, and purity, including potency and, where
applicable, content uniformity, disintegration times and/or dissolution
rates.
(d) Pharmaceutical alternatives means drug products that contain the
identical therapeutic moiety, or its precursor, but not necessarily in
the same amount or dosage form or as the same salt or ester. Each such
drug product individually meets either the identical or its own
respective compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable,
content uniformity, disintegration times and/or dissolution rates.
(e) Bioequivalent drug products means pharmaceutical equivalents or
pharmaceutical alternatives whose rate and extent of absorption do not
show a significant difference when administered at the same molar dose
of the therapeutic moiety under similar experimental conditions, either
single dose or multiple dose. Some pharmaceutical equivalents or
pharmaceutical alternatives may be equivalent in the extent of their
absorption but not in their rate of absorption and yet may be considered
bioequivalent because such differences in the rate of absorption are
intentional and are reflected in the labeling, are not essential to the
attainment of effective body drug concentrations on chronic use, or are
considered medically insignificant for the particular drug product
studied.
(f) Bioequivalence requirement means a requirement imposed by the
Food and Drug Administration for in vitro and/or in vivo testing of
specified drug products which must be satisfied as a condition of
marketing.
(42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977)
21 CFR 320.1 Subpart B -- Procedures for Determining the
Bioavailability of Drug Products
Source: 42 FR 1648, Jan. 7, 1977, unless otherwise noted.
21 CFR 320.21 Requirements for submission of in vivo bioavailability
data.
(a) Any person submitting a full or abbreviated new drug application
to the Food and Drug Administration after July 7, 1977, shall include in
the application either:
(1) Evidence demonstrating the in vivo bioavailability of the drug
product that is the subject of the application; or,
(2) Information to permit the Food and Drug Administration to waive
demonstration of in vivo bioavailability.
(b) Any person submitting a supplemental application to the Food and
Drug Administration after July 7, 1977, shall include in the
supplemental application the evidence or information set forth in
paragraph (a) of this section if the supplemental application proposes
any of the following changes:
(1) A change in the manufacturing process, including a change in
product formulation or dosage strength, beyond the variations provided
for in the approved application.
(2) A change in the labeling to provide for a new indication for use
of the drug product, if clinical studies are required to support the new
indication for use.
(3) A change in the labeling to provide for a new dosage regimen or
for an additional dosage regimen for a special patient population, e.g.,
infants, if clinical studies are required to support the new or
additional dosage regimen.
(c) The Food and Drug Administration may approve a full or
abbreviated new drug application, or a supplemental application
proposing any of the changes set forth in paragraph (b) of this section,
that does not contain evidence of in vivo bioavailability or information
to permit waiver of the requirement for in vivo bioavailability data, if
all of the following conditions are met:
(1) The application is under review by the Food and Drug
Administration on July 7, 1977.
(2) The application is otherwise approvable.
(3) The applicant agrees to submit, within the time specified by the
Food and Drug Administration, either:
(i) Evidence demonstrating the in vivo bioavailability of the drug
product that is the subject of the application; or,
(ii) Information to permit the Food and Drug Administration to waive
demonstration of in vivo bioavailability.
(d) Evidence demonstrating the in vivo bioavailability of a drug
product shall be obtained using one of the approaches for determining
bioavailability set forth in 320.24.
(e) Information to permit the Food and Drug Administration to waive
demonstration of in vivo bioavailability shall meet the criteria set
forth in 320.22.
(f) Any person holding an approved full or abbreviated new drug
application shall submit to the Food and Drug Administration a
supplemental application containing new evidence demonstrating the in
vivo bioavailability of the drug product that is the subject of the
application if notified by the Food and Drug Administration that:
(1) There are data demonstrating that the dosage regimen in the
labeling is based on incorrect assumptions or facts regarding the
pharmacokinetics of the drug product and following this dosage regimen
could potentially result in subtherapeutic or toxic levels; or,
(2) There are data demonstrating significant intra-batch and
batch-to-batch variability, e.g., plus or minus 25 percent, in the
bioavailability of the drug product.
(g) The requirements of this section regarding the submission of
evidence demonstrating in vivo bioavailability apply only to a full or
abbreviated new drug application or a supplemental application for a
finished dosage formulation.
21 CFR 320.22 Criteria for waiver of evidence of in vivo
bioavailability.
(a) Any person submitting a full or abbreviated new drug application,
or a supplemental application proposing any of the changes set forth in
320.21(b), may request the Food and Drug Administration to waive the
requirement for the submission of evidence demonstrating the in vivo
bioavailability of the drug product that is the subject of the
application. A request for waiver shall be submitted with the
application. The Food and Drug Administration shall waive the
requirement for the submission of evidence of in vivo bioavailability if
the drug product meets any of the provisions of paragraph (b), (c), or
(d) of this section.
(b) For certain drug products the in vivo bioavailability of the drug
product may be self evident or not necessary for the product to achieve
any of its intended purposes. The Food and Drug Administration shall
waive the requirement for the submission of evidence obtained in vivo
demonstrating the bioavailability of the drug product if the product
meets one of the following criteria:
(1) The drug product meets both of the following conditions:
(i) It is a solution intended solely for intravenous administration.
(ii) It contains an active drug ingredient or therapeutic moiety in
the same solvent and concentration as an intravenous solution that is
the subject of an approved full new drug application.
(2) The drug product is a topically applied preparation, e.g., a
cream, ointment, or gel, intended for local therapeutic effect.
(3) The drug product is an oral dosage form that is not intended to
be absorbed, e.g., an antacid or a radiopaque medium.
(4) The drug product meets both of the following conditions:
(i) It is administered by inhalation as a gas or vapor, e.g., a
medicinal or an inhalation anesthetic.
(ii) It contains an active drug ingredient or therapeutic moiety in
the same dosage form as a drug product that is the subject of an
approved full new drug application.
(5) The drug product meets all of the following conditions:
(i) It is an oral solution, elixir, syrup, tincture, or similar other
solubilized form.
(ii) It contains an active drug ingredient or therapeutic moiety in
the same concentration as a drug product that is the subject of an
approved full new drug application.
(iii) It contains no inactive ingredient that is known to
significantly affect absorption of the active drug ingredient or
therapeutic moiety.
(c)(1) The Food and Drug Administration shall waive the requirement
for the submission of evidence demonstrating the in vivo bioavailability
of a solid oral dosage form (other than an enteric coated or controlled
release dosage form) of a drug product determined to be effective for at
least one indication in a Drug Efficacy Study Implementation notice or
which is identical, related, or similar to such a drug product under
310.6 of this chapter if the drug product is neither one of the
following nor an identical, related, or similar drug product under
310.6 of this chapter:
Methyltestosterone tablets.
Procainamide hydrochloride capsules.
Quinidine polygalacturonate tablets.
Diphemanil methylsulfate tablets.
Bishydroxycoumarin tablets and capsules.
Warfarin, sodium and potassium tablets.
Ethosuximide capsules.
Ethotoin tablets.
Mephenytoin tablets.
Methsuximide capsules.
Paramethadione capsules.
Phenacemide tablets.
Phensuximide capsules and suspension.
Phenytoin suspension.
Primidone tablets and suspension.
Trimethadione capsules.
Imipramine hydrochloride tablets.
Trimethobenzamide capsules.
Alseroxylon tablets.
Bendroflumethiazide tablets.
Benzthiazide tablets.
Chlorthalidone tablets.
Chlorothiazide tablets.
Deserpidine tablets.
Guanethidine sulfate tablets.
Hydrochlorothiazide tablets.
Hydroflumethiazide tablets.
Methyclothiazide tablets.
Polythiazide tablets.
Quinethazone tablets.
Rauwolfia serpentina tablets.
Rescinnamine tablets.
Reserpine tablets.
Spironolactone tablets.
Trichlormethiazide tablets.
Chlorothiazide and reserpine tablets.
Hydralazine and reserpine tablets.
Hydralazine hydrochloride and hydrochlorothiazide tablets.
Hydrochlorothiazide and deserpidine tablets.
Hydrochlorothiazide and reserpine tablets.
Hydroflumethiazide and reserpine tablets.
Methyclothiazide and deserpidine tablets.
Reserpine, hydralazine hydrochloride and hydrochlorothiazide tablets.
Spironolactone and hydrochlorothiazide tablets.
Trichloromethiazide and reserpine tablets.
Nitrofurantoin tablets and suspension.
Sodium sulfoxone tablets.
Sulfadiazine sodium bicarbonate suspension.
Sulfasalazine tablets.
Sulfadiazine, sulfamethazine, and sulfamerazine (triple sulfa)
tablets and suspension.
Sulfadiazine tablets.
Sulfadimethoxine tablets, drops, and suspension.
Sulfamerazine tablets.
Sulfamethoxypyridazine acetyl tablets and suspension.
Sulfaphenazole suspension.
Sulfapyridine tablets.
Sulfasalazine tablets.
Sulfisomidine tablets.
Sulfisoxazole acetyl suspension.
Sulfisoxazole tablets.
Pyrimethamine tablets.
Chlorambucil tablets.
Cyclophosphamide tablets.
Methotrexate tablets.
Triethylene melamine tablets.
Uracil mustard tablets.
Methdilazine tablets.
Oxyphenbutazone tablets.
Phenylbutazone tablets.
Propylthiouracil tablets.
Aminosalicylic acid and isoniazid tablets.
Aminosalicylic acid powder, tablets, and resin.
Aminosalicylic calcium granules, tablets, and capsules.
Aminosalicylic potassium tablets, capsules, and powder.
Aminosalicylic sodium powder, tablets, and granules.
Benzoylpas calcium tablets and powder.
Para-aminosalicylate sodium and isoniazid tablets.
Phenylaminosalicylate powder and tablets.
Aminophylline tablets.
Dyphylline tablets.
Oxtriphylline tablets.
Theophylline sodium glycinate tablets.
Acetazolamide tablets.
Dichlorphenamide tablets.
Ethoxzolamide tablets.
Methazolamide tablets.
Acetyldigitoxin tablets.
Betamethasone tablets.
Cortisone acetate tablets.
Dexamethasone tablets.
Fludrocortisone acetate tablets.
Fluprednisolone tablets.
Hydrocortisone acetate tablets and powder.
Hydrocortisone tablets.
Methylprednisolone tablets.
Paramethasone acetate tablets.
Prednisolone tablets.
Prednisone tablets.
Triamcinolone tablets.
Conjugated estrogens with meprobamate tablets. /1/
Dienestrol tablets.
Diethylstilbestrol diphosphate tablets.
Diethylstilbestrol tablets.
Ethinyl estradiol tablets.
Chlorpropamide tablets.
Tolbutamide tablets.
Butalbital, aspirin, phenacetin, and caffeine tablets and capsules
/1/
Carisoprodol in combination with phenacetin and caffeine (with or
without codeine phosphate). /1/
Methocarbamol with aspirin tablets. /1/
Isoproterenol sublingual tablets.
Liothyronine, sodium tablets.
Thyroglobulin tablets.
Chlordiazepoxide hydrochloride capsules.
Chlorpromazine tablets.
Fluphenazine hydrochloride tablets.
Hydroxyzine hydrochloride tablets. /1/
Hydroxyzine pamoate capsules and oral suspension.
Perphenazine tablets.
Prochlorperazine tablets.
Promazine tablets.
Promethazine tablets.
Thioridazine tablets.
Trifluoperazine tablets.
Triflupromazine tablets.
Trimeprazine tablets.
Probenecid tablets.
Sulfinpyrazone tablets and capsules.
Menadione tablets.
Phytonadione tablets.
(2) The Food and Drug Administration shall waive the requirement for
the submission of evidence demonstrating the in vivo bioavailability of
a parenteral drug product that is determined to be effective for at
least one indication in a Drug Efficacy Study Implementation notice or
that, upon submission of evidence, is shown to be identical in both
active and inactive ingredient formulation to that drug as currently
approved in a new drug application, if the drug product is not one of
the following:
A drug in suspension form. Phenytoin sodium powder for injection.
(3) A waiver shall not be granted for a drug product for which an
initial determination that the drug product is effective for one or more
indications is published after January 7, 1977, in a Drug Efficacy Study
Implementation notice stating that the drug is subject to a
bioavailability requirement.
(d) For certain drug products bioavailability may be demonstrated by
evidence obtained in vitro in lieu of in vivo data. The Food and Drug
Administration shall waive the requirement for the submission of
evidence obtained in vivo demonstrating the bioavailability of the drug
product if the drug product meets one of the following criteria:
(1) The drug product is subject to a bioequivalence requirement
established by the Food and Drug Administration under Subpart C of this
Part that specifies only an in vitro testing requirement.
(2) The drug product is in the same dosage form, but in a different
strength, and is proportionally similar in its active and inactive
ingredients to another drug product made by the same manufacturer and
the following conditions are met:
(i) The bioavailability of this other drug product has been
demonstrated.
(ii) Both drug products meet an appropriate in vitro test approved by
the Food and Drug Administration.
(iii) The applicant submits evidence showing that both drug products
are proportionally similar in their active and inactive ingredients.
(3) The drug product is, on the basis of scientific evidence
submitted in the application, shown to meet an in vitro test that
assures bioavailability, i.e., an in vitro test that has been correlated
with in vivo data.
(4) The drug product is a reformulated product that is identical,
except for color, flavor, or preservative, to another drug product made
by the same manufacturer and both of the following conditions are met:
(i) The bioavailability of the other product has been demonstrated.
(ii) Both drug products meet an appropriate in vitro test approved by
the Food and Drug Administration.
(5) The drug product contains the same active drug ingredient or
therapeutic moiety and is in the same strength and dosage form as a drug
product that is the subject of an approved full or abbreviated new drug
application, and both drug products meet an appropriate in vitro test
that has been approved by the Food and Drug Administration.
(e) The Food and Drug Administration, for good cause, may defer or
waive a requirement for the submission of evidence of in vivo
bioavailability if deferral or waiver is compatible with the protection
of the public health.
(42 FR 1648, Jan. 7, 1977, as amended at 42 FR 42311, Aug. 23, 1977;
46 FR 36130, July 14, 1981)
/1/ In vivo bioavailability must be demonstrated only if product
fails to achieve adequate dissolution when compared to the test drug
product.
21 CFR 320.23 Basis for demonstrating bioavailability.
(a) The in vivo bioavailability of a drug product is demonstrated if
the product's rate and extent of absorption, as determined by comparison
of measured parameters, e.g., concentration of the active drug
ingredient in the blood, urinary excretion rates, or pharmacological
effects, do not indicate a significant difference from the reference
material's rate and extent of absorption.
(b) Statistical techniques used shall be of sufficient sensitivity to
detect differences in rate and extent of absorption that are not
attributable to subject variability.
(c) A drug product that differs from the reference material in its
rate of absorption, but not in its extent of absorption, may be
considered to be bioavailable if:
(1) The difference in the rate of absorption is intentional and
appropriately reflected in the labeling; and/or
(2) The rate of absorption is not detrimental to the safety and
effectiveness of the drug product.
21 CFR 320.24 General approaches for determining bioavailability.
(a) Bioavailability is usually determined by measurement of:
(1) The concentration of the active drug ingredient or therapeutic
moiety, or its metabolite(s), in biological fluids as a function of
time; or
(2) The urinary excretion of the therapeutic moiety or its
metabolite(s) as a function of time; or
(3) An appropriate acute pharmacological effect.
(b) Bioavailability may be determined by several direct or indirect
in vivo methods, generally involving testing in humans. The selection
of the method depends upon the purpose of the study, the analytical
method available, and the nature of the drug product. These limitations
affect the degree to which precise pharmacokinetic studies can be
applied and, in some cases, necessitate the use of other methods.
Bioavailability testing shall be conducted using the most accurate,
sensitive, and reproducible approach available among those set forth in
paragraph (c) of this section.
(c) The following in vivo approaches, in descending order of
accuracy, sensitivity, and reproducibility, are acceptable for
determining the bioavailability of a drug product.
(1) In vivo testing in humans in which the concentration of the
active drug ingredient or therapeutic moiety or its metabolite(s), in
whole blood, plasma, serum, or other appropriate biological fluid is
measured as a function of time, or in which the urinary excretion of the
therapeutic moiety, or its metabolite(s), is measured as a function of
time. This approach is particularly applicable to dosage forms intended
to deliver the active drug ingredient or therapeutic moiety, or to the
blood stream for systemic distribution within the body, i.e., injectable
drugs, most oral dosage forms, most suppositories, certain drugs
administered by inhalation, and some drugs administered by local
application to mucous membranes.
(2) In vivo testing in humans in which an appropriate acute
pharmacological effect of the active drug ingredient or therapeutic
moiety, or metabolite(s), is measured as a function of time if such
effect can be measured with sufficient accuracy, sensitivity, and
reproducibility. This approach is applicable when appropriate methods
are not available for measurement of the concentration of the active
drug ingredient or therapeutic moiety, or its metabolite(s), in
biological fluids or excretory products but a method is available for
the measurement of an appropriate acute pharmacological effect. This
approach is applicable to the same dosage forms listed in paragraph
(c)(1) of this section.
(3) Well-controlled clinical trials in humans that establish the
safety and effectiveness of the drug product. This approach is the
least accurate, sensitive, and reproducible of the general approaches
for determining in vivo bioavailability in humans. For dosage forms
intended to deliver the active drug ingredient or therapeutic moiety to
the bloodstream for systemic distribution within the body, this approach
shall be considered as providing a sufficiently accurate estimate of in
vivo bioavailability only when analytical methods are not available to
permit use of one of the approaches outlined in paragraphs (c) (1) and
(2) of this section. This approach shall also be considered as
sufficiently accurate for determining the bioavailability of dosage
forms intended to deliver the therapeutic moiety locally, e.g., topical
preparations for the skin, eye, ear, mucous membranes; oral dosage
forms not intended to be absorbed, e.g., an antacid or a radiopaque
medium; and bronchodilators administered by inhalation if the onset and
duration of pharmacological activity are defined.
(4) Any other in vivo approach approved by the Food and Drug
Administration. This provision is intended for special situations and
to include those circumstances where the in vivo bioavailability of a
drug product might be determined in a suitable animal model rather than
in humans or by using a radioactive or nonradioactive isotopically
labeled drug product.
21 CFR 320.25 Guidelines for the conduct of an in vivo bioavailability
study.
(a) Guiding principles. (1) The basic principle in an in vivo
bioavailability study is that no unnecessary human research should be
done.
(2) An in vivo bioavailability study shall not be conducted in humans
if an appropriate animal model exists and correlation of results in
animals and humans has been demonstrated. If an appropriate animal
model does not exist, however, an in vivo bioavailability study shall
ordinarily be done in normal adults under standardized conditions.
(3) In some situations, an in vivo bioavailability study in humans
may preferably and more properly be done in suitable patients.
Critically ill patients shall not be included in an in vivo
bioavailability study unless the attending physician determines that
there is a potential benefit to the patient.
(b) Basic design. The basic design of an in vivo bioavailability
study is determined by the following:
(1) The scientific questions to be answered.
(2) The nature of the reference material and the dosage form to be
tested.
(3) The availability of analytical methods.
(4) Benefit-risk considerations in regard to testing in humans.
(c) Comparison to a reference material. In vivo bioavailability
testing of a drug product shall be in comparison to an appropriate
reference material unless some other approach is more appropriate for
valid scientific reasons.
(d) Previously unmarketed active drug ingredients or therapeutic
moieties. (1) The purpose of an in vivo bioavailability study involving
a drug product containing an active drug ingredient or therapeutic
moiety that has not been approved for marketing is to determine:
(i) The bioavailability of the formulation proposed for marketing;
and
(ii) The essential pharmacokinetic characteristics of the active drug
ingredient or therapeutic moiety, such as the rate of absorption, the
extent of absorption, the half-life of the therapeutic moiety in vivo,
and the rate of excretion and/or metabolism. Dose proportionality of
the active drug ingredient or the therapeutic moiety needs to be
established after single-dose administration and in certain instances
after multiple-dose administration. This characterization is a
necessary part of the investigation of the drug to support drug
labeling.
(2) The reference material in such a bioavailability study should be
a solution or suspension containing the same quantity of the active drug
ingredient or therapeutic moiety as the formulation proposed for
marketing.
(3) The reference material should be administered by the same route
as the formulation proposed for marketing unless an alternative or
additional route is necessary to answer the scientific question under
study. For example, in the case of an active drug ingredient or
therapeutic moiety that is poorly absorbed after oral administration, it
may be necessary to compare the oral dosage form proposed for marketing
with the active drug ingredient or therapeutic moiety administered in
solution both orally and intravenously.
(e) New formulations of active drug ingredients or therapeutic
moieties approved for marketing. (1) The purpose of an in vivo
bioavailability study involving a drug product that is a new
formulation, a new dosage form, or a new salt or ester of an active drug
ingredient or therapeutic moiety that has been approved for marketing is
to:
(i) Determine the bioavailability of the new formulation, new dosage
form, or new salt or ester relative to an appropriate reference
material; and
(ii) Define the pharmacokinetic parameters of the new formulation,
new dosage form, or new salt or ester to establish dosage
recommendation.
(2) The selection of the reference material(s) in such a
bioavailability study depends upon the scientific questions to be
answered, the data needed to establish comparability to a currently
marketed drug product, and the data needed to establish dosage
recommendations.
(3) The reference material should be taken from a current batch of a
drug product that is the subject of an approved new drug application and
that contains the same active drug ingredient or therapeutic moiety, if
the new formulation, new dosage form, or new salt or ester is intended
to be comparable to or to meet any comparative labeling claims made in
relation to the drug product that is the subject of an approved new drug
application.
(f) Controlled release formulations. (1) The purpose of an in vivo
bioavailability study involving a drug product for which a controlled
release claim is made is to determine if all of the following conditions
are met:
(i) The drug product meets the controlled release claims made for it.
(ii) The bioavailability profile established for the drug product
rules out the occurrence of any dose dumping.
(iii) The drug product's steady-state performance is equivalent to a
currently marketed noncontrolled release or controlled release drug
product that contains the same active drug ingredient or therapeutic
moiety and that is subject to an approved full new drug application.
(iv) The drug product's formulation provides consistent
pharmacokinetic performance between individual dosage units.
(2) The reference material(s) for such a bioavailability study shall
be chosen to permit an appropriate scientific evaluation of the
controlled release claims made for the drug product. The reference
material shall be one of the following or any combination thereof:
(i) A solution or suspension of the active drug ingredient or
therapeutic moiety.
(ii) A currently marketed noncontrolled release drug product
containing the same active drug ingredient or therapeutic moiety and
administered according to the dosage recommendations in the labeling of
the noncontrolled release drug product.
(iii) A currently marketed controlled release drug product subject to
an approved full new drug application containing the same active drug
ingredient or therapeutic moiety and administered according to the
dosage recommendations in the labeling proposed for the controlled
release drug product.
(iv) A reference material other than one set forth in paragraph
(f)(2) (i), (ii) or (iii) of this section that is appropriate for valid
scientific reasons.
(g) Combination drug products. (1) Generally, the purpose of an in
vivo bioavailability study involving a combination drug product is to
determine if the rate and extent of absorption of each active drug
ingredient or therapeutic moiety in the combination drug product is
equivalent to the rate and extent of absorption of each active drug
ingredient or therapeutic moiety administered concurrently in separate
single-ingredient preparations.
(2) The reference material in such a bioavailability study should be
two or more currently marketed, single-ingredient drug products each of
which contains one of the active drug ingredients or therapeutic
moieties in the combination drug product. The Food and Drug
Administration may, for valid scientific reasons, specify that the
reference material shall be a combination drug product that is the
subject of an approved new drug application.
(3) The Food and Drug Administration may permit a bioavailability
study involving a combination drug product to determine the rate and
extent of absorption of selected, but not all, active drug ingredients
or therapeutic moieties in the combination drug product. The Food and
Drug Administration may permit this determination if the
pharmacokinetics and the interactions of the active drug ingredients or
therapeutic moieties in the combination drug product are well known and
the therapeutic activity of the combination drug product is generally
recognized to reside in only one of the active drug ingredients or
therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid
combination drug product.
(h) Use of a placebo as the reference material. Where appropriate or
where necessary to demonstrate the sensitivity of the test, the
reference material in a bioavailability study may be a placebo if:
(1) The study measures the therapeutic or acute pharmacological
effect of the active drug ingredient or therapeutic moiety; or
(2) The study is a clinical trial to establish the safety and
effectiveness of the drug product.
(i) Standards for test drug product and reference material. (1) Both
the drug product to be tested and the reference material, if it is
another drug product, shall be shown to meet all compendial or other
applicable standards of identity, strength, quality, and purity,
including potency and, where applicable, content uniformity,
disintegration times, and dissolution rates.
(2) Samples of the drug product to be tested shall be manufactured
using the same equipment and under the same conditions as those used for
full-scale production.
21 CFR 320.26 Guidelines on the design of a single-dose in vivo
bioavailability study.
(a) Basic principles. (1) An in vivo bioavailability study should be
a single-dose comparison of the drug product to be tested and the
appropriate reference material conducted in normal adults.
(2) The test product and the reference material should be
administered to subjects in the fasting state, unless some other
approach is more appropriate for valid scientific reasons.
(b) Study design. (1) A single-dose study should be crossover in
design, unless a parallel design or other design is more appropriate for
valid scientific reasons, and should provide for a drug elimination
period.
(2) Unless some other approach is appropriate for valid scientific
reasons, the drug elimination period should be either:
(i) At least three times the half-life of the active drug ingredient
or therapeutic moiety, or its metabolite(s), measured in the blood or
urine; or
(ii) At least three times the half-life of decay of the acute
pharmacological effect.
(c) Collection of blood samples. (1) When comparison of the test
product and the reference material is to be based on blood concentration
time curves, unless some other approach is more appropriate for valid
scientific reasons, blood samples should be taken with sufficient
frequency to permit an estimate of both:
(i) The peak concentration in the blood of the active drug ingredient
or therapeutic moiety, or its metabolite(s), measured; and
(ii) The total area under the curve for a time period at least three
times the half-life of the active drug ingredient or therapeutic moiety,
or its metabolite(s), measured.
(2) In a study comparing oral dosage forms, the sampling times should
be identical.
(3) In a study comparing an intravenous dosage form and an oral
dosage form, the sampling times should be those needed to describe both:
(i) The distribution and elimination phase of the intravenous dosage
form; and
(ii) The absorption and elimination phase of the oral dosage form.
(4) In a study comparing drug delivery systems other than oral or
intravenous dosage forms with an appropriate reference standard, the
sampling times should be based on valid scientific reasons.
(d) Collection of urine samples. When comparison of the test product
and the reference material is to be based on cumulative urinary
excretion-time curves, unless some other approach is more appropriate
for valid scientific reasons, samples of the urine should be collected
with sufficient frequency to permit an estimate of the rate and extent
of urinary excretion of the active drug ingredient or therapeutic
moiety, or its metabolite(s), measured.
(e) Measurement of an acute pharmacological effect. (1) When
comparison of the test product and the reference material is to be based
on acute pharmacological effect-time curves, measurements of this effect
should be made with sufficient frequency to permit a reasonable estimate
of the total area under the curve for a time period at least three times
the half-life of decay of the pharmacological effect, unless some other
approach is more appropriate for valid scientific reasons.
(2) The use of an acute pharmacological effect to determine
bioavailability may further require demonstration of dose-related
response. In such a case, bioavailability may be determined by
comparison of the dose-response curves as well as the total area under
the acute pharmacological effect-time curves for any given dose.
21 CFR 320.27 Guidelines on the design of a multiple-dose in vivo
bioavailability study.
(a) Basic principles. (1) In selected circumstances it may be
necessary for the test product and the reference material to be compared
after repeated administration to determine steady-state levels of the
active drug ingredient or therapeutic moiety in the body.
(2) The test product and the reference material should be
administered to subjects in the fasting or nonfasting state, depending
upon the conditions reflected in the proposed labeling of the test
product.
(3) A multiple-dose study may be required to determine the
bioavailability of a drug product in the following circumstances:
(i) There is a difference in the rate of absorption but not in the
extent of absorption.
(ii) There is excessive variability in bioavailability from subject
to subject.
(iii) The concentration of the active drug ingredient or therapeutic
moiety, or its metabolite(s), in the blood resulting from a single dose
is too low for accurate determination by the analytical method.
(iv) The drug product is a controlled release dosage form.
(b) Study design. (1) A multiple-dose study should be crossover in
design, unless a parallel design or other design is more appropriate for
valid scientific reasons, and should provide for a drug elimination
period if steady-state conditions are not achieved.
(2) A multiple-dose study is not required to be of crossover design
if the study is to establish dose proportionality under a multiple-dose
regimen or to establish the pharmacokinetic profile of a new drug
product, a new drug delivery system, or a controlled release dosage
form.
(3) If a drug elimination period is required, unless some other
approach is more appropriate for valid scientific reasons, the drug
elimination period should be either:
(i) At least five times the half-life of the active drug ingredient
or therapeutic moiety, or its metabolite(s), measured in the blood or
urine; or
(ii) At least five times the half-life of decay of the acute
pharmacological effect.
(c) Achievement of steady-state conditions. Whenever a multiple-dose
study is conducted, unless some other approach is more appropriate for
valid scientific reasons, sufficient doses of the test product and
reference material should be administered in accordance with the
labeling to achieve steady-state conditions.
(d) Collection of blood or urine samples. (1) Whenever comparison of
the test product and the reference material is to be based on blood
concentration-time curves at steady-state, sufficient samples of blood
should be taken to define adequately the maximum (Cmax) and minimum
(Cmin) blood concentrations on 2 or more consecutive days to establish
that steady-state conditions are achieved.
(2) Whenever comparison of the test product and the reference
material is to be based on cumulative urinary excretion-time curves at
steady-state, sufficient samples of urine should be taken to define the
rate and extent of urinary excretion on 2 or more consecutive days to
establish that steady-state conditions are achieved.
(3) A more complete characterization of the blood concentration or
urinary excretion rate during the absorption and elimination phases of a
single dose administered at steady-state is encouraged to permit
estimation of the total area under concentration-time curves or
cumulative urinary excretion-time curves and to obtain pharmacokinetic
information, e.g., half-life or blood clearance, that is essential in
preparing adequate labeling for the drug product.
(e) Steady-state parameters. (1) In certain instances, e.g., in a
study involving a new drug entity, blood clearances at steady-state
obtained in a multiple-dose study should be compared to blood clearances
obtained in a single-dose study to support adequate dosage
recommendations.
(2) In a linear system, the area under the blood concentration-time
curve during a dosing interval in a multiple-dose steady-state study is
directly proportional to the fraction of the dose absorbed and is equal
to the corresponding ''zero to infinity'' area under the curve for a
single-dose study. Therefore, when steady-state conditions are
achieved, a comparison of blood concentrations during a dosing interval
may be used to define the fraction of the active drug ingredient or
therapeutic moiety absorbed.
(3) Other methods based on valid scientific reasons should be used to
determine the bioavailability of a drug product having dose-dependent
kinetics (non-linear system).
(f) Measurement of an acute pharmacological effect. When comparison
of the test product and the reference material is to be based on acute
pharmacological effect-time curves, measurements of this effect should
be made with sufficient frequency to demonstrate a maximum effect and a
lack of significant difference between the test product and the
reference material.
21 CFR 320.28 Correlation of bioavailability with an acute
pharmacological effect or clinical evidence.
Correlation of in vivo bioavailability data with an acute
pharmacological effect or clinical evidence of safety and effectiveness
may be required if needed to establish the clinical significance of a
special claim, e.g., in the case of a controlled release preparation.
21 CFR 320.29 Analytical methods for an in vivo bioavailability study.
(a) The analytical method used in an in vivo bioavailability study to
measure the concentration of the active drug ingredient or therapeutic
moiety, or its metabolite(s), in body fluids or excretory products, or
the method used to measure an acute pharmacological effect shall be
demonstrated to be accurate and of sufficient sensitivity to measure,
with appropriate precision, the actual concentration of the active drug
ingredient or therapeutic moiety, or its metabolite(s), achieved in the
body.
(b) When the analytical method is not sensitive enough to measure
accurately the concentration of the active drug ingredient or
therapeutic moiety, or its metabolite(s), in body fluids or excretory
products produced by a single dose of the test product, two or more
single doses may be given together to produce higher concentration if
the requirements of 320.31 are met.
21 CFR 320.30 Inquiries regarding bioavailability requirements and
review of protocols by the Food and Drug Administration.
(a) The Commissioner of Food and Drugs strongly recommends that, to
avoid the conduct of an improper study and unnecessary human research,
any person planning to conduct a bioavailability study submit the
proposed protocol for the study to the Food and Drug Administration for
review prior to the initiation of the study.
(b) The Food and Drug Administration shall review a proposed protocol
for a bioavailability study and determine if all of the following
conditions are met:
(1) The design of the proposed bioavailability study is appropriate.
(2) The reference material to be used in the bioavailability study is
appropriate.
(3) The proposed chemical and statistical analytical methods are
adequate.
(c) General inquiries relating to in vivo bioavailability
requirements and methodology shall be submitted to the Food and Drug
Administration, Center for Drug Evaluation and Research, Division of
Biopharmaceutics (HFD-420), 5600 Fishers Lane, Rockville, MD 20857.
(42 FR 1648, Jan. 7, 1977, as amended at 50 FR 8996, Mar. 6, 1985;
55 FR 11581, Mar. 29, 1990)
21 CFR 320.31 Applicability of requirements regarding an
''Investigational New Drug Application.''
(a) Any person planning to conduct an in vivo bioavailability study
in humans shall submit an ''Investigational New Drug Application'' (IND)
if either:
(1) The test product contains a new chemical entity that is not the
subject of an approved new drug application; or
(2) The study involves a radioactively labeled drug product.
(b) Any person planning to conduct a bioavailability study in humans
using a currently commercially available drug product that is the
subject of an approved new drug application, or is identical, similar,
or related to such a drug product shall submit an IND if the study is
one of the following:
(1) A single-dose study in normal subjects or patients where the dose
exceeds that specified in the labeling of the drug product that is the
subject of an approved new drug application.
(2) A multiple-dose study in patients where the dose exceeds that
specified in the labeling of the drug product that is the subject of an
approved new drug application.
(3) A multiple-dose study in normal subjects whether or not the dose
exceeds that specified in the labeling of the drug product that is the
subject of an approved new drug application.
(c) The provisions of parts 50, 56, and 312 of this chapter are
applicable to any bioavailability study conducted under an IND.
(d) A bioavailability study in humans other than one described in
paragraphs (a) through (c) of this section is exempt from the
requirements of part 312 of this chapter if the following conditions are
satisfied:
(1) The person conducting the study, including any contract research
organization, shall retain reserve samples of any test article and
reference standard used in the study and release the reserve samples to
FDA upon request, in accordance with, and for the period specified in,
320.32, and;
(2) An in vivo bioavailability study in humans shall be conducted in
compliance with the requirements for institutional review set forth in
part 56 of this chapter, and informed consent set forth in part 50 of
this chapter.
(42 FR 1648, Jan. 7, 1977, as amended at 55 FR 11581, Mar. 29, 1990;
55 FR 47038, Nov. 8, 1990)
21 CFR 320.32 Retention of bioavailability samples.
(a) The applicant of an application or supplemental application
submitted under section 505 or 507 of the Federal Food, Drug, and
Cosmetic Act, or, if bioavailability testing was performed under
contract, the contract research organization shall retain an
appropriately identified reserve sample of the drug product for which
the applicant is seeking approval (test article) and of the reference
standard used to perform an in vivo bioavailability study required for
approval of the application or supplemental application that is
representative of each sample of the test article and reference standard
provided by the applicant for the testing. Each reserve sample shall
consist of a sufficient quantity to permit FDA to perform five times all
of the release tests required in the application or supplemental
application.
(b) Each reserve sample shall be adequately identified so that the
reserve sample can be positively identified as having come from the same
sample as used in the specific bioavailability study.
(c) Each reserve sample shall be stored under conditions that will
maintain the sample's integrity, identity, strength, quality, and purity
and shall be retained for a period of at least 5 years following the
date on which the application or supplemental application is approved,
or, if such application or supplemental application is not approved, at
least 5 years following the date of completion of the bioavailability
study in which the sample from which the reserve sample was obtained was
used.
(d) Authorized FDA personnel will ordinarily collect reserve samples
directly from the applicant or contract research organization at the
storage site during a preapproval inspection. If authorized FDA
personnel are unable to collect samples, FDA may require the applicant
or contract research organization to submit the reserve samples to the
place identified in the agency's request. If FDA has not collected or
requested delivery of a reserve sample, or if FDA has not collected or
requested delivery of any portion of a reserve sample, the applicant or
contract research organization shall retain the sample or remaining
sample for the 5-year period specified in paragraph (c) of this section.
(e) Upon release of the reserve samples to FDA, the applicant or
contract research organization shall provide a written assurance that
the reserve samples came from the same samples as used in the specific
bioavailability or bioequivalence study identified by the agency. The
assurance shall be executed by an individual authorized to act for the
applicant or contract research organization in releasing the reserve
samples to FDA.
(55 FR 47038, Nov. 8, 1990; 55 FR 50279, Dec. 5, 1990; 55 FR 52991,
Dec. 26, 1990)
21 CFR 320.32 Subpart C -- Bioequivalence Requirements
Source: 42 FR 1635, Jan. 7, 1977, unless otherwise noted.
21 CFR 320.50 Purpose.
This subpart establishes criteria and procedures for:
(a) Identifying pharmaceutical equivalents and pharmaceutical
alternatives that are intended to be used interchangeably for the same
therapeutic effect and that are not bioequivalent drug products; and
(b) Establishing a bioequivalence requirement for these drug
products.
21 CFR 320.51 Procedures for establishing or amending a bioequivalence
requirement.
(a) The Commissioner of Food and Drugs, on his own initiative or in
response to a petition by an interested person, may propose and
promulgate a regulation to establish a bioequivalence requirement if he
finds there is well-documented evidence that specific pharmaceutical
equivalents or pharmaceutical alternatives intended to be used
interchangeably for the same therapeutic effect:
(1) Are not bioequivalent drug products; or
(2) May not be bioequivalent drug products based on the criteria set
forth in 320.52; or
(3) May not be bioequivalent drug products because they are members
of a class of drug products that have close structural similarity and
similar physicochemical or pharmacokinetic properties to other drug
products in the same class that the Commissioner finds are not
bioequivalent drug products.
(b) Any person submitting a petition to the Commissioner to propose a
regulation to establish or amend a bioequivalence requirement shall
submit the petition under 10.20 and 10.30 of this chapter, and include
in the petition the applicable information set forth in 320.54.
(c) The Commissioner shall include in a notice of proposed rulemaking
to establish a bioequivalence requirement the evidence and criteria set
forth in 320.52 that are to be considered in determining whether to
issue the proposal. If the rulemaking is proposed in response to a
petition, the Commissioner shall include in the proposal a summary and
analysis of the relevant information that was submitted in the petition
as well as other available information to support the establishment of a
bioequivalence requirement.
(d) The Commissioner, on his own initiative or in response to a
petition by an interested person, may propose and promulgate an
amendment to a bioequivalence requirement established under this
subpart.
(42 FR 1635, Jan. 7, 1977, as amended at 42 FR 15674, Mar. 22, 1977)
21 CFR 320.52 Criteria and evidence to establish a bioequivalence
requirement.
The Commissioner shall consider the following factors, when supported
by well-documented evidence, to identify specific pharmaceutical
equivalents and pharmaceutical alternatives that are not or may not be
bioequivalent drug products and to determine whether to propose or
promulgate a regulation to establish a bioequivalence requirement for
these products:
(a) Evidence from well-controlled clinical trials or controlled
observations in patients that such drug products do not give comparable
therapeutic effects.
(b) Evidence from well-controlled bioequivalence studies that such
products are not bioequivalent drug products.
(c) Evidence that the drug products exhibit a narrow therapeutic
ratio, e.g., there is less than a 2-fold difference in median lethal
dose (LD50) and median effective dose (ED50) values, or have less than a
2-fold difference in the minimum toxic concentrations and minimum
effective concentrations in the blood, and safe and effective use of the
drug products requires careful dosage titration and patient monitoring.
(d) Competent medical determination that a lack of bioequivalence
would have a serious adverse effect in the treatment or prevention of a
serious disease or condition.
(e) Physicochemical evidence that:
(1) The active drug ingredient has a low solubility in water, e.g.,
less than 5 milligrams per 1 milliliter, or, if dissolution in the
stomach is critical to absorption, the volume of gastric fluids required
to dissolve the recommended dose far exceeds the volume of fluids
present in the stomach (taken to be 100 milliliters for adults and
prorated for infants and children).
(2) The dissolution rate of one or more such products is slow, e.g.,
less than 50 percent in 30 minutes when tested using either a general
method specified in an official compendium or a paddle method at 50
revolutions per minute in 900 milliliters of distilled or deionized
water at 37 C, or differs significantly from that of an appropriate
reference material such as an identical drug product that is the subject
of an approved full new drug application.
(3) The particle size and/or surface area of the active drug
ingredient is critical in determining its bioavailability.
(4) Certain physical structural characteristics of the active drug
ingredient, e.g., polymorphic forms, conforms, solvates, complexes, and
crystal modifications, dissolve poorly and this poor dissolution may
affect absorption.
(5) Such drug products have a high ratio of excipients to active
ingredients, e.g., greater than 5 to 1.
(6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic
excipients and lubricants, either may be required for absorption of the
active drug ingredient or therapeutic moiety or, alternatively, if
present, may interfere with such absorption.
(f) Pharmacokinetic evidence that:
(1) The active drug ingredient, therapeutic moiety, or its precursor
is absorbed in large part in a particular segment of the
gastrointestinal tract or is absorbed from a localized site.
(2) The degree of absorption of the active drug ingredient,
therapeutic moiety, or its precursor is poor, e.g., less than 50
percent, ordinarily in comparison to an intravenous dose, even when it
is administered in pure form, e.g., in solution.
(3) There is rapid metabolism of the therapeutic moiety in the
intestinal wall or liver during the process of absorption (first-class
metabolism) so the therapeutic effect and/or toxicity of such drug
product is determined by the rate as well as the degree of absorption.
(4) The therapeutic moiety is rapidly metabolized or excreted so that
rapid dissolution and absorption are required for effectiveness.
(5) The active drug ingredient or therapeutic moiety is unstable in
specific portions of the gastrointestinal tract and requires special
coatings or formulations, e.g., buffers, enteric coatings, and film
coatings, to assure adequate absorption.
(6) The drug product is subject to dose dependent kinetics in or near
the therapeutic range, and the rate and extent of absorption are
important to bioequivalence.
21 CFR 320.53 Types of bioequivalence requirements.
(a) A bioequivalence requirement may be one or more of the following,
as specified by the Food and Drug Administration:
(1) An in vivo test in humans.
(2) An in vivo test in animals other than humans that has been
correlated with human in vivo data.
(3) An in vivo test in animals other than humans that has not been
correlated with human in vivo data.
(4) An in vitro bioequivalence standard, i.e., and in vitro test that
has been correlated with human in vivo bioavailability data.
(5) A currently available in vitro test (usually a dissolution rate
test) that has not been correlated with human in vivo bioavailability
data.
(b) In vivo testing in humans shall ordinarily be required if there
is well-documented evidence that pharmaceutical equivalents or
pharmaceutical alternatives intended to be used interchangeably for the
same therapeutic effect meet one of the following conditions:
(1) They do not give comparable therapeutic effects.
(2) They are not bioequivalent drug products.
(3) They exhibit a narrow therapeutic ratio, e.g., there is less than
a 2-fold difference in LD50 and ED50 values, or there is less than a
2-fold difference in the minimum toxic concentrations and minimum
effective concentration in the blood, and safe and effective use of the
product requires careful dosage titration and patient monitoring.
21 CFR 320.54 Contents of a petition to establish a bioequivalence
requirement.
(a) Each person submitting a petition to establish a bioequivalence
requirement under this subpart shall include in the petition each of the
following three types of information to justify this action:
(1) A statement summarizing the bioequivalence problem.
(2) Well-documented evidence that the drug products for which a
bioequivalence requirement should be established are pharmaceutical
equivalents or pharmaceutical alternatives that are labeled to be
administered at the same dose of the same therapeutic moiety for the
same therapeutic effect.
(3) Well-documented evidence and data in the categories listed in
this paragraph, as applicable, to support the contention that a
documented or potential bioequivalence problem exists.
(i) Well-documented evidence that the subject pharmaceutical
equivalents or pharmaceutical alternatives do not give comparable
therapeutic effects, together with a citation of supporting
well-controlled observations or clinical trials in patients and a
summary of their contents.
(ii) Well-documented evidence that the subject pharmaceutical
equivalents or pharmaceutical alternatives are not bioequivalent drug
products, together with appropriate data and/or citations of supporting
well-controlled bioequivalence studies and a summary of their contents.
(iii) Well-documented evidence that the subject pharmaceutical
equivalents or pharmaceutical alternatives exhibit a narrow therapeutic
ratio, e.g., there is less than a 2-fold difference in LD50 or ED50
values, or have a less than 2-fold difference in the minimum toxic
concentration and minimum effective concentrations in the blood, and
safe and effective use of the drug product requires careful dosage
titration and patient monitoring.
(iv) Competent medical determination that lack of bioequivalence
would have a serious adverse effect in the treatment of a serious
disease or condition.
(v) Well-documented evidence that the subject pharmaceutical
equivalents or pharmaceutical alternatives, because of the
physicochemical and/or pharmacokinetic characteristics set forth in
320.52(e) and (f), may not be bioequivalent drug products.
(vi) Well-documented evidence to support a finding that the
pharmaceutical equivalents or pharmaceutical alternatives are members of
a class of drug products that have close structural similarity and
physicochemical or pharmacokinetic properties similar to other drug
products that have been specifically shown to lack therapeutic
equivalence or bioequivalence.
(b) Each person submitting a petition to establish a bioequivalence
requirement under this subpart is requested, but is not required, to
include in the petition a description of a proposed bioequivalence test
as follows:
(1) A description of any proposed current in vitro test to be used
pending the development of a definitive in vitro bioequivalence standard
together with the evidence described in paragraph (c) of this section
that this current in vitro test is suitable for comparing the subject
pharmaceutical equivalents or pharmaceutical alternatives to a reference
material.
(2) A description of any proposed in vitro bioequivalence standard,
including a citation of in vivo data and other evidence described in
paragraph (c) of this section which support the applicability of the
proposed in vitro bioequivalence standard.
(3) A description of any proposed in vivo bioequivalence test,
including the reference material to be used and other technical
specification needed to assure uniform testing of the subject
pharmaceutical equivalents or pharmaceutical alternatives together with
a citation of supporting evidence described in paragraph (c) of this
section and a summary of its contents.
(c) Scientific evidence cited in the petition shall include specific,
precise information such as:
(1) The product names, batch numbers, labeling, and the identity of
the manufacturer, packer, or distributor of the batches of the subject
pharmaceutical equivalents or pharmaceutical alternatives included in
the studies on which the evidence is based.
(2) The results of all in vitro physical and chemical tests conducted
on the batches of the subject pharmaceutical equivalents or
pharmaceutical alternatives to determine whether they meet compendial or
other applicable standards of identity, strength, quality, and purity,
including potency and, where applicable, content uniformity,
disintegration rates, and dissolution rates.
(3) The results of any in vitro physicochemical tests conducted on
the batches of the subject pharmaceutical equivalents or pharmaceutical
alternatives studied other than those specified in the compendial or
other applicable standard, e.g., particle size.
(4) The results of any in vivo bioequivalence test or in vitro
bioequivalence test conducted on the batches of the subject
pharmaceutical equivalents or pharmaceutical alternatives studied.
These results shall present a validation of the analytical methodology,
including the standard curve used and a description of the method of
calculation of results, and a description of the pharmacokinetic model
and/or statistical model used in analyzing the data.
(5) A full description of the analytical procedures and equipment
used in conducting an in vivo or in vitro test on the subject
pharmaceutical equivalents or pharmaceutical alternatives.
(d) Each person submitting a petition to establish a bioequivalence
requirement under this subpart shall include in the petition copies of
published reports in the scientific literature and unpublished material
that support the establishment of a bioequivalence requirement for the
subject pharmaceutical equivalents or pharmaceutical alternatives.
(e) Each person submitting a petition to establish a bioequivalence
requirement under this subpart shall include in the petition information
as to the availability of sufficient samples of the subject
pharmaceutical equivalents or pharmaceutical alternatives studied to
permit confirmatory testing by the Food and Drug Administration.
21 CFR 320.55 Requirements for batch testing and certification by the
Food and Drug Administration.
(a) If the Commissioner determines that individual batch testing by
the Food and Drug Administration is necessary to assure that all batches
of the same drug product meet an appropriate in vitro test, he shall
include in the bioequivalence requirement a requirement for
manufacturers to submit samples of each batch to the Food and Drug
Administration and to withhold distribution of the batch until notified
by the Food and Drug Administration that the batch may be introduced
into interstate commerce.
(b) The Commissioner will ordinarily terminate a requirement for a
manufacturer to submit samples for batch testing on a finding that the
manufacturer has produced four consecutive batches that were tested by
the Food and Drug Administration and found to meet the bioequivalence
requirement, unless the public health requires that batch testing be
extended to additional batches.
21 CFR 320.56 Requirements for in vitro testing of each batch.
If a bioequivalence requirement specifies a currently available in
vitro test or an in vitro bioequivalence standard comparing the drug
product to a reference standard, the manufacturer shall conduct the test
on a sample of each batch of the drug product to assure batch-to-batch
uniformity.
21 CFR 320.57 Requirements for the conduct of in vivo bioequivalence
testing in humans.
(a) If a bioequivalence requirement provides for in vivo testing in
humans, a manufacturer shall conduct this testing according to the
procedures in 320.24, using the most accurate, sensitive, and
reproducible method available, and using the reference material
specified in the bioequivalence requirement.
(b) Clinical trials demonstrating safety and effectiveness shall be
used to establish bioequivalence only if other methods are not
available.
(c) If a bioequivalence requirement provides for in vivo testing in
humans using a method other than clinical trials, a manufacturer shall
conduct this testing to assure that his product meets the bioequivalence
requirement even though his product is the subject of an approved full
new drug application containing clinical evidence of safety and
effectiveness.
(d) (Reserved)
(e) If a bioequivalence requirement provides for in vivo testing in
humans, any person conducting such testing shall comply with the
requirements of 320.31.
(42 FR 1635, Jan. 7, 1977, as amended at 46 FR 8954, Jan. 27, 1981)
21 CFR 320.58 Requirements for marketing a drug product subject to a
bioequivalence requirement.
(a) If a bioequivalence requirement is established for a drug product
subject to a new drug application that became effective before October
10, 1962, or for an identical, related, or similar drug product under
310.6 of this chapter, the product may lawfully be introduced into
interstate commerce as follows:
(1) Any manufacturer who holds an approved full or abbreviated new
drug application for the drug product on the date the bioequivalence
requirement becomes effective shall submit and obtain approval by the
Food and Drug Administration of a supplemental application that provides
evidence that the drug product meets the bioequivalence requirement. If
a supplemental application is submitted within the time frame specified
in the regulation establishing the bioequivalence requirement, the
manufacturer may continue to market the drug product unless and until
the supplemental application is disapproved and approval of the new drug
application is withdrawn.
(2) Any manufacturer who does not hold an approved full or
abbreviated new drug application for the drug product on the effective
date of the bioequivalence requirement shall, before introducing the
drug product into interstate commerce submit and obtain approval by the
Food and Drug Administration of a full or abbreviated new drug
application, as applicable, that provides evidence that the drug product
meets the bioequivalence requirement.
(b) If a bioequivalence requirement is established for a drug product
subject to a new drug application that was approved on or after October
10, 1962, the product may lawfully be introduced into interstate
commerce as follows:
(1) Any manufacturer who holds an approved full new drug application
for the drug product on the effective date of the bioequivalence
requirement shall submit and obtain approval by the Food and Drug
Administration of a supplemental application that provides evidence that
the drug product meets the bioequivalence requirement. If a
supplemental application is submitted within the time frame specified in
the regulation establishing the bioequivalence requirement, the
manufacturer may continue to introduce the drug product into interstate
commerce unless and until the supplemental application is disapproved
and approval of the new drug application is withdrawn.
(2) Any manufacturer who does not hold an approved full new drug
application for the drug product on the effective date of the
bioequivalence requirement shall, before introducing the drug product
into interstate commerce, submit and obtain approval by the Food and
Drug Administration of a full new drug application that provides
evidence that the drug product meets the bioequivalence requirement.
(c) If a bioequivalence requirement is established for a drug product
that is not subject to the new drug provisions of the act, the product
may lawfully be introduced into interstate commerce as follows:
(1) The manufacturer records and maintains evidence that the drug
product meets the bioequivalence requirement. Upon written request or
notice in the Federal Register, the manufacturer shall promptly submit
this evidence to the Food and Drug Administration.
(2) The drug product is manufactured in accordance with current good
manufacturing practice, as determined by the requirements in Part 211 of
this chapter.
(3) The drug product is labeled in compliance with the act and this
chapter.
(d) A manufacturer may introduce into interstate commerce a drug
product for which a bioequivalence requirement is established only if he
complies with this section. Introduction of the drug product into
interstate commerce not in compliance with this section is illegal and
subject to regulatory action.
(e) Upon disapproval of a full or abbreviated new drug application or
supplemental application, the procedures for disapproval of any new drug
application under section 505(d) of the act apply. Introduction of the
drug product involved into interstate commerce is illegal unless the
Commissioner, in his discretion, determines to stay this disapproval for
a particular drug product on a finding that all of the following
conditions are met:
(1) The drug product was being lawfully marketed on the effective
date of the bioequivalence requirement, i.e., if a new drug, it was
already subject to an approved full or abbreviated new drug application.
(2) The drug product is medically necessary, e.g., it is used in
treatment of a serious disease or condition for which no alternative
therapy is available.
(3) There is not an adequate supply of identical or similar drug
products subject to an approved full or abbreviated new drug application
containing bioequivalence data to fulfill medical needs.
(4) The manufacturer submits a full or abbreviated new drug
application or supplemental application, as applicable, containing an
acceptable protocol for the conduct of bioequivalence studies and
initiates action to conduct and complete the necessary studies within
the time frame set forth in the bioequivalence requirement.
21 CFR 320.59 Bioequivalence requirements based on data voluntarily
submitted.
(a) A bioequivalence requirement established under this subpart may
specify an analytical method, e.g., a current in vitro test, an in vitro
bioequivalence standard, or an in vivo bioequivalence test, that is
based on data and information voluntarily submitted to the Food and Drug
Administration, even though these data and information are exempt from
public disclosure under 20.61 of this chapter.
(b) A summary of the voluntarily submitted data and information on
which the bioequivalence requirement is based, prepared in one of the
following two alternative ways, shall be publicly released when the
bioequivalence requirement is proposed:
(1) The Food and Drug Administration may at an appropriate time
before proposing the bioequivalence requirement require the person who
voluntarily submitted the data and information to prepare a summary of
these data and information, that will be reviewed and, where
appropriate, revised by the agency.
(2) The Food and Drug Administration may prepare its own summary of
these data and information.
(c) A bioequivalence requirement may specify an analytical method
contained in a petition or approved new drug application, or based on
data and information voluntarily submitted to the Food and Drug
Administration, unless the method serves no regulatory or compliance
purpose and is shown to be exempt from public disclosure under 20.61 of
this chapter.
(42 FR 1635, Jan. 7, 1977, as amended at 42 FR 15674, Mar. 22, 1977)
21 CFR 320.60 Bioequivalence requirements for a drug product subject to
an old drug monograph.
If the Commissioner establishes an old drug monograph for a drug
product for which a bioequivalence requirement has been established
under this subpart, the provisions of this subpart as they relate to
that drug product are thereby revoked.
21 CFR 320.61 Requirements for in vivo testing of a drug product not
meeting an in vitro bioequivalence standard.
(a) If a drug product fails to meet an in vitro bioequivalence
standard established under this subpart and a manufacturer nevertheless
wishes to market the product without reformulation, the manufacturer may
do so if he demonstrates the bioequivalence of the drug product by in
vivo testing in humans of three consecutive batches of the drug product
and develops an in vitro test that assures the bioequivalence of his
product from batch-to-batch.
(b) The reference material to be used by a manufacturer in conducting
in vivo testing in humans under this section shall be a drug product
that meets the in vitro bioequivalence standard.
21 CFR 320.62 Requirements for maintenance of records of bioequivalence
testing.
All records of in vivo or in vitro tests conducted on any marketed
batch of a drug product to assure that the product meets a
bioequivalence requirement shall be maintained by the manufacturer for
at least 2 years after the expiration date of the batch and submitted to
the Food and Drug Administration on request.
21 CFR 320.63 Retention of bioequivalence samples.
The applicant of a full or abbreviated application or a supplemental
application submitted under section 505 or 507 of the Federal Food,
Drug, and Cosmetic Act, or, if bioequivalence testing was performed
under contract, the contract research organization shall retain reserve
samples of any test article and reference standard used in conducting an
in vivo or in vitro bioequivalence study required for approval of, or
submitted in support of the approval of, the full or abbreviated
application or supplemental application. The applicant or contract
research organization shall retain the reserve samples in accordance
with, and for the period specified in, 320.32 and shall release the
reserve samples to FDA upon request in accordance with 320.32.
(55 FR 47038, Nov. 8, 1990)
21 CFR 320.63 PART 329 -- HABIT-FORMING DRUGS
21 CFR 320.63 Subpart A -- Derivatives Designated as Habit Forming
Sec.
329.1 Habit-forming drugs which are chemical derivatives of
substances specified in section 502(d) of the Federal Food, Drug, and
Cosmetic Act.
21 CFR 320.63 Subpart B -- Labeling
329.10 Labeling requirements for habit-forming drugs.
21 CFR 320.63 Subpart C -- Exemptions
329.20 Exemption of certain habit-forming drugs from prescription
requirements.
Authority: Secs. 502, 503, 505, 701 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 352, 353, 355, 371).
Source: 39 FR 11736, Mar. 29, 1974, unless otherwise noted.
21 CFR 320.63 Subpart A -- Derivatives Designated as Habit Forming
21 CFR 329.1 Habit-forming drugs which are chemical derivatives of
substances specified in section 502(d) of the Federal Food, Drug, and
Cosmetic Act.
Each of the following chemical derivatives of a substance named in
section 502(d) of the Federal Food, Drug, and Cosmetic Act is hereby
designated as habit forming:
21 CFR 329.1 Subpart B -- Labeling
21 CFR 329.10 Labeling requirements for habit-forming drugs.
(a)(1) The name of a substance or derivative required to be borne on
the label of a drug by section 502(d) of the act shall be the common or
usual name of such substance or derivative, unless it is designated
solely by a name recognized in an official compendium and such
designation complies with the provisions of section 502(c).
(2) A statement on the label of a drug of the name of a constituent,
which constituent is a chemical derivative of a substance named in
section 502(d) of the act, shall show the substance from which such
constituent is derived and that such constituent is a derivative
thereof.
(b) If the drug is in tablet, capsule, ampul, or other unit form, the
statement of the quantity or proportion of such substance or derivative
contained therein shall express the weight or measure of such substance
or derivative in each such unit. If the drug is not in such unit form
the statement shall express the weight or measure of such substance or
derivative in a specified unit of weight or measure of the drug. Such
statement shall be in terms which are informative to the ordinary
consumer and user of the drug.
(c) The names and quantities or proportions of all such substances
and derivatives, and the statement ''Warning -- May be habit forming'',
shall immediately follow (without intervening written, printed, or
graphic matter) the name by which such drug is titled in the part or
panel of the label thereof which is presented or displayed under
customary conditions of purchase.
(d) A drug shall not be considered to be misbranded by reason of
failure of its label to bear the statement ''Warning -- May be habit
forming'':
(1) If such drug is not suitable for internal use, and is distributed
and sold exclusively for such external use as involves no possibility of
habit formation; or
(2) If the only substance or derivative subject to section 502(d) of
the act contained in such drug is chlorobutanol, which is present solely
as a preservative and in a quantity not more than 0.5 percent by weight,
and such drug is for parenteral use only; or
(3) If the only substance or derivative subject to section 502(d) of
the act contained in such drug is chlorobutanol which is present as an
analgesic or as an analgesic and a preservative in a quantity not more
than 3.0 percent, and such drug contains one or more other active
ingredients and is for parenteral use only.
Cross Reference: For the Spanish-language version of the required
labeling statement, see 201.16(b) of this chapter.
(39 FR 11736, Mar. 29, 1974, as amended at 40 FR 13496, Mar. 27,
1975)
21 CFR 329.10 Subpart C -- Exemptions
21 CFR 329.20 Exemption of certain habit-forming drugs from
prescription requirements.
The prescription-dispensing requirements of section 503(b)(1)(A) of
the act are not necessary for the protection of the public health with
respect to the following drugs subject to section 502(d):
(a) The following exempt narcotic preparations:
(1) Pharmaceutical preparations containing not more than 100
milligrams of opium per 100 milliliters or per 100 grams.
(2) Pharmaceutical preparations containing not more than 16.2
milligrams ( 1/4 grain) morphine, or any of its salts, per 29.5729 cubic
centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois ounce);
(3) Pharmaceutical preparations containing not more than 64.8
milligrams (1 grain) codeine, or any of its salts, per 29.5729 cubic
centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois ounce);
(4) Pharmaceutical preparations containing not more than 32.4
milligrams ( 1/2 grain) dihydrocodeine, or any of its salts, per 29.5729
cubic centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois
ounce);
(5) Pharmaceutical preparations containing not more than 16.2
milligrams ( 1/4 grain) ethylmorphine, or any of its salts, per 29.5729
cubic centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois
ounce);
Provided, That the preparations described in this paragraph contain
one or more nonnarcotic active medicinal ingredients in sufficient
proportion to confer upon the preparation valuable medicinal qualities
other than those possessed by the narcotic drug alone.
(b) Drugs containing chlorobutanol, intended for external use only.
(c) Epinephrine solution, 1 percent, preserved with chlorobutanol and
intended for use solely as a spray.
(d) Combination drugs listed in part 329 as exempted from section 511
of the act.
(39 FR 11736, Mar. 29, 1974, as amended at 55 FR 11581, Mar. 29,
1990)
21 CFR 329.20 Pt. 330
21 CFR 329.20 PART 330 -- OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED
21 CFR 329.20 Subpart A -- General Provisions
Sec.
330.1 General conditions for general recognition as safe, effective
and not misbranded.
330.2 Pregnancy-nursing warning.
330.5 Drug categories.
21 CFR 329.20 Subpart B -- Administrative Procedures
330.10 Procedures for classifying OTC drugs as generally recognized
as safe and effective and not misbranded, and for establishing
monographs.
330.11 NDA deviations from applicable monograph.
330.12 Status of over-the-counter (OTC) drugs previously reviewed
under the Drug Efficacy Study (DESI).
330.13 Conditions for marketing ingredients recommended for
over-the-counter (OTC) use under the OTC drug review.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 39 FR 11741, Mar. 29, 1974, unless otherwise noted.
21 CFR 329.20 Subpart A -- General Provisions
21 CFR 330.1 General conditions for general recognition as safe,
effective and not misbranded.
An over-the-counter (OTC) drug listed in this subchapter is generally
recognized as safe and effective and is not misbranded if it meets each
of the conditions contained in this part and each of the conditions
contained in any applicable monograph. Any product which fails to
conform to each of the conditions contained in this part and in an
applicable monograph is liable to regulatory action.
(a) The product is manufactured in compliance with current good
manufacturing practices, as established by Parts 210 and 211 of this
chapter.
(b) The establishment(s) in which the drug product is manufactured is
registered, and the drug product is listed, in compliance with Part 207
of this chapter. It is requested but not required that the number
assigned to the product pursuant to Part 207 of this chapter appear on
all drug labels and in all drug labeling. If this number is used, it
shall be placed in the manner set forth in Part 207 of this chapter.
(c)(1) The product is labeled in compliance with Chapter V of the act
and Subchapter C et seq. of this chapter. For purposes of 201.61(b)
of this chapter, the statement of identity of the product shall be the
term or phrase used in the applicable monograph established in this
part.
(2)(i) The label and labeling of the product contain in a prominent
and conspicuous location the labeling describing the ''Indications''
that have been established in an applicable final monograph. At the
option of the manufacturer, this labeling may be designated ''APPROVED
USES,'' or be given a similar designation as permitted by this
paragraph, each time it appears in the labeling, e.g., on the outer
carton, inner bottle label, and on any package insert or display
material. If the ''APPROVED USES'' or a similar designation is used,
the labeling involved shall appear within a boxed area. Other
applicable labeling established under this Subchapter and Subchapter C
of this chapter may be included in the boxed area. If such other
labeling is included, the boxed area shall be designated ''APPROVED
INFORMATION'' rather than ''APPROVED USES.'' The ''indications''
information appearing in the boxed area shall be stated in the exact
language of the monograph. Other information within the boxed area also
shall be stated in exact language where exact language has been
established and identified by quotation marks in an applicable monograph
or by regulation (e.g., 201.63 of this chapter). A statement that the
information in the box was ''published by the Food and Drug
Administration'' shall appear within the boxed area, or reasonably close
by. In lieu of such statement, the designation of the boxed area may be
modified to read: ''FDA APPROVED USES'' or ''FDA APPROVED
INFORMATION,'' as appropriate, or ''USES (or ''INFORMATION'') APPROVED
BY THE FOOD AND DRUG ADMINISTRATION,'' or other similar wording.
(ii) At the option of the manufacturer, as an alternative to the
requirements of paragraph (c)(2)(i) of this section, the label and
labeling of the product may contain in a prominent and conspicuous
location other truthful and nonmisleading statements describing only
those indications for use that have been established in an applicable
monograph, subject to the provisions of section 502 of the act relating
to misbranding and the prohibition in section 301(d) of the act against
the introduction or delivery for introduction into interstate commerce
of unapproved new drugs in violation of section 505(a) of the act. Such
labeling shall not be boxed and shall not contain the statements
provided in paragraph (c)(2)(i) of this section relating to ''APPROVED
USES,'' or ''APPROVED INFORMATION,'' or contain a statement that the
labeling has been published by the Food and Drug Administration.
(iii) At the option of the manufacturer, the label and labeling may
meet the boxed-area requirements of paragraph (c)(2)(i) of this section
and, in addition, other truthful and nonmisleading statements describing
only those indications for use that have been established in an
applicable monograph may appear elsewhere in the labeling, that is,
outside the boxed area, subject to the provisions of section 502 of the
act relating to misbranding and the prohibition in section 301(d) of the
act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(iv) At the option of the manufacturer, more than one of the
alternatives described in paragraphs (c)(2)(i), (ii), and (iii) may be
used in separate labeling, e.g., container label, outer carton, package
insert, display material, for a particular OTC drug product provided
each labeling complies with all applicable statutory and regulatory
labeling requirements in all respects.
(v) The term ''prominent and conspicuous location'' as used in
paragraphs (c)(2) (i) and (ii) of this section means that the labeling
within the boxed or nonboxed area shall be presented and displayed in
such a manner as to render it likely to be read as understood by the
ordinary individual under customary conditions at both time of purchase
and use.
(vi) Regardless of the alternative selected by the manufacturer to
describe indications, paragraphs (c)(2)(i), (ii), and (iii) of this
section require other labeling established under this Subchapter and
Subchapter C of this chapter to be stated in the exact language where
exact language has been established and identified by quotation marks in
an applicable monograph or by regulation (e.g., 201.63 of this
chapter).
(d) The advertising for the product prescribes, recommends, or
suggests its use only under the conditions stated in the labeling.
(e) The product contains only suitable inactive ingredients which are
safe in the amounts administered and do not interfere with the
effectiveness of the preparation or with suitable tests or assays to
determine if the product meets its professed standards of identity,
strength, quality, and purity. Color additives may be used only in
accordance with section 706 of the act and Subchapter A of this chapter.
(f) The product container and container components meet the
requirements of 211.94 of this chapter.
(g) The labeling for all drugs contains the general warning: ''Keep
this and all drugs out of the reach of children.'' The labeling of drugs
used for oral administation shall also state: ''In case of accidental
overdose, seek professional assistance or contact a poison control
center immediately.'' The labeling for drugs administered rectally or
used topically shall state: ''In case of accidental ingestion, seek
professional assistance or contact a Poison Control Center
immediately.'' The Food and Drug Administration will grant an exemption
from these general warnings where appropriate upon petition, which shall
be maintained in a permanent file for public review by the Dockets
Management Branch, Food and Drug Administration, Room 4-62, Parklawn
Building, 5600 Fishers Lane, Rockville, MD 20857.
(h) Where no maximum daily dosage limit for an active ingredient is
established in this part, it is used in a product at a level that does
not exceed the amount reasonably required to achieve its intended
effect.
(i) (Reserved)
(j) It is recommended that the labeling of the product contain the
quantitative amount of each active ingredient, expressed in terms of the
dosage unit stated in the directions for use (e.g., tablet,
teaspoonful).
(39 FR 11741, Mar. 29, 1974, as amended at 40 FR 11718, Mar. 13,
1975; 40 FR 13496, Mar. 27, 1975; 42 FR 15674, Mar. 22, 1977; 46 FR
8459, Jan. 27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR 16266, May 1,
1986; 55 FR 11581, Mar. 29, 1990)
21 CFR 330.2 Pregnancy-nursing warning.
A pregnancy-nursing warning for OTC drugs is set forth under 201.63
of this chapter.
(47 FR 54758, Dec. 3, 1982)
21 CFR 330.5 Drug categories.
Monographs promulgated pursuant to the provisions of this part shall
be established in this Part 330 and following parts and shall cover the
following designated categories:
(a) Antacids.
(b) Laxatives.
(c) Antidiarrheal products.
(d) Emetics.
(e) Antiemetics.
(f) Antiperspirants.
(g) Sunburn prevention and treatment products.
(h) Vitamin-mineral products.
(i) Antimicrobial products.
(j) Dandruff products.
(k) Oral hygiene aids.
(l) Hemorrhoidal products.
(m) Hematinics.
(n) Bronchodilator and antiasthmatic products.
(o) Analgesics.
(p) Sedatives and sleep aids.
(q) Stimulants.
(r) Antitussives.
(s) Allergy treatment products.
(t) Cold remedies.
(u) Antirheumatic products.
(v) Ophthalmic products.
(w) Contraceptive products.
(x) Miscellaneous dermatologic products.
(y) Dentifrices and dental products such as analgesics, antiseptics,
etc.
(z) Miscellaneous (all other OTC drugs not falling within one of the
above therapeutic categories).
21 CFR 330.5 Subpart B -- Administrative Procedures
21 CFR 330.10 Procedures for classifying OTC drugs as generally
recognized as safe and effective and not misbranded, and for
establishing monographs.
For purposes of classifying over-the-counter (OTC) drugs as drugs
generally recognized among qualified experts as safe and effective for
use and as not misbranded drugs, the following regulations shall apply:
(a) Procedure for establishing OTC drug monographs -- (1) Advisory
review panels. The Commissioner shall appoint advisory review panels of
qualified experts to evaluate the safety and effectiveness of OTC drugs,
to review OTC drug labeling, and to advise him on the promulgation of
monographs establishing conditions under which OTC drugs are generally
recognized as safe and effective and not misbranded. A single advisory
review panel shall be established for each designated category of OTC
drugs and every OTC drug category will be considered by a panel. The
members of a panel shall be qualified experts (appointed by the
Commissioner) and may include persons from lists submitted by
organizations representing professional, consumer, and industry
interests. The Commissioner shall designate the chairman of each panel.
Summary minutes of all meetings shall be made.
(2) Request for data and views. The Commissioner will publish a
notice in the Federal Register requesting interested persons to submit,
for review and evaluation by an advisory review panel, published and
unpublished data and information pertinent to a designated category of
OTC drugs. Data and information submitted pursuant to a published
notice, and falling within the confidentiality provisions of 18 U.S.C.
1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the
advisory review panel and the Food and Drug Administration as
confidential until publication of a proposed monograph and the full
report(s) of the panel. Thirty days thereafter such data and
information shall be made publicly available and may be viewed at the
office of the Dockets Management Branch of the Food and Drug
Administration, except to the extent that the person submitting it
demonstrates that it still falls within the confidentiality provisions
of one or more of those statutes. To be considered, eight copies of the
data and/or views on any marketed drug within the class must be
submitted, preferably bound, indexed, and on standard sized paper
(approximately 8 1/2 x 11 inches). When requested, abbreviated
submissions should be sent. All submissions must be in the following
format:
I. Label(s) and all labeling (preferably mounted and filed with the
other data -- facsimile labeling is acceptable in lieu of actual
container labeling).
II. A statement setting forth the quantities of active ingredients of
the drug.
III. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
IV. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
as to the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
as to the safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
as to the safety of the finished drug product.
5. Pertinent medical and scientific literature.
V. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
on the efficacy of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination
on the efficacy of the finished drug product.
5. Pertinent medical and scientific literature.
VI. A summary of the data and views setting forth the medical
rationale and purpose (or lack thereof) for the drug and its ingredients
and the scientific basis (or lack thereof) for the conclusion that the
drug and its ingredients have been proven safe and effective for the
intended use. If there is an absence of controlled studies in the
material submitted, an explanation as to why such studies are not
considered necessary must be included.
(3) Deliberations of an advisory review panel. An advisory review
panel will meet as often and for as long as is appropriate to review the
data submitted to it and to prepare a report containing its conclusions
and recommendations to the Commissioner with respect to the safety and
effectiveness of the drugs in a designated category of OTC drugs. A
panel may consult any individual or group. Any interested person may
request an opportunity to present oral views to the panel; such request
may be granted or denied by the panel. Such requests for oral
presentations should be in written form including a summarization of the
data to be presented to the panel. Any interested person may present
written data and views which shall be considered by the panel. This
information shall be presented to the panel in the format set forth in
paragraph (a)(2) of this section and within the time period established
for the drug category in the notice for review by a panel.
(4) Standards for safety, effectiveness, and labeling. The advisory
review panel, in reviewing the data submitted to it and preparing its
conclusions and recommendations, and the Commissioner, in reviewing the
conclusions and recommendations of the panel and the published proposed,
tentative, and the final monographs, shall apply the following standards
to determine general recognition that a category of OTC drugs is safe
and effective and not misbranded:
(i) Safety means a low incidence of adverse reactions or significant
side effects under adequate directions for use and warnings against
unsafe use as well as low potential for harm which may result from abuse
under conditions of widespread availability. Proof of safety shall
consist of adequate tests by methods reasonably applicable to show the
drug is safe under the prescribed, recommended, or suggested conditions
of use. This proof shall include results of significant human
experience during marketing. General recognition of safety shall
ordinarily be based upon published studies which may be corroborated by
unpublished studies and other data.
(ii) Effectiveness means a reasonable expectation that, in a
significant proportion of the target population, the pharmacological
effect of the drug, when used under adequate directions for use and
warnings against unsafe use, will provide clinically significant relief
of the type claimed. Proof of effectiveness shall consist of controlled
clinical investigations as defined in 314.126(b) of this chapter,
unless this requirement is waived on the basis of a showing that it is
not reasonably applicable to the drug or essential to the validity of
the investigation and that an alternative method of investigation is
adequate to substantiate effectiveness. Investigations may be
corroborated by partially controlled or uncontrolled studies, documented
clinical studies by qualified experts, and reports of significant human
experience during marketing. Isolated case reports, random experience,
and reports lacking the details which permit scientific evaluation will
not be considered. General recognition of effectiveness shall
ordinarily be based upon published studies which may be corroborated by
unpublished studies and other data.
(iii) The benefit-to-risk ratio of a drug shall be considered in
determining safety and effectiveness.
(iv) An OTC drug may combine two or more safe and effective active
ingredients and may be generally recognized as safe and effective when
each active ingredient makes a contribution to the claimed effect(s);
when combining of the active ingredients does not decrease the safety or
effectiveness of any of the individual active ingredients; and when the
combination, when used under adequate directions for use and warnings
against unsafe use, provides rational concurrent therapy for a
significant proportion of the target population.
(v) Labeling shall be clear and truthful in all respects and may not
be false or misleading in any particular. It shall state the intended
uses and results of the product; adequate directions for proper use;
and warnings against unsafe use, side effects, and adverse reactions in
such terms as to render them likely to be read and understood by the
ordinary individual, including individuals of low comprehension, under
customary conditions of purchase and use.
(vi) A drug shall be permitted for OTC sale and use by the laity
unless, because of its toxicity or other potential for harmful effect or
because of the method or collateral measures necessary to its use, it
may safely be sold and used only under the supervision of a practitioner
licensed by law to administer such drugs.
(5) Advisory review panel report to the Commissioner. An advisory
review panel shall submit to the Commissioner a report containing its
conclusions and recommendations with respect to the conditions under
which OTC drugs falling within the category covered by the panel are
generally recognized as safe and effective and not misbranded. Included
within this report shall be:
(i) A recommended monograph or monographs covering the category of
OTC drugs and establishing conditions under which the drugs involved are
generally recognized as safe and effective and not misbranded (Category
I). This monograph may include any conditions relating to active
ingredients, labeling indications, warnings and adequate directions for
use, prescription or OTC status, and any other conditions necessary and
appropriate for the safety and effectiveness of drugs covered by the
monograph.
(ii) A statement of all active ingredients, labeling claims or other
statements, or other conditions reviewed and excluded from the monograph
on the basis of the panel's determination that they would result in the
drug's not being generally recognized as safe and effective or would
result in misbranding (Category II).
(iii) A statement of all active ingredients, labeling claims or other
statements, or other conditions reviewed and excluded from the monograph
on the basis of the panel's determination that the available data are
insufficient to classify such condition under either paragraph (a)(5)
(i) or (ii) of this section and for which further testing is therefore
required (Category III). The report may recommend the type of further
testing required and the time period within which it might reasonably be
concluded.
(6) Proposed monograph. After reviewing the conclusions and
recommendations of the advisory review panel, the Commissioner shall
publish in the Federal Register a proposed order containing:
(i) A monograph or monographs establishing conditions under which a
category of OTC drugs is generally recognized as safe and effective and
not misbranded (Category I).
(ii) A statement of the conditions excluded from the monograph on the
basis of the Commissioner's determination that they would result in the
drug's not being generally recognized as safe and effective or would
result in misbranding (Category II).
(iii) A statement of the conditions excluded from the monograph on
the basis of the Commissioner's determination that the available data
are insufficient to classify such conditions under either paragraph
(a)(6)(i) or (ii) of this section (Category III).
(iv) The full report(s) of the panel to the Commissioner.
The proposed order shall specify a reasonable period of time within
which conditions falling within paragraph (a)(6)(iii) of this section
may be continued in marketed products while the data necessary to
support them are being obtained for evaluation by the Food and Drug
Administration. The summary minutes of the panel meetings shall be made
available to interested persons upon request. Any interested person
may, within 90 days after publication of the proposed order in the
Federal Register, file with the Dockets Management Branch of the Food
and Drug Administration written comments in quintuplicate. Comments may
be accompanied by a memorandum or brief in support thereof. All
comments may be reviewed at the office of the Dockets Management Branch
during regular working hours, Monday through Friday. Within 30 days
after the final day for submission of comments, reply comments may be
filed with the Dockets Management Branch; these comments shall be
utilized to reply to comments made by other interested persons and not
to reiterate a position. The Commissioner may satisfy this requirement
by publishing in the Federal Register a proposed order summarizing the
full report of the advisory review panel, containing its conclusions and
recommendations, to obtain full public comment before undertaking his
own evaluation and decision on the matters involved.
(7) Tentative final monograph. (i) After reviewing all comments,
reply comments, and any new data and information, the Commissioner shall
publish in the Federal Register a tentative order containing a monograph
establishing conditions under which a category of OTC drugs is generally
recognized as safe and effective and not misbranded. Within 60 days,
any interested person may file with the Dockets Management Branch, Food
and Drug Administration, written comments or written objections
specifying with particularity the omissions or additions requested.
These objections are to be supported by a brief statement of the grounds
therefor. A request for an oral hearing may accompany such objections.
(ii) The Commissioner may publish in the Federal Register a separate
tentative order containing a statement of those active ingredients
reviewed and proposed to be excluded from the monograph on the basis of
the Commissioner's determination that they would result in a drug
product not being generally recognized as safe and effective or would
result in misbranding, and for which no substantive comments in
opposition to the panel report or new data and information were received
by the Food and Drug Administration pursuant to paragraph (a)(6)(iv) of
this section. Within 60 days, any interested person may file with the
Dockets Management Branch, Food and Drug Administration, written
objections specifying with particularity the provision of the tentative
order to which objection is made. These objections are to be supported
by a brief statement of the grounds therefor. A request for an oral
hearing may accompany such objections.
(iii) Within 12 months after publishing a tentative order pursuant to
paragraph (a)(7)(i) of this section, any interested person may file with
the Dockets Management Branch, Food and Drug Administration, new data
and information to support a condition excluded from the monograph in
the tentative order.
(iv) Within 60 days after the final day for submission of new data
and information, comments on the new data and information may be filed
with the Dockets Management Branch, Food and Drug Administration.
(v) New data and information submitted after the time specified in
this paragraph but prior to the establishment of a final monograph will
be considered as a petition to amend the monograph and will be
considered by the Commissioner only after a final monograph has been
published in the Federal Register unless the Commisisoner finds that
good cause has been shown that warrants earlier consideration.
(8) Oral hearing before the Commissioner. After reviewing objections
filed in response to the tentative final monograph, the Commissioner, if
he finds reasonable grounds in support thereof, shall by notice in the
Federal Register schedule an oral hearing. The notice scheduling an
oral hearing shall specify the length of the hearing and how the time
shall be divided among the parties requesting the hearing. The hearing
shall be conducted by the Commissioner and may not be delegated.
(9) Final monograph. After reviewing the objections, the entire
administrative record including all new data and information and
comments, and considering the arguments made at any oral hearing, the
Commissioner shall publish in the Federal Register a final order
containing a monograph establishing conditions under which a category of
OTC drugs is generally recognized as safe and effective and not
misbranded. The monograph shall become effective as specified in the
order.
(10) Administrative record. (i) All data and information to be
considered in any proceeding pursuant to this section shall be submitted
in response to the request for data and views pursuant to paragraph
(a)(2) of this section or accepted by the panel during its deliberations
pursuant to paragraph (a)(3) of this section or submitted to the Dockets
Management Branch as part of the comments during the 90-day period and
30-day rebuttal comment period permitted pursuant to paragraph (a)(6) of
this section or submitted to the Dockets Management Branch during the
12-month period or as part of the comments during the 60-day period
permitted pursuant to paragraph (a)(7) of this section.
(ii) The Commissioner shall make all decisions and issue all orders
pursuant to this section solely on the basis of the administrative
record, and shall not consider data or information not included as part
of the administrative record.
(iii) The administrative record shall consist solely of the following
material: All notices and orders published in the Federal Register, all
data and views submitted in response to the request published pursuant
to paragraph (a)(2) of this section or accepted by the panel during its
deliberations pursuant to paragraph (a)(3) of this section, all minutes
of panel meetings, the panel report(s), all comments and rebuttal
comments submitted on the proposed monograph and all new data and
information submitted pursuant to paragraph (a)(6) of this section, all
objections submitted on the tentative final monograph and all new data
and information and comments submitted pursuant to paragraph (a)(7) of
this section, the complete record of any oral public hearing conducted
pursuant to paragraph (a)(8) of this section, all other comments
requested at any time by the Commissioner, all data and information for
which the Commissioner has reopened the administrative record, and all
other material that the Commissioner includes in the administrative
record as part of the basis for the Commissioner's decision.
(11) Court appeal. The monograph contained in the final order
constitutes final agency action from which appeal lies to the courts.
The Food and Drug Administration will request consolidation of all
appeals in a single court. Upon court appeal, the Commissioner may, at
his discretion, stay the effective date for part or all of the monograph
pending appeal and final court adjudication.
(12) Amendment of monographs. (i) The Commissioner may propose on
the Commissioner's own initiative to amend or repeal any monograph
established pursuant to this section. Any interested person may
petition the Commissioner for such proposal pursuant to 10.30 of this
chapter. The Commissioner may deny the petition if the Commissioner
finds a lack of safety or effectiveness employing the standards in
paragraph (a)(4) of this section (in which case the appeal provisions of
paragraph (a)(11) of this section shall apply), or the Commissioner may
publish a proposed amendment or repeal in the Federal Register if the
Commissioner finds general recognition of safety and effectiveness
employing the standards in paragraph (a)(4) of this section. Any
interested person may, within 60 days after publication of the proposed
order in the Federal Register, file with the Dockets Management Branch,
Food and Drug Administration, written comments in quadruplicate.
Comments may be accompanied by a memorandum or brief in support thereof.
All comments may be reviewed in the Dockets Management Branch between
the hours of 9 a.m. and 4 p.m., Monday through Friday. After reviewing
the comments, the Commissioner shall publish a final order amending the
monograph established under the provisions of paragraph (a)(9) of this
section or withdraw the proposal if comments opposing the amendment are
persuasive. A new drug application may be submitted in lieu of, or in
addition to, a petition under this paragraph.
(ii) A new drug application may be submitted in lieu of a petition to
amend the OTC drug monograh only if the drug product with the condition
that is the subject of the new drug application has not been marketed on
an interim basis (such as under the provisions of paragraph (a)(6)(iii)
of this section), all clinical testing has been conducted pursuant to a
new drug application plan, and no marketing of the product with the
condition for which approval is sought is undertaken prior to approval
of the new drug application. The Food and Drug Administration shall
handle a new drug application as a petition for amendment of a
monograph, and shall review it on that basis, if the provisions of this
paragraph preclude approval of a new drug application but permit the
granting of such a petition.
(b) Regulatory action. Any product which fails to conform to an
applicable monograph after its effective date is liable to regulatory
action.
(c) Information and data submitted under this section shall include,
with respect to each nonclinical laboratory study contained in the
application, either a statement that the study was conducted in
compliance with the good laboratory practice regulations set forth in
Part 58 of this chapter, or, if the study was not conducted in
compliance with such regulations, a brief statement of the reason for
the noncompliance.
(d) (Reserved)
(e) Institutional review and informed consent. Information and data
submitted under this section after July 27, 1981, shall include
statements regarding each clinical investigation involving human
subjects, from which the information and data are derived, that it
either was conducted in compliance with the requirements for
institutional review set forth in Part 56 of this chapter, or was not
subject to such requirements in accordance with 56.104 or 56.105, and
that it was conducted in compliance with the requirements for informed
consent set forth in Part 50 of this chapter.
(39 FR 11741, Mar. 29, 1974, as amended at 39 FR 39556, Nov. 8, 1974;
42 FR 19141, Apr. 12, 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460,
8955, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; 46 FR 21360, Apr. 10,
1981; 46 FR 47738, Sept. 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR
11581, Mar. 29, 1990)
21 CFR 330.11 NDA deviations from applicable monograph.
A new drug application requesting approval of an OTC drug deviating
in any respect from a monograph that has become final shall be in the
form required by 314.50 of this chapter, but shall include a statement
that the product meets all conditions of the applicable monograph except
for the deviation for which approval is requested and may omit all
information except that pertinent to the deviation.
(39 FR 11741, Mar. 29, 1974, as amended at 55 FR 11581, Mar. 29,
1990)
21 CFR 330.12 Status of over-the-counter (OTC) drugs previously
reviewed under the Drug Efficacy Study (DESI).
(a) There were 420 OTC drugs reviewed in the Drug Efficacy Study (a
review of drugs introduced to the market through new drug procedures
between 1938 and 1962). A careful review has been made of the reports
on these drugs to determine those drugs for which implementation may be
deferred without significant risk to the public health, pending review
by appropriate OTC drug advisory review panels and promulgation of a
monograph.
(b) On and after April 20, 1972, a number of notices were published
in the Federal Register concerning previously unpublished OTC drugs
reviewed by the National Academy of Sciences-National Research Council
Drug Efficacy Study Group. Only the evaluations and comments of the
panels were published, with no conclusions of the Commissioner of Food
and Drugs. Those publications were for the purpose of giving interested
persons the benefit of the Academy's opinions. For those products, and
also for OTC drug products previously published with the Commissioner's
conclusions (except for the products listed in paragraphs (b) (1) and
(2) of this section, all requests for data, revised labeling, requests
for new drug applications, abbreviated new drug applications, updating
supplements, data to support less than effective claims, if any, etc.,
are deferred, and such OTC drug products are instead subject to the OTC
drug review in their appropriate classes pursuant to the procedures
established in this subpart.
(1) The requirements of the following DESI announcements are not
deferred (the reference document may also pertain to prescription
drugs):
(i) Certain Surgical Sutures (DESI 4725), published in the Federal
Register of November 11, l971 (36 FR 21612).
(ii) Absorbable Dusting Powder (DESI 6264), published in the Federal
Register of May 25, 1971 (36 FR 9475).
(iii) Certain Insulin Preparations (DESI 4286), published in the
Federal Register of April 9, 1971 (36 FR 6842).
(iv) Sulfo-Van Ointment (DESI 2230), published in the Federal
Register of October 8, 1970 (35 FR 15860).
(v) Antiperspirants and Deodorants Containing Neomycin Sulfate (DESI
11048) for which an order revoking provisions for certification or
release was published in the Federal Register of December 5, 1972 (37 FR
25820) and has been stayed by the filing of objections.
(vi) Thorexin Cough Medicine (DESI 11160) for which a notice of
opportunity for hearing was published in the Federal Register of
February 2, 1973 (38 FR 3210).
(vii) Antibiotic susceptibility discs (DESI 90235) for which an order
providing for certain discs to be certified and removing provisions for
certification of other discs was published in the Federal Register of
September 30, 1972 (37 FR 20525) and has been stayed by the filing of
objections notice of which was published in the Federal Register of
March 15, 1973 (38 FR 7007).
(2) Deferral of requirements is not appropriate when an announcement
has been published and has been followed by a final order classifying a
drug either as lacking substantial evidence of effectiveness or as not
shown to be safe. These products will be removed from the market, if
they have not already been removed. Regulatory action will also be
undertaken against identical, similar and related products (21 CFR
310.6). Deferral of requirements is not appropriate for the following
(the referenced document may also pertain to prescription drugs):
(i) Certain Sulfonamide-Decongestant Nasal Preparation (DESI 4850),
for which notice of withdrawal of approval of new drug applications was
published in the Federal Register of October 24, 1970 (35 FR 16605,
16606).
(ii) Eskay's Theranates, containing strychnine, sodium, and calcium
glycerophosphates, thiamine hydrochloride, alcohol, and phosphoric acid
(DESI 2220), for which notice of withdrawal of approval of the new drug
application was published in the Federal Register of February 18, 1971
(36 FR 3152).
(iii) The following topical drugs (DESI 1726), for which notice of
withdrawal of new drug applications was published in the Federal
Register of August 28, 1971 (36 FR 17368):
(a) Rhulitol Solution, containing tannic acid, chlorobutanol, phenol,
camphor, alum, and isopropyl alcohol.
(b) Zirnox Topical Lotion, containing phenyitoloxamine citrate and
zirconium oxide.
(iv) Menacyl Tablets, containing aspirin, menadione, and ascorbic
acid (DESI 6363), for which notice of withdrawal of approval of the new
drug application was published in the Federal Register of July 23, 1970
(35 FR 11827).
(v) Curad Medicated Adhesive Bandage containing sulfathiazole (DESI
4964), for which notice of withdrawal of approval of the new drug
application was published in the Federal Register of December 31, 1969
(34 FR 20441).
(vi) Drugs Containing Rutin, Quercetin, Hesperidin, or any
Bioflavonoids (DESI 5960), for which notice of withdrawal of approval of
new drug applications was published in the Federal Register of July 3,
1970 (35 FR 10872, 10873) and October 17, 1970 (35 FR 16332). A further
notice of opportunity for hearing with respect to the drugs covered by
the October 17, 1970 Federal Register notice will be published at a
later date.
(vii) Antibiotics in Combination with Other Drugs for Nasal Use (DESI
7561), for which an order revoking provision for certification was
published in the Federal Register of August 6, 1971 (36 FR 14469) and
confirmed in the Federal Register of October 28, 1971 (36 FR 20686).
(viii) Antibiotic Troches (DESI 8328), for which an order revoking
provision for certification was published in the Federal Register of
July 14, 1971 (36 FR 13089) and confirmed in the Federal Register of
October 9, 1971 (36 FR 19695).
(ix) Certain Drugs Containing Oxyphenisatin or Oxyphenisatin Acetate
(DESI 10732), for which notices of withdrawal of approval of new drug
applications were published in the Federal Register of February 1, 1972
(37 FR 2460), and March 9, 1973 (38 FR 6419).
(x) Curad Medicated Adhesive Bandage containing
tyrothricin-nitrofurazone (DESI 6898), for which an order revoking
provision for certification was published March 14, 1972 (37 FR 5294),
and confirmed in the Federal Register of July 6, 1972 (37 FR 13254).
(xi) Candette Cough Gel (DESI 11562), for which notice of withdrawal
of approval of the new drug application was published in the Federal
Register of November 19, 1972 (37 FR 25249).
(xii) Certain OTC Multiple-Vitamin Preparations for Oral Use
containing excessive amounts of vitamin D and/or vitamin A (DESI 97),
for which notice of withdrawal of approval of the new drug applications
was published in the Federal Register of November 29, 1972 (37 FR
25249).
(xiii) Certain Sulfonamide-Containing Preparations for Topical
Ophthalmic or Otic Use (DESI 368, for which a notice of withdrawal of
approval was published in the Federal Register of February 2, 1973 (38
FR 3208).
(xiv) Those parts of the publication entitled ''Certain Mouthwash and
Gargle Preparations'' (DESI 2855) pertaining to Tyrolaris Mouthwash,
containing tyrothricin, panthenol, and alcohol, for which an order
revoking provision for certification was published in the Federal
Register of February 2, 1967 (32 FR 1172) prior to the drug efficacy
study implementation.
(c) Manufacturers and distributors should take notice that the
information on OTC drugs provided by the Drug Efficacy Study review is
valuable information as to the deficiencies in the data available to
support indications for use. They are encouraged to perform studies to
obtain adequate evidence of effectiveness for the review of OTC drugs
which is already in progress. In the interim it is in the public
interest that manufacturers and distributors of all OTC drugs effect
changes in their formulations and/or labeling to bring the products into
conformity with current medical knowledge and experience.
(d) Manufacturers and distributors of OTC drugs may be reluctant to
make appropriate formulation and/or labeling changes for fear of losing
the protection of the so-called ''grandfather'' provisions of the 1938
Federal Food, Drug, and Cosmetic Act (sec. 201(p)(1)) and the 1962
amendments to the act (sec. 107(c) of those amendments). To encourage
and facilitate prompt changes, the Food and Drug Administration will not
take legal action against any OTC drug, other than those not deferred,
based on a charge that the product is a new drug and not grandfathered
under the act as a result of the changes if the changes in formulation
and/or labeling are of the following kind:
(1) The addition to the labeling of warning, contraindications, side
effects, and/or precaution information.
(2) The deletion from the labeling of false, misleading, or
unsupported indications for use or claims of effectiveness.
(3) Changes in the components or composition of the drug that will
give increased assurance that the drug will have its intended effect,
yet not raise or contribute any added safety questions.
(4) Changes in the components or composition of the drug which may
reasonably be concluded to improve the safety of the drug, without
diminishing its effectiveness.
(e) The forbearance from legal action for lack of grandfather
protection is an interim procedure designed to encourage appropriate
change in formulation and/or labeling during the time period required to
review the various classes of OTC drugs. At such time as an applicable
OTC drug monograph becomes effective, the interim procedure will
automatically be terminated and any appropriate regulatory action will
be initiated.
21 CFR 330.13 Conditions for marketing ingredients recommended for
over-the-counter (OTC) use under the OTC drug review.
(a) Before the publication in the Federal Register of an applicable
proposed monograph, an OTC drug product that contains: (1) An active
ingredient limited, on or after May 11, 1972, to prescription use for
the indication and route of administration under consideration by an OTC
advisory review panel, and not thereafter exempted from such limitation
pursuant to 310.200 of this chapter, or
(2) An active ingredient at a dosage level higher than that available
in an OTC drug product on December 4, 1975, shall be regarded as a new
drug within the meaning of section 201(p) of the act for which an
approved new drug application is required.
(b)(1) An OTC drug product that contains: (i) An active ingredient
limited, on or after May 11, 1972, to prescription use for the
indication and route of administration under consideration by an OTC
advisory review panel, and not thereafter exempted from such limitation
pursuant to 310.200 of this chapter, or
(ii) An active ingredient at a dosage level higher than that
available in an OTC drug product on December 4, 1975, which ingredient
and/or dosage level is classified by the panel in category I (conditions
subject to 330.10(a)(6)(i)) shall be regarded as a new drug within the
meaning of section 201(p) of the act for which an approved new drug
application is required if marketed for OTC use prior to the date of
publication in the Federal Register of a proposed monograph.
(2) An OTC drug product covered by paragraph (b)(1) of this section
which is marketed after the date of publication in the Federal Register
of a proposed monograph but prior to the effective date of a final
monograph shall be subject to the risk that the Commissioner may not
accept the panel's recommendation and may instead adopt a different
position that may require relabeling, recall, or other regulatory
action. The Commissioner may state such position at any time by notice
in the Federal Register, either separately or as part of another
document; appropriate regulatory action will commence immediately and
will not await publication of a final monograph. Marketing of such a
product with a formulation or labeling not in accord with a proposed
monograph or tentative final monograph also may result in regulatory
action against the product, the marketer, or both.
(c) An OTC drug product that contains: (1) An active ingredient
limited, on or after May 11, 1972, to prescription use for the
indication and route of administration under consideration by an OTC
advisory review panel, and not thereafter exempted from such limitation
pursuant to 310.200 of this chapter, or
(2) An active ingredient at a dosage level higher than that available
in any OTC drug product on December 4, 1975, which ingredient and/or
dosage level is classified by the panel in category II (conditions
subject to 330.10(a)(6)(ii)), may be marketed only after:
(i) The Center for Drug Evaluation and Research or the Commissioner
tentatively determines that the ingredient is generally recognized as
safe and effective, and the Commissioner states by notice in the Federal
Register (separately or as part of another document) that marketing
under specified conditions will be permitted;
(ii) The ingredient is determined by the Commissioner to be generally
recognized as safe and effective and is included in the appropriate
published OTC drug final monograph; or
(iii) A new drug application for the product has been approved.
(d) An OTC drug product that contains: (1) An active ingredient
limited, on or after May 11, 1972, to prescription use for the
indication and route of administration under consideration by an OTC
advisory review panel, and not thereafter exempted from such limitation
pursuant to 310.200 of this chapter, or
(2) An active ingredient at a dosage level higher than that available
in any OTC drug product on December 4, 1975, which ingredient and/or
dosage level is classified by the panel in category III (conditions
subject to 330.10(a)(6)(iii)), may be marketed only after:
(i) The Center for Drug Evaluation and Research or the Commissioner
tentatively determines that the ingredient is generally recognized as
safe and effective, and the Commissioner states by notice in the Federal
Register (separately or as part of another document) that marketing
under specified conditions will be permitted;
(ii) The ingredient is determined by the Commissioner to be generally
recognized as safe and effective and is included in the appropriate
published OTC drug final monograph; or
(iii) A new drug application for the product has been approved.
(41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982;
50 FR 8996, Mar. 6, 1985; 55 FR 11581, Mar. 29, 1990)
21 CFR 330.13 PART 331 -- ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE
21 CFR 330.13 Subpart A -- General Provisions
Sec.
331.1 Scope.
21 CFR 330.13 Subpart B -- Active Ingredients
331.10 Antacid active ingredients.
331.11 Listing of specific active ingredients.
331.15 Combination with nonantacid active ingredients.
21 CFR 330.13 Subpart C -- Testing Procedures
331.20 Apparatus and reagents.
331.21 Determination of percent contribution of active ingredients.
331.22 Reagent standardization.
331.23 Temperature standardization.
331.24 Tablet disintegration test.
331.25 Preliminary antacid test.
331.26 Acid neutralizing capacity test.
331.29 Test modifications.
21 CFR 330.13 Subpart D -- Labeling
331.30 Labeling of antacid products.
331.80 Professional labeling.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 39 FR 19874, June 4, 1974, unless otherwise noted.
21 CFR 330.13 Subpart A -- General Provisions
21 CFR 331.1 Scope.
An over-the-counter antacid product in a form suitable for oral
administration is generally recognized as safe and effective and is not
misbranded if it meets each of the following conditions and each of the
general conditions established in 330.1 of this chapter.
21 CFR 331.1 Subpart B -- Active Ingredients
21 CFR 331.10 Antacid active ingredients.
(a) The active antacid ingredients of the product consist of one or
more of the ingredients permitted in 331.11 within any maximum daily
dosage limit established, each ingredient is included at a level that
contributes at least 25 percent of the total acid neutralizing capacity
of the product, and the finished product contains at least 5 mEq. of
acid neutralizing capacity and results in a pH of 3.5 or greater at the
end of the initial 10-minute period as measured by the method
established in 331.25. The method established in 331.21 shall be used
to determine the percent contribution of each antacid active ingredient.
(b) This section does not apply to an antacid ingredient specifically
added as a corrective to prevent a laxative or constipating effect.
21 CFR 331.11 Listing of specific active ingredients.
(a) Aluminum-containing active ingredients:
(1) Basic aluminum carbonate gel.
(2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized
polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum
hydroxide-magnesium trisilicate codried gel, aluminum-hydroxide sucrose
powder hydrated).
(3) Dihydroxyaluminum aminoacetate and dihydroxyaluminum aminoacetic
acid.
(4) Aluminum phosphate gel when used as part of an antacid
combination product and contributing at least 25 percent of the total
acid neutralizing capacity; maximum daily dosage limit is 8 grams.
(5) Dihydroxyaluminum sodium carbonate.
(b) Bicarbonate-containing active ingredients: Bicarbonate ion;
maximum daily dosage limit 200 mEq. for persons up to 60 years old and
100 mEq. for persons 60 years or older.
(c) Bismuth-containing active ingredients:
(1) Bismuth aluminate.
(2) Bismuth carbonate.
(3) Bismuth subcarbonate.
(4) Bismuth subgallate.
(5) Bismuth subnitrate.
(d) Calcium-containing active ingredients: Calcium, as carbonate or
phosphate; maximum daily dosage limit 160 mEq. calcium (e.g., 8 grams
calcium carbonate).
(e) Citrate-containing active ingredients: Citrate ion, as citric
acid or salt; maximum daily dosage limit 8 grams.
(f) Glycine (aminoacetic acid).
(g) Magnesium-containing active ingredients:
(1) Hydrate magnesium aluminate activated sulfate.
(2) Magaldrate.
(3) Magnesium aluminosilicates.
(4) Magnesium carbonate.
(5) Magnesium glycinate.
(6) Magnesium hydroxide.
(7) Magnesium oxide.
(8) Magnesium trisilicate.
(h) Milk solids, dried.
(i) Phosphate-containing active ingredients:
(1) Aluminum phosphate; maximum daily dosage limit 8 grams.
(2) Mono or dibasic calcium salt; maximum daily dosage limit 2
grams.
(3) Tricalcium phosphate; maximum daily dosage limit 24 grams.
(j) Potassium-containing active ingredients:
(1) Potassium bicarbonate (or carbonate when used as a component of
an effervescent preparation); maximum daily dosage limit 200 mEq. of
bicarbonate ion for persons up to 60 years old and 100 mEq. of
bicarbonate ion for persons 60 years or older.
(2) Sodium potassium tartrate.
(k) Sodium-containing active ingredients:
(1) Sodium bicarbonate (or carbonate when used as a component of an
effervescent preparation); maximum daily dosage limit 200 mEq. of
sodium for persons up to 60 years old and 100 mEq. of sodium for
persons 60 years or older, and 200 mEq. of bicarbonate ion for persons
up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years
or older. That part of the warning required by 330.1(g), which states,
''Keep this and all drugs out of the reach of children'' is not required
on a product which contains only sodium bicarbonate powder and which is
intended primarily for other than drug uses.
(2) Sodium potassium tartrate.
(l) Silicates:
(1) Magnesium aluminosilicates.
(2) Magnesium trisilicate.
(m) Tartrate-containing active ingredients. Tartaric acid or its
salts; maximum daily dosage limit 200 mEq. (15 grams) of tartrate.
(39 FR 19874, June 4, 1974, as amended at 51 FR 27763, Aug. 1, 1986;
55 FR 19859, May 11, 1990)
21 CFR 331.15 Combination with nonantacid active ingredients.
(a) An antacid may contain any generally recognized as safe and
effective nonantacid laxative ingredient to correct for constipation
caused by the antacid. No labeling claim of the laxative effect may be
used for such a product.
(b) An antacid may contain any generally recognized as safe and
effective analgesic ingredient(s), if it is indicated for use solely for
the concurrent symptoms involved, e.g., headache and acid indigestion,
and is marketed in a form intended for ingestion as a solution.
(c) An antacid may contain any generally recognized as safe and
effective antiflatulent ingredient if it is indicated for use solely for
the concurrent symptoms of gas associated with heartburn, sour stomach
or acid indigestion.
21 CFR 331.15 Subpart C -- Testing Procedures
21 CFR 331.20 Apparatus and reagents.
(a) pH meter, equipped with glass and saturated calomel electrodes.
(b) Magnetic stirrer.
(c) Magnetic stirring bars (about 40 mm. long and 10 mm. in
diameter).
(d) 50 ml. buret.
(e) Buret stand.
(f) 100 ml. beakers.
(g) 250 ml. beakers.
(h) 10 ml., 20 ml. and 30 ml. pipets calibrated to deliver.
(i) Tablet comminuting device.
(j) A number 20 and 100 U.S. standard mesh sieve.
(k) Tablet disintegration apparatus.
(l) 0.1 N, 0.5 N and 1.0 N hydrochloric acid.
(m) 0.5 N sodium hydroxide.
(n) Standard pH 4.0 buffer solution (0.05 M potassium hydrogen
phthalate).
(o) 95 percent ethanol.
(p) Purified Water U.S.P.
(39 FR 19874, June 4, 1974, as amended at 40 FR 48343, Oct. 15, 1975)
21 CFR 331.21 Determination of percent contribution of active
ingredients.
To determine the percent contribution of an antacid active
ingredient, place an accurately weighed amount of the antacid active
ingredient equal to the amount present in a unit dose of the product
into a 250 ml. beaker. If wetting is desired, add not more than 5 ml.
of 95 percent ethanol and mix thoroughly to wet the sample (ethanol may
affect the acid neutralizing capacity). Add water to a volume of 70 ml.
and mix on magnetic stirrer at 300 30 r.p.m. for about one minute.
Analyze the sample according to the procedure set forth in 331.26 and
calculate the percent contribution of the antacid active ingredient in
the total product as follows:
Percent contribution=(Total mEq. Antacid Active Ingredient
100)/(Total mEq. Antacid Product)
21 CFR 331.22 Reagent standardization.
Standardize the sodium hydroxide (NaOH) and hydrochloric acid (HCl)
solutions according to the procedures in the United States Pharmacopeia
XVIII (NaOH page 1036 and HCl page 1034) or the Official Methods of
Analysis of the Association of Official Analytical Chemists, 11th Ed.,
1970, (NaOH page 876 and HCl page 873), which is incorporated by
reference. Copies are available from the Association of Official
Analytical Chemists, 2200 Wilson Blvd., suite 400, Arlington, VA
22201-3301, or available for inspection at the Office of the Federal
Register, 1100 L St. NW., Washington, DC 20408.
(39 FR 19874, June 4, 1974; 39 FR 22140, June 20, 1974, as amended
at 47 FR 9396, Mar. 5, 1982; 55 FR 11581, Mar. 29, 1990)
21 CFR 331.23 Temperature standardization.
All tests shall be conducted at 25 C 3 , or 37 C 3 .
(40 FR 48343, Oct. 15, 1975)
21 CFR 331.24 Tablet disintegration test.
A tablet disintegration test shall be performed on tablets that are
not to be chewed following the procedures described in the United States
Pharmacopeia XVIII (page 932). If the label states the tablet may be
swallowed, it must disintegrate within a 10-minute time limit pursuant
to the test procedure using simulated gastric fluid test solution
without enzymes, the United States Pharmacopeia XVIII page 1026, rather
than water as the immersion fluid.
21 CFR 331.25 Preliminary antacid test.
(a) pH meter. Standardize the pH meter at pH 4.0 with the
standardizng buffer and check for proper operation at pH 1 with 0.1 N
HCl.
(b) Dosage form testing -- (1) Liquid sample. Place an accurately
weighed (calculate density) and well mixed amount of the antacid product
equivalent to the minimum labeled dosage; e.g., 5 ml., into a 100 ml.
beaker. Add sufficient water to obtain a total volume of about 40 ml.
and mix on magnetic stirrer at 300 30 r.p.m. for about one minute.
Analyze the sample according to the procedure set forth in 331.25.
(2) Chewable and non-chewable tablet sample. Place an accurately
weighed amount of a tablet composite equivalent to the minimum labeled
dosage into a 100 ml. beaker. (The composite shall be prepared by
determining the average weight of not less than 20 tablets and then
comminuting the tablets sufficiently to pass through a number 20 U.S.
standard mesh sieve and held by a number 100 U.S. standard mesh sieve.)
Mix the sieved material to obtain a uniform sample. If wetting is
desired, add not more than 5 ml. of 95 percent ethanol and mix to wet
the sample thoroughly (ethanol may effect the acid neutralizing
capacity). Add water to a volume of 40 ml. and mix on magnetic stirrer
at 300 30 r.p.m. for about one minute. (Capsules should be tested in
the same manner using the sieved capsule powder as the sample.) Analyze
the sample according to the procedure set forth in 331.25.
(3) Effervescent sample. Place an amount equivalent to the minimum
labeled dosage into a 100 ml. beaker. Add 10 ml. water and swirl the
beaker gently while allowing the reaction to subside. Add another 10
ml. of water and swirl the beaker gently. Wash down the walls of the
beaker with 20 ml. of water and mix on magnetic stirrer at 300 30
r.p.m. for about one minute. Analyze the sample according to the
procedure set forth in 331.25.
(4) Chewing gum samples with antacid in coating. Place the number of
pieces of gum equivalent to the minimum labeled dosage in a 100 ml.
beaker. Add 40 ml. of water and mix on magnetic stirrer at 300 30
r.p.m. for about 2 to 3 minutes. Analyze the sample according to the
procedure set forth in 331.25.
(c) Test procedure. (1) Add 10.0 ml. 0.5 N HCl to the test solution
while stirring on the magnetic stirrer at 300 30 r.p.m.
(2) Stir for exactly 10 minutes after addition of acid.
(3) Read and record pH.
(4) If pH is below 3.5, the product shall not be labeled as an
antacid. If the pH is 3.5 or greater, determine the acid neutralizing
capacity according to the procedure set forth in 331.26.
21 CFR 331.26 Acid neutralizing capacity test.
(a) pH meter. Standardize the pH meter at pH 4.0 with the
standardizing buffer and check for proper operation at pH 1 with 0.1 N
HCl.
(b) Dosage form testing -- (1) Liquidsample. Place an accurately
weighed (calculate density) and well mixed amount of product equivalent
to the minimum labeled dosage (e.g., 5 ml., etc.) into a 250 ml.
beaker. Add sufficient water to obtain a total volume of about 70 ml.
and mix on the magnetic stirrer at 300 30 r.p.m. for about one minute.
Analyze the sample according to the procedure set forth in 331.26.
(2) Chewable and non-chewable tablet sample. Place an accurately
weighed amount of a tablet composite equivalent to the minimum labeled
dosage into a 250 ml. beaker. (The composite shall be prepared by
determining the average weight of not less than 20 tablets and then
comminuting the tablets sufficiently to pass through a number 20 U.S.
standard mesh sieve and held by a number 100 U.S. standard mesh sieve.
Mix the sieved material to obtain a uniform sample.) If wetting is
desired, add not more than 5 ml. of 95 percent ethanol and mix to wet
the sample thoroughly (ethanol may effect the acid neutralizing
capacity). Add water to a volume of 70 ml. and mix on magnetic stirrer
at 300 30 r.p.m. for about one minute. (Capsules should be tested in
the same manner using the sieved capsule powder as the sample.) Analyze
the sample according to the procedure set forth in 331.26.
(3) Effervescent sample. Place an amount equivalent to the minimum
labeled dosage into a 250 ml. beaker. Add 10 ml. water and swirl the
beaker gently while allowing the reaction to subside. Add another 10
ml. of water and swirl the beaker gently. Wash down the walls of the
beaker with 50 ml. of water and mix on magnetic stirrer at 300 30
r.p.m. for about one minute. Analyze the sample according to the
procedure set forth in 331.26.
(4) Sample and test procedure for chewing gum with antacid in
coating. Assay six pieces of gum individually in the following manner.
(i) Place one piece of gum in a 250 ml. beaker and add 50 ml. of
water.
(ii) Pipette in 30.0 ml. of 1.0 N HCl and stir on magnetic stirrer at
300 30 r.p.m.
(iii) Stir for exactly 10 minutes after addition of acid.
(iv) Stop the stirrer and remove the gum using a long needle or
similar utensil.
(v) Rinse the long needle or utensil and the gum with 20 ml. of
water into the sample beaker.
(vi) Stir for exactly 5 additional minutes.
(vii) Begin titrating immediately and in a period of time not to
exceed 5 minutes titrate the excess 1.0 N HCl with 0.5 N NaOH to stable
pH of 3.5.
(viii) Check sample solution 10 to 15 seconds after obtaining pH 3.5
to determine that the pH is stable.
(ix) Average the results of the six individual assays and calculate
the total mEq. based on the minimum labeled dosage as follows:
mEq./piece of gum=(30.0 ml.) (normality of HCl)^(ml. of NaOH)
(normality of (NaOH). Total mEq. per labeled minimum dose=(number of
pieces of gum in minimum dosage) (mEq./piece of gum).
(c) Acid neutralizing capacity test procedure (except chewing gum).
(1) Pipette 30.0 ml. of 1.0 N HCl into the sample solution while
stirring on the magnetic stirrer at 300 30 r.p.m.
(2) Stir for exactly 15 minutes after addition of acid.
(3) Begin titrating immediately and in a period not to exceed an
additional 5 minutes titrate the excess 1.0 N HCl with 0.5 N NaOH to
stable pH of 3.5.
(4) Check the sample solution 10 to 15 seconds after obtaining pH 3.5
to make sure the pH is stable.
(5) Calculate the number of mEq. of acid neutralized by the sample
as follows:
Total mEq.=(30.0 ml.) (normality of HCl)^(ml. of NaOH) (N of NaOH).
Use appropriate factors, i.e., density, average tablet weight, etc.,
to calculate the total mEq. of acid neutralized per minimum labeled
dosage.
(39 FR 19874, June 4, 1974; 39 FR 22140, June 20, 1974)
21 CFR 331.29 Test modifications.
The formulation or mode of administration of certain products may
require modification of this in vitro test. Any proposed modification
and the data to support it shall be submitted as a petition under the
rules established in 10.30 of this chapter. All information submitted
will be subject to the disclosure rules in Part 20 of this chapter.
(47 FR 38480, Aug. 31, 1982)
21 CFR 331.29 Subpart D -- Labeling
21 CFR 331.30 Labeling of antacid products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''antacid.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''For the relief of''
(optional, any or all of the following:) ''heartburn,'' ''sour
stomach,'' and/or ''acid indigestion'' (which may be followed by the
optional statement:) ''and upset stomach associated with'' (optional, as
appropriate) ''this symptom'' or ''these symptoms.'' Other truthful and
nonmisleading statements, describing only the indications for use that
have been established and listed in this paragraph (b), may also be
used, as provided in 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) Warnings. The labeling of the product contains the following
warnings, under the heading ''Warnings'', which may be combined but not
rearranged to eliminate duplicative words or phrases if the resulting
warning is clear and understandable:
(1) ''Do not take more than (maximum recommended daily dosage, broken
down by age groups if appropriate, expressed in units such as tablets or
teaspoonfuls) in a 24-hour period, or use the maximum dosage of this
product for more than 2 weeks, except under the advice and supervision
of a physician.''
(2) For products which cause constipation in 5 percent or more of
persons who take the maximum recommended dosage: ''May cause
constipation.''
(3) For products which cause laxation in 5 percent or more of persons
who take the maximum recommended dosage: ''May have laxative effect.''
(4) For products containing more than 50 mEq. of magnesium in the
recommended daily dosage: ''Do not use this product except under the
advice and supervision of a physician if you have kidney disease.''
(5) For products containing more than 5 mEq. sodium in the maximum
recommended daily dose: ''Do not use this product except under the
advice and supervision of a physician if you are on a sodium restricted
diet.''
(6) For products containing more than 25 mEq. potassium in the
maximum recommended daily dose: ''Do not use this product except under
the advice and supervision of a physician if you have kidney disease.''
(7) For products containing more than 5 gm per day lactose in a
maximum daily dosage: ''Do not use this product except under advice and
supervision of a physician if you are allergic to milk or milk
products.''
(d) Drug interaction precautions. The labeling of the product
contains the following drug interaction precautions, under the heading
''Drug Interaction Precautions'':
(1) If the product is an aluminum containing antacid: ''Do not take
this product if you are presently taking a prescription antibiotic drug
containing any form of tetracycline.''
(e) Directions for use. The labeling of the product contains the
recommended dosage, under the heading ''Directions'', per time interval
(e.g., every 4 hours) or time period (e.g., 4 times a day) broken down
by age groups if appropriate, followed by ''or as directed by a
physician.''
(f) Statement of sodium containing ingredients. The labeling of the
product contains the sodium content per dosage unit (e.g., tablet,
teaspoonful) if it is 0.2 mEq. (5 mg.) or higher.
(g) Exemption from the general accidental overdose warning. The
labeling for antacid drug products containing the active ingredients
identified in 331.11(a), (b), and (d) through (m); permitted
combinations of these ingredients provided for in 331.10; and any of
these ingredients or combinations of these ingredients in combination
with simethicone (identified in 332.10 of this chapter and provided for
in 331.15(c)), are exempt from the requirement in 330.1(g) of this
chapter that the labeling bear the general warning statement ''In case
of accidental overdose, seek professional assistance or contact a poison
control center immediately.'' With the exception of sodium bicarbonate
powder products identified in 331.11(k)(1), the labeling must continue
to bear the first part of the general warning in 330.1(g) of this
chapter, which states, ''Keep this and all drugs out of the reach of
children.''
(39 FR 19874, June 4, 1974, as amended at 47 FR 38484, Aug. 31, 1982;
51 FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar.
13, 1987; 55 FR 11581, Mar. 29, 1990)
21 CFR 331.80 Professional labeling.
(a) The labeling of the product provided to health professionals (but
not to the general public):
(1) Shall after June 4, 1976 contain the neutralizing capacity of the
product as calculated using the procedure set forth in 331.26 expressed
in terms of the dosage recommended per minimum time interval or, if the
labeling recommends more than one dosage, in terms of the minimum dosage
recommended per minimum time interval. For compliance purposes, the
value determined by the acid neutralizing test at any point in time
shall be at least 90 percent of the labeled value. No product shall be
marketed with an acid neutralizing capacity below 5 mEq.
(2) May contain an indication for the symptomatic relief of
hyperacidity associated with the diagnosis of peptic ulcer, gastritis,
peptic esophagitis, gastric hyperacidity, and hiatal hernia.
(3) For products containing basic aluminum carbonate gel identified
in 331.11(a)(1) -- Indication. ''For the treatment, control, or
management of hyperphosphatemia, or for use with a low phosphate diet to
prevent formation of phosphate urinary stones, through the reduction of
phosphates in the serum and urine.''
(4) For products containing aluminum identified in 331.11(a) --
Warnings. (i) Prolonged use of aluminum-containing antacids in patients
with renal failure may result in or worsen dialysis osteomalacia.
Elevated tissue aluminum levels contribute to the development of the
dialysis encephalopathy and osteomalacia syndromes. Small amounts of
aluminum are absorbed from the gastrointestinal tract and renal
excretion of aluminum is impaired in renal failure. Aluminum is not
well removed by dialysis because it is bound to albumin and transferrin,
which do not cross dialysis membranes. As a result, aluminum is
deposited in bone, and dialysis osteomalacia may develop when large
amounts of aluminum are ingested orally by patients with impaired renal
function.
(ii) Aluminum forms insoluble complexes with phosphate in the
gastrointestinal tract, thus decreasing phosphate absorption. Prolonged
use of aluminum-containing antacids by normophosphatemic patients may
result in hypophosphatemia if phosphate intake is not adequate. In its
more severe forms, hypophosphatemia can lead to anorexia, malaise,
muscle weakness, and osteomalacia.
(b) Professional labeling for an antacid-antiflatulent combination
may contain the information allowed for health professionals for
antacids and antiflatulents.
(39 FR 19874, June 4, 1974. Redesignated and amended at 55 FR 19859,
May 11, 1990)
21 CFR 331.80 PART 332 -- ANTIFLATULENT PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 331.80 Subpart A -- General Provisions
Sec.
332.1 Scope.
21 CFR 331.80 Subpart B -- Active Ingredients
332.10 Antiflatulent active ingredients.
332.15 Combination with non-antiflatulent active ingredients.
21 CFR 331.80 Subpart C -- (Reserved)
21 CFR 331.80 Subpart D -- Labeling
332.30 Labeling of antiflatulent products.
332.31 Professional labeling.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 39 FR 19877, June 4, 1974, unless otherwise noted.
21 CFR 331.80 Subpart A -- General Provisions
21 CFR 332.1 Scope.
An over-the-counter antiflatulent product in a form suitable for oral
administration is generally recognized as safe and effective and is not
misbranded if it meets each of the following conditions and each of the
general conditions established in 330.1 of this chapter.
21 CFR 332.1 Subpart B -- Active Ingredients
21 CFR 332.10 Antiflatulent active ingredients.
Simethicone; maximum daily dose 500 mg. There is no dosage
limitation at this time for professional labeling.
21 CFR 332.15 Combination with non-antiflatulent active ingredients.
An antiflatulent may contain any generally recognized as safe and
effective antacid ingredient(s) if it is indicated for use solely for
the concurrent symptoms of gas associated with heartburn, sour stomach
or acid indigestion.
21 CFR 332.15 Subpart C -- (Reserved)
21 CFR 332.15 Subpart D -- Labeling
21 CFR 332.30 Labeling of antiflatulent products.
(a) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''antiflatulent'' and/or ''to
alleviate or relieve the symptoms of gas.'' Other truthful and
nonmisleading statements, describing only the indications for use that
have been established and listed in this paragraph (a), may also be
used, as provided in 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(b) Directions for use. The labeling of the product contains the
recommended dosage per time interval (e.g., every 4 hours) or time
period (e.g., 4 times a day) broken down by age groups if appropriate,
followed by ''except under the advice and supervision of a physician.''
The words ''or as needed'' may be used after the recommended dosage per
time interval or time period.
(c) Exemption from the general accidental overdose warning. The
labeling for antiflatulent drug products containing simethicone
identified in 332.10 and antacid/antiflatulent combination drug
products provided for in 332.15, containing the active ingredients
identified in 331.11(a), (b), and (d) through (m) of this chapter are
exempt from the requirement in 330.1(g) of this chapter that the
labeling bear the general warning statement ''In case of accidental
overdose, seek professional assistance or contact a poison control
center immediately.'' The labeling must continue to bear the first part
of the general warning in 330.1(g) of this chapter, which states,
''Keep this and all drugs out of the reach of children.''
(39 FR 19877, June 4, 1974, as amended at 40 FR 11719, Mar. 13, 1975;
51 FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar.
13, 1987)
21 CFR 332.31 Professional labeling.
(a) The labeling of the product provided to health professionals (but
not to the general public) may contain as additional indications
postoperative gas pain or for use in endoscopic examination.
(b) Professional labeling for an antiflatulent-antacid combination
may contain information allowed for health professionals for antacids
and antiflatulents.
21 CFR 332.31 PART 333 -- TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 332.31 Subpart A -- (Reserved)
21 CFR 332.31 Subpart B -- First Aid Antibiotic Drug Products
Sec.
333.101 Scope.
333.103 Definitions.
333.110 First aid antibiotic active ingredients.
333.120 Permitted combinations of active ingredients.
333.150 Labeling of first aid antibiotic drug products.
333.160 Labeling of permitted combinations of active ingredients.
21 CFR 332.31 Subpart C -- (Reserved)
21 CFR 332.31 Subpart D -- Topical Acne Drug Products (Eff. 8-16-92)
333.301 Scope.
333.303 Definitions.
333.310 Acne active ingredients.
333.320 Permitted combinations of active ingredients.
333.350 Labeling of acne drug products.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371), unless otherwise noted.
Source: 52 FR 47322, Dec. 11, 1987, unless otherwise noted.
21 CFR 332.31 Subpart A -- (Reserved)
21 CFR 332.31 Subpart B -- First Aid Antibiotic Drug Products
21 CFR 333.101 Scope.
(a) An over-the-counter first aid antibiotic drug product in a form
suitable for topical administration is generally recognized as safe and
effective and is not misbranded if it meets each of the conditions in
this subpart and each of the general conditions established in 330.1.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 333.103 Definitions.
As used in this subpart:
(a) Antibiotic drug. In accordance with section 507(a) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 357(a)), ''any drug
intended for use by man containing any quantity of any chemical
substance which is produced by a microorganism and which has the
capacity to inhibit or destroy microorganisms in dilute solution
(including the chemically synthesized equivalent of any such
substance).''
(b) First aid antibiotic. An antibiotic-containing drug product
applied topically to the skin to help prevent infection in minor cuts,
scrapes, and burns.
21 CFR 333.110 First aid antibiotic active ingredients.
The product consists of any of the following active ingredients
within the specified concentration established for each ingredient and
in the specified dosage form:
(a) Bacitracin ointment containing, in each gram, 500 units of
bacitracin in a suitable ointment base: Provided, That it meets the
tests and methods of assay in 448.510a(b).
(b) Bacitracin zinc ointment containing, in each gram, 500 units of
bacitracin zinc in a suitable ointment base: Provided, That it meets
the tests and methods of assay in 448.513f(b).
(c) Chlortetracycline hydrochloride ointment containing, in each
gram, 30 milligrams of chlortetracycline hydrochloride in a suitable
ointment base: Provided, That it meets the tests and methods of assay
in 446.510(b).
(d) Neomycin sulfate ointment containing, in each gram, 3.5
milligrams of neomycin in a suitable water soluble or oleaginous
ointment base: Provided, That it meets the tests and methods of assay
in 444.542a(b).
(e) Neomycin sulfate cream containing, in each gram, 3.5 milligrams
of neomycin in a suitable cream base: Provided, that it meets the tests
and methods of assay in 444.542b(b).
(f) Tetracycline hydrochloride ointment containing, in each gram, 30
milligrams of tetracycline hydrochloride in a suitable ointment base:
Provided, That it meets the tests and methods of assay in 446.581d(b).
(52 FR 47322, Dec. 11, 1987, as amended at 53 FR 18838, May 25, 1988)
21 CFR 333.120 Permitted combinations of active ingredients.
The following combinations are permitted provided each active
ingredient is present within the established concentration and in the
specified dosage form, and the product is labeled in accordance with
333.160.
(a) Combinations of antibiotic active ingredients. (1)
Bacitracin-neomycin sulfate ointment containing, in each gram, 500 units
of bacitracin and 3.5 milligrams of neomycin in a suitable ointment
base: Provided, That it meets the tests and methods of assay in
448.510d(b).
(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment
containing, in each gram, in a suitable ointment base the following:
(i) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000
units of polymyxin B; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000
units of polymyxin B;
Provided, That it meets the tests and methods of assay in
448.510e(b).
(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in
each gram, 500 units of bacitracin and 5,000 units of polymyxin B in a
suitable vehicle, packaged in a pressurized container with suitable
inert gases: Provided, That it meets the tests and methods of assay in
448.510f(b).
(4) Bacitracin zinc-neomycin sulfate ointment containing, in each
gram, 500 units of bacitracin and 3.5 milligrams of neomycin in a
suitable ointment base: Provided, That it meets the tests and methods
of assay in 448.513b(b).
(5) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment
containing, in each gram, in a suitable ointment base the following:
(i) 400 units of bacitracin, 3 milligrams of neomycin, and 8,000
units of polymyxin B; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000
units of polymyxin B; or
(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000
units of polymyxin B; or
(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, and 10,000
units of polymyxin B;
Provided, That it meets the tests and methods of assay in
448.513c(b).
(6) Bacitracin zinc-polymyxin B sulfate ointment containing, in each
gram, 500 units of bacitracin and 10,000 units of polymyxin B in a
suitable ointment base: Provided, That it meets the tests and methods
assay in 448.513a(b).
(7) Bacitracin zinc-polymyxin B sulfate topical aerosol containing,
in each gram, 120 units of bacitracin and 2,350 units of polymyxin B in
a suitable vehicle, packaged in a pressurized container with suitable
inert gases: Provided, That is meets the tests and methods of assay in
448.513e(b) of this chapter.
(8) Bacitracin zinc-polymyxin B sulfate topical powder containing, in
each gram, 500 units of bacitracin and 10,000 units of polymyxin B in a
suitable base: Provided, That it meets the tests and methods of assay
in 448.513d(b).
(9) Neomycin sulfate-polymyxin B sulfate ointment containing, in each
gram, 3.5 milligrams of neomycin and 5,000 units of polymyxin B in a
suitable water miscible base: Provided, That it meets the tests and
methods of assay in 444.542e(b).
(10) Neomycin sulfate-polymyxin B sulfate cream containing, in each
gram, 3.5 milligrams of neomycin and 10,000 units of polymyxin B in a
suitable vehicle: Provided, that it meets the tests, methods of assay,
and potency in 444.5421(b).
(11) Oxytetracycline hydrochloride-polymyxin B sulfate ointment
containing, in each gram, 30 milligrams of oxytetracycline and 10,000
units of polymyxin B in a suitable ointment base: Provided, That it
meets the tests and methods assay in 446.567b(b).
(12) Oxytetracycline hydrochloride-polymyxin B sulfate topical powder
containing, in each gram, 30 milligrams of oxytetracycline and 10,000
units of polymyxin B with a suitable filler: Provided, That it meets
the tests and methods assay in 446.567c(b).
(b) Combinations of first aid antibiotic active ingredients and local
anesthetic active ingredients.
(1) Bacitracin ointment containing, in each gram, 500 units of
bacitracin and any single generally recognized as safe and effective
amine or ''caine''-type local anesthetic active ingredient in a suitable
ointment base: Provided, That it meets the tests and methods of assay
in 448.510a(b).
(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment
containing, in each gram, in a suitable ointment base the following:
(i) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units
of polymyxin B, and any single generally recognized as safe and
effective amine or ''caine''-type local anesthetic active ingredient;
or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units
of polymyxin B, and any single generally recognized as safe and
effective amine or ''caine''-type local anesthetic active ingredient.
Provided, That it meets the tests and methods of assay in
448.510e(b).
(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in
each gram, 500 units of bacitracin and 5,000 units of polymyxin B and
any single generally recognized as safe and effective amine or
''caine''-type local anesthetic active ingredient in a suitable vehicle,
packaged in a pressurized container with suitable inert gases:
Provided, That it meets the tests and methods of assay in 448.510f(b)
of this chapter.
(4) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment
containing, in each gram, in a suitable ointment base the following:
(i) 400 units of bacitracin, 3 milligrams of neomycin, 8,000 units of
polymyxin B, and any single generally recognized as safe and effective
amine or ''caine''-type local anesthetic active ingredient; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units
of polymyxin B, and any single generally recognized as safe and
effective amine or ''caine''-type local anesthetic active ingredient;
or
(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000
units of polymyxin B, and any single generally recognized as safe and
effective amine or ''caine''-type local anesthetic active ingredient;
or
(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, 10,000
units of polymyxin B, and any single generally recognized as safe and
effective amine or ''caine''-type local anesthetic active ingredieint;
Provided, That it meets the tests and methods of assay in
448.513c(b) of this chapter.
(5) Bacitracin zinc-polymyxin B sulfate ointment containing, in each
gram, 500 units of bacitracin, 10,000 units of polymyxin B, and any
single generally recognized as safe and effective amine or
''caine''-type local anesthetic active ingredient in a suitable ointment
base: Provided, That it meets the tests and methods of assay in
448.513a(b) of this chapter.
(6) Neomycin sulfate-polymyxin B sulfate cream containing, in each
gram, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any
single generally recognized as safe and effective amine or
''caine''-type local anesthetic active ingredient in a suitable vehicle:
Provided, That it meets the tests and methods of assay in 444.542l(b)
of this chapter.
(52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. 24, 1987, as amended
at 53 FR 18838, May 25, 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381,
Oct. 3, 1990; 55 FR 50172, Dec. 5, 1990)
21 CFR 333.150 Labeling of first aid antibiotic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''first aid antibiotic.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''First aid to help'' (select
one of the following: ''prevent,'' (''decrease'' (''the risk of'' or
''the chance of'')), (''reduce'' (''the risk of'' or ''the chance
of'')), ''guard against,'' or ''protect against'') (select one of the
following: ''infection,'' ''bacterial contamination,'' or ''skin
infection'') ''in minor cuts, scrapes, and burns.'' Other truthful and
nonmisleading statements describing only the indications for use that
have been established and listed in this paragraph (b), may also be
used, as provided in 330.1(c)(2), subject to the provisions of section
502 of the act relating to misbranding and the prohibition in section
301(d) of the act against the introduction or delivery for introduction
into interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''For external use only. Do not use in the eyes or apply over
large areas of the body. In case of deep or puncture wounds, animal
bites, or serious burns, consult a doctor.''
(2) ''Stop use and consult a doctor if the condition persists or gets
worse. Do not use longer than 1 week unless directed by doctor.''
(d) Directions. The labeling of the product contains the following
statements under the heading ''Directions'': (1) For ointment and cream
products. ''Clean the affected area. Apply a small amount of this
product (an amount equal to the surface area of the tip of a finger) on
the area 1 to 3 times daily. May be covered with a sterile bandage.''
(2) For powder products. ''Clean the affected area. Apply a light
dusting of the powder on the area 1 to 3 times daily. May be covered
with a sterile bandage.''
(3) For aerosol products. ''Clean the affected area. Spray a small
amount of this product on the area 1 to 3 times daily. May be covered
with a sterile bandage.''
(e) The word ''doctor'' may be substituted for the word ''physician''
in any of the labeling statements in this subpart.
21 CFR 333.160 Labeling of permitted combinations of active
ingredients.
Statements of identity, indications, warnings, and directions for
use, respectively, applicable to each ingredient in the product may be
combined to eliminate duplicative words or phrases so that the resulting
information is clear and understandable.
(a) Statement of identity. For a combination drug product that has
an established name, the labeling of the product states the established
name of the combination drug product, followed by the statement of
identity for each ingredient in the combination, as established in the
statement of identity sections of the applicable OTC drug monographs.
For a combination drug product that does not have an established name,
the labeling of the product states the statement of identity for each
ingredient in the combination, as established in the statement of
identity sections of the applicable OTC drug monographs.
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the indication(s) for each ingredient in the
combination, as established in the ''Indications'' sections of the
applicable OTC drug monographs, unless otherwise stated in this
paragraph. Other truthful and nonmisleading statements, describing only
the indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2), subject to
the provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(1) For permitted combinations identified in 333.120(a). The
indications in 333.150 should be used.
(2) For permitted combinations identified in 333.120(b). In addition
to the required indication identified in 333.150, the labeling of the
product may state, under the heading ''Indications,'' the following
additional indication: ''First aid for the temporary relief of''
(select one of the following: ''pain,'' ''discomfort,'' ''pain or
discomfort'' or ''pain and itching'') ''in minor cuts, scrapes, and
burns.''
(c) Warnings. The labeling of the product states, under the heading
''Warnings,'' the warning(s) for each ingredient in the combination, as
established in the warnings sections of the applicable OTC drug
monographs.
(d) Directions. The labeling of the product states, under the
heading ''Directions,'' directions that conform to the directions
established for each ingredient in the directions sections of the
applicable OTC drug monographs. When the time intervals or age
limitations for administrations of the individual ingredients differ,
the directions for the combination product may not exceed any maximum
dosage limits established for the individual ingredients in the
applicable OTC drug monograph.
21 CFR 333.160 Subpart C -- (Reserved)
21 CFR 333.160 Subpart D -- Topical Acne Drug Products
Source: 56 FR 41019, Aug. 16, 1991, unless otherwise noted.
Effective Date Note: At 56 FR 41019, Aug. 16, 1991, 333.301 --
333.350 (subpart D) was added effective August 16, 1992.
21 CFR 333.301 Scope.
(a) An over-the-counter acne drug product in a form suitable for
topical application is generally recognized as safe and effective and is
not misbranded if it meets each of the conditions in this subpart and
each general condition established in 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21 unless otherwise noted.
21 CFR 333.303 Definitions.
As used in this subpart:
(a) Acne. A disease involving the oil glands and hair follicles of
the skin which is manifested by blackheads, whiteheads, acne pimples,
and acne blemishes.
(b) Acne blemish. A flaw in the skin resulting from acne.
(c) Acne drug product. A drug product used to reduce the number of
acne blemishes, acne pimples, blackheads, and whiteheads.
(d) Acne pimple. A small, prominent, inflamed elevation of the skin
resulting from acne.
(e) Blackhead. A condition of the skin that occurs in acne and is
characterized by a black tip.
(f) Whitehead. A condition of the skin that occurs in acne and is
characterized by a small, firm, whitish elevation of the skin.
21 CFR 333.310 Acne active ingredients.
The active ingredient of the product consists of any of the following
when labeled according to 333.350.
(a) Resorcinol 2 percent when combined in accordance with
333.320(a).
(b) Resorcinol monoacetate 3 percent when combined in accordance with
333.320(b).
(c) Salicylic acid 0.5 to 2 percent.
(d) Sulfur 3 to 10 percent.
(e) Sulfur 3 to 8 percent when combined in accordance with 333.320.
21 CFR 333.320 Permitted combinations of active ingredients.
(a) Resorcinol identified in 333.310(a) when combined with sulfur
identified in 333.310(e) provided the product is labeled according to
333.350.
(b) Resorcinol monoacetate identified in 333.310(b) when combined
with sulfur identified in 333.310(e) provided the product is labeled
according to 333.350.
21 CFR 333.350 Labeling of acne drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''acne medication,'' ''acne treatment,'' ''acne medication'' (insert
dosage form, e.g., ''cream,'' ''gel,'' ''lotion,'' or ''ointment''), or
''acne treatment'' (insert dosage form, e.g., ''cream,'' ''gel,''
''lotion,'' or ''ointment'').
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the phrase listed in paragraph (b)(1) of this
section and may contain any of the additional phrases listed in
paragraph (b)(2) of this section. Other truthful and nonmisleading
statements, describing only the indications for use that have been
established and listed in paragraph (b) of this section, may also be
used, as provided in 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
(the act) relating to misbranding and the prohibition in section 301(d)
of the act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(1) ''For the'' (select one of the following: ''management'' or
''treatment'') ''of acne.''
(2) In addition to the information identified in paragraph (b)(1) of
this section, the labeling of the product may contain any one or more of
the following statements:
(i) (Select one of the following: ''Clears,'' ''Clears up,''
''Clears up most,'' ''Dries,'' ''Dries up,'' ''Dries and clears,''
''Helps clear,'' ''Helps clear up,'' ''Reduces the number of,'' or
''Reduces the severity of'') (select one or more of the following:
''acne blemishes,'' ''acne pimples,'' ''blackheads,'' or ''whiteheads'')
which may be followed by ''and allows skin to heal.''
(ii) ''Penetrates pores to'' (select one of the following:
''eliminate most,'' ''control,'' ''clear most,'' or ''reduce the number
of'') (select one or more of the following: ''acne blemishes,'' ''acne
pimples,'' ''blackheads,'' or ''whiteheads'').
(iii) ''Helps keep skin clear of new'' (select one or more of the
following: ''acne blemishes,'' ''acne pimples,'' ''blackheads,'' or
''whiteheads'').
(iv) ''Helps prevent new'' (select one or more of the following:
''acne blemishes,'' ''acne pimples,'' ''blackheads,'' or ''whiteheads'')
which may be followed by ''from forming.''
(v) ''Helps prevent the development of new'' (select one or more of
the following: ''acne blemishes,'' ''acne pimples,'' ''blackheads,'' or
''whiteheads'').
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) For products containing any ingredient identified in 333.310.
(i) ''For external use only.''
(ii) ''Using other topical acne medications at the same time or
immediately following use of this product may increase dryness or
irritation of the skin. If this occurs, only one medication should be
used unless directed by a doctor.''
(2) For products containing sulfur identified in 333.310 (d) and
(e). ''Do not get into eyes. If excessive skin irritation develops or
increases, discontinue use and consult a doctor.''
(3) For products containing any combination identified in 333.320.
''Apply to affected areas only. Do not use on broken skin or apply to
large areas of the body.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) ''Cleanse the skin thoroughly before applying medication. Cover
the entire affected area with a thin layer one to three times daily.
Because excessive drying of the skin may occur, start with one
application daily, then gradually increase to two or three times daily
if needed or as directed by a doctor. If bothersome dryness or peeling
occurs, reduce application to once a day or every other day.''
(2) The directions described in paragraph (d)(1) of this section are
intended for products that are applied and left on the skin. Other
products, such as soaps or masks, may be applied and removed and should
have appropriate directions.
(3) Optional directions. In addition to the required directions in
paragraphs (d)(1) and (d)(2) of this section, the product may contain
the following optional labeling: ''Sensitivity Test for a New User.
Apply product sparingly to one or two small affected areas during the
first 3 days. If no discomfort occurs, follow the directions stated:
(select one of the following: 'elsewhere on this label,' 'above,' or
'below.')''
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
21 CFR 333.350 PART 336 -- ANTIEMETIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 333.350 Subpart A -- General Provisions
Sec.
336.1 Scope.
336.3 Definition.
21 CFR 333.350 Subpart B -- Active Ingredients
336.10 Antiemetic active ingredients.
21 CFR 333.350 Subpart C -- Labeling
336.50 Labeling of antiemetic drug products.
336.80 Professional labeling.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 52 FR 15892, Apr. 30, 1987, unless otherwise noted.
21 CFR 333.350 Subpart A -- General Provisions
21 CFR 336.1 Scope.
(a) An over-the-counter antiemetic drug product in a form suitable
for oral administration is generally recognized as safe and effective
and is not misbranded if it meets each of the conditions in this part
and each of the general conditions established in 330.1.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 336.3 Definition.
As used in this part:
Antiemetic. An agent that prevents or treats nausea and vomiting.
21 CFR 336.3 Subpart B -- Active Ingredients
21 CFR 336.10 Antiemetic active ingredients.
The active ingredient of the product consists of any of the following
when used within the dosage limits established for each ingredient in
336.50(d):
(a) Cyclizine hydrochloride.
(b) Dimenhydrinate.
(c) Diphenhydramine hydrochloride.
(d) Meclizine hydrochloride.
21 CFR 336.10 Subpart C -- Labeling
21 CFR 336.50 Labeling of antiemetic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''antiemetic.''
(b) Indications. The labeling of the product states the following
under the heading ''Indications,'' ''For the prevention and treatment of
the nausea, vomiting, or dizziness associated with motion sickness.''
Other truthful and nonmisleading statements, describing only the
indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2), subject to
the provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings:''
(1) For products containing any ingredient identified in 336.10.
''Do not take this product if you have asthma, glaucoma, emphysema,
chronic pulmonary disease, shortness of breath, difficulty in breathing,
or difficulty in urination due to enlargement of the prostate gland
unless directed by a doctor.''
(2) For products containing cyclizine hydrochloride identified in
336.10(a). ''Do not give to children under 6 years of age unless
directed by a doctor.''
(3) For products containing dimenhydrinate identified in 336.10(b).
''Do not give to children under 2 years of age unless directed by a
doctor.''
(4) For products containing diphenhydramine hydrochloride identified
in 336.10(c). ''Do not give to children under 6 years of age unless
directed by a doctor.''
(5) For products containing meclizine hydrochloride identified in
336.10(d). ''Do not give to children under 12 years of age unless
directed by a doctor.''
(6) For products containing cyclizine hydrochloride identified in
336.10(a) or meclizine hydrochloride identified in 330.10(d). ''May
cause drowsiness; alcohol, sedatives, and tranquilizers may increase
the drowsiness effect. Avoid alcoholic beverages while taking this
product. Do not take this product if you are taking sedatives or
tranquilizers, without first consulting your doctor. Use caution when
driving a motor vehicle or operating machinery.''
(7) For products containing dimenhydrinate identified in 336.10(b)
or diphenhydramine hydrochloride identified in 336.10(c). ''May cause
marked drowsiness; alcohol, sedatives, and tranquilizers may increase
the drowsiness effect. Avoid alcoholic beverages while taking this
product. Do not take this product if you are taking sedatives or
tranquilizers, without first consulting your doctor. Use caution when
driving a motor vehicle or operating machinery.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For products containing cyclizine hydrochloride identified in
336.10(a). Adults and children 12 years of age and over: Oral dosage is
50 milligrams every 4 to 6 hours, not to exceed 200 milligrams in 24
hours, or as directed by a doctor. Children 6 to under 12 years of age:
Oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 75
milligrams in 24 hours, or as directed by a doctor.
(2) For products containing dimenhydrinate identified in 336.10(b).
Adults and children 12 years of age and over: Oral dosage is 50 to 100
milligrams every 4 to 6 hours, not to exceed 400 milligrams in 24 hours,
or as directed by a doctor. Children 6 to under 12 years of age: Oral
dosage is 25 to 50 milligrams every 6 to 8 hours, not to exceed 150
milligrams in 24 hours, or as directed by a doctor. Children 2 to under
6 years of age: Oral dosage is 12.5 to 25 milligrams every 6 to 8
hours, not to exceed 75 milligrams in 24 hours, or as directed by a
doctor.
(3) For products containing diphenhydramine hydrochloride identified
in 336.10(c). Adults and children 12 years of age and over: Oral
dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300
milligrams in 24 hours, or as directed by a doctor. Children 6 to under
12 years of age: Oral dosage is 12.5 to 25 milligrams every 4 to 6
hours, not to exceed 150 milligrams in 24 hours, or as directed by a
doctor.
(4) For products containing meclizine hydrochloride identified in
336.10(d). Adults and children 12 years of age and over: Oral dosage is
25 to 50 milligrams once daily, or as directed by a doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(52 FR 15892, Apr. 30, 1987, as amended at 53 FR 35809, Sept. 15,
1988)
21 CFR 336.80 Professional labeling.
The labeling provided to health professionals (but not to the general
public) may contain the following additional indications.
(a) For products containing cyclizine hydrochloride, dimenhydrinate,
and diphenhydramine hydrochloride identified in 336.10 (a), (b), and
(c). ''For the treatment of vertigo of motion sickness.''
(b) For products containing meclizine hydrochloride identified in
336.10(d). ''For the treatment of vertigo.''
21 CFR 336.80 PART 338 -- NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 336.80 Subpart A -- General Provisions
Sec.
338.1 Scope.
338.3 Definition.
21 CFR 336.80 Subpart B -- Active Ingredients
338.10 Nighttime sleep-aid active ingredients.
21 CFR 336.80 Subpart C -- Labeling
338.50 Labeling of nighttime sleep-aid drug products.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 54 FR 6826, Feb. 14, 1989, unless otherwise noted.
21 CFR 336.80 Subpart A -- General Provisions
21 CFR 338.1 Scope.
(a) An over-the-counter nighttime sleep-aid drug product in a form
suitable for oral administration is generally recognized as safe and
effective and is not misbranded if it meets each condition in this part
and each general condition established in 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 338.3 Definition.
As used in this part:
Nighttime sleep-aid. A drug that is useful for the relief of
occasional sleeplessness by individuals who have difficulty falling
asleep.
21 CFR 338.3 Subpart B -- Active Ingredients
21 CFR 338.10 Nighttime sleep-aid active ingredients.
The active ingredient of the product consists of any of the following
when used within the dosage limits established for each ingredient in
338.50(d):
(a) Diphenhydramine hydrochloride.
(b) Diphenhydramine citrate.
21 CFR 338.10 Subpart C -- Labeling
21 CFR 338.50 Labeling of nighttime sleep-aid drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''nighttime sleep-aid.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' one or more of the phrases listed in this
paragraph. Other truthful and nonmisleading statements, describing only
the indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2) of this
chapter, subject to the provisions of section 502 of the act relating to
misbranding and the prohibition in section 301(d) of the act against the
introduction or delivery for introduction into interstate commerce of
unapproved new drugs in violation of section 505(a) of the act.
(1) (''Helps you'' or ''Reduces time to'') ''fall asleep if you have
difficulty falling asleep.''
(2) ''For relief of occasional sleeplessness.''
(3) ''Helps to reduce difficulty falling asleep.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''Do not give to children under 12 years of age.''
(2) ''If sleeplessness persists continuously for more than 2 weeks,
consult your doctor. Insomnia may be a symptom of serious underlying
medical illness.''
(3) ''Do not take this product if you have asthma, glaucoma,
emphysema, chronic pulmonary disease, shortness of breath, difficulty in
breathing, or difficulty in urination due to enlargement of the prostate
gland unless directed by a doctor.''
(4) ''Avoid alcoholic beverages while taking this product. Do not
take this product if you are taking sedatives or tranquilizers, without
first consulting your doctor.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For products containing diphenhydramine hydrochloride identified
in 338.10(a). Adults and children 12 years of age and over: Oral
dosage is 50 milligrams at bedtime if needed, or as directed by a
doctor.
(2) For products containing diphenhydramine citrate identified in
338.10(b). Adults and children 12 years of age and over: Oral dosage is
76 milligrams at bedtime if needed, or as directed by a doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
21 CFR 338.50 PART 340 -- STIMULANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 338.50 Subpart A -- General Provisions
Sec.
340.1 Scope.
340.3 Definition.
21 CFR 338.50 Subpart B -- Active Ingredient
340.10 Stimulant active ingredient.
21 CFR 338.50 Subpart C -- Labeling
340.50 Labeling of stimulant drug products.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 53 FR 6105, Feb. 29, 1988, unless otherwise noted.
21 CFR 338.50 Subpart A -- General Provisions
21 CFR 340.1 Scope.
(a) An over-the-counter stimulant drug product in a form suitable for
oral administration is generally recognized as safe and effective and is
not misbranded if it meets each of the conditions in this part and each
of the general conditions established in 330.1.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 340.3 Definition.
As used in this part:
Stimulant. A drug which helps restore mental alertness or wakefulness
during fatigue or drowsiness.
21 CFR 340.3 Subpart B -- Active Ingredient
21 CFR 340.10 Stimulant active ingredient.
The active ingredient of the product consists of caffeine when used
within the dosage limits established in 340.50(d).
21 CFR 340.10 Subpart C -- Labeling
21 CFR 340.50 Labeling of stimulant drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''altertness aid'' or a ''stimulant.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''Helps restore mental
alertness or wakefulness when experiencing fatigue or drowsiness.''
Other truthful and nonmisleading statements, describing only the
indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2), subject to
the provisions of section 502 of the Act relating to misbranding and the
prohibition in section 301(d) of the Act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the Act.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''The recommended dose of this product contains about as much
caffeine as a cup of coffee. Limit the use of caffeine-containing
medications, foods, or beverages while taking this product because too
much caffeine may cause nervousness, irritability, sleeplessness, and,
occasionally, rapid heart beat.''
(2) ''For occasional use only. Not intended for use as a substitute
for sleep. If fatigue or drowsiness persists or continues to recur,
consult a'' (select one of the following: ''physician'' or ''doctor'').
(3) ''Do not give to children under 12 years of age.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Adults and children 12
years of age and over: Oral dosage is 100 to 200 milligrams not more
often than every 3 to 4 hours.
21 CFR 340.50 PART 341 -- COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 340.50 Subpart A -- General Provisions
Sec.
341.1 Scope.
341.3 Definitions.
21 CFR 340.50 Subpart B -- Active Ingredients
341.14 Antitussive active ingredients.
341.16 Bronchodilator active ingredients.
341.18 Expectorant active ingredient.
21 CFR 340.50 Subpart C -- Labeling
341.74 Labeling of antitussive drug products.
341.76 Labeling of bronchodilator drug products.
341.78 Labeling of expectorant drug products.
341.90 Professional labeling.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
21 CFR 340.50 Subpart A -- General Provisions
21 CFR 341.1 Scope.
(a) An over-the-counter cold, cough, allergy, bronchodilator, or
antiasthmatic drug product in a form suitable for oral, inhalant, or
topical administration is generally recognized as safe and effective and
is not misbranded if it meets each of the conditions in this part and
each of the general conditions established in 330.1.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
(51 FR 35339, Oct. 2, 1986)
21 CFR 341.3 Definitions.
As used in this part:
(a) Bronchodilator drug. A drug used to overcome spasms that cause
narrowing of the bronchial air tubes, such as in the symptomatic
treatment of the wheezing and shortness of breath of asthma.
(b) Oral antitussive drug. A drug that either is taken by mouth or
is dissolved in the mouth in the form of a lozenge and acts systemically
to relieve cough.
(c) Topical antitussive drug. A drug that relieves cough when
inhaled after being applied topically to the throat or chest in the form
of an ointment or from a steam vaporizer, or when dissolved in the mouth
in the form of a lozenge for a local effect.
(d) Expectorant drug. A drug taken orally to promote or facilitate
the removal of secretions from the respiratory airways.
(51 FR 35339, Oct. 2, 1986, as amended at 54 FR 8509, Feb. 28, 1989;
55 FR 40382, Oct. 3, 1990)
21 CFR 341.3 Subpart B -- Active Ingredients
21 CFR 341.14 Antitussive active ingredients.
The active ingredients of the product consist of any of the following
when used within the dosage limits and in the dosage forms established
for each ingredient in 341.74(d):
(a) Oral antitussives. (1) Chlophedianol hydrochloride.
(2) Codeine ingredients. The following ingredients may be used only
in combination in accordance with 329.20(a) and 341.40 and 21 CFR
1308.15(c).
(i) Codeine.
(ii) Codeine phosphate.
(iii) Codeine sulfate.
(3) Dextromethorphan.
(4) Dextromethorphan hydrobromide.
(b) Topical antitussives.
(1) Camphor.
(2) Menthol.
(52 FR 30055, Aug. 12, 1987)
21 CFR 341.16 Bronchodilator active ingredients.
The active ingredients of the product consist of any of the following
when used within the dosage limits established for each ingredient:
(a) Ephedrine.
(b) Ephedrine hydrochloride.
(c) Ephedrine sulfate.
(d) Epinephrine.
(e) Epinephrine bitartrate.
(f) Racephedrine hydrochloride.
(g) Racepinephrine hydrochloride.
(51 FR 35339, Oct. 2, 1986)
21 CFR 341.18 Expectorant active ingredient.
The active ingredient of the product is guaifenesin when used within
the dosage limits established in 341.78(d).
(54 FR 8509, Feb. 28, 1989)
21 CFR 341.18 Subpart C -- Labeling
21 CFR 341.74 Labeling of antitussive drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''cough suppressant'' or an ''antitussive (cough suppressant).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' any of the phrases listed in this paragraph
(b), as appropriate. Other truthful and nonmisleading statements,
describing only the indications for use that have been established and
listed in this paragraph, may also be used, as provided in 330.1(c)(2),
subject to the provisions of section 502 of the act relating to
misbranding and the prohibition in section 301(d) of the act against the
introduction or delivery for introduction into interstate commerce of
unapproved new drugs in violation of section 505(a) of the act.
(1) ''Temporarily'' (select one of the following: ''alleviates,''
''calms,'' ''controls,'' ''decreases,'' ''quiets,'' ''reduces,''
''relieves,'' or ''suppresses'') ''cough due to'' (select one of the
following: ''minor bronchial irritation'' or ''minor throat and
bronchial irritation'') (select one of the following: ''as may occur
with,'' ''associated with,'' or ''occurring with'') (select one of the
following: ''A cold'' or ''the common cold'') ''or inhaled irritants.''
(2) ''Temporarily'' (select one of the following: ''alleviates,''
''calms,'' ''controls,'' ''decreases,'' ''quiets,'' ''reduces,''
''relieves,'' or ''suppresses'') ''cough'' (select one of the following:
''as may occur with,'' ''associated with,'' or ''occurring with'')
(select one of the following: ''A cold,'' ''the common cold,'' or
''inhaled irritants'').
(3) In addition to the required information identified in paragraphs
(b) (1) and (2) of this section, the labeling of the product may contain
any (one or more) of the following statements:
(i) ''Cough suppressant which temporarily'' (select one of the
following: ''Alleviates,'' ''controls,'' ''decreases,'' ''reduces,''
''relieves,'' or ''suppresses'') ''the impulse to cough.''
(ii) ''Temporarily helps you cough less.''
(iii) ''Temporarily helps to'' (select one of the following:
''Alleviate,'' ''control,'' ''decrease,'' ''reduce,'' ''relieve,'' or
''suppress'') ''the cough reflex that causes coughing.''
(iv) ''Temporarily'' (select one of the following: ''Alleviates,''
''controls,'' ''decreases,'' ''reduces,'' ''relieves,'' or
''suppresses'') ''the intensity of coughing.''
(v) (Select one of the following: ''Alleviates,'' ''Controls,''
''Decreases,'' ''Reduces,'' ''Relieves,'' or ''Suppresses'') (select one
of the following: ''Cough,'' ''the impulse to cough,'' or ''your
cough'') ''to help you'' (select one of the following: ''Get to
sleep,'' ''sleep,'' or ''rest'').
(vi) For products containing chlophedianol hydrochloride, codeine
ingredients, dextromethorphan, or dextromethorphan hydrobromide
identified in 341.14(a) (1), (2), (3), and (4). ''Calms the cough
control center and relieves coughing.''
(vii) For products containing chlophedianol hydrochloride,
dextromethorphan, dextromethorphan hydrobromide, camphor, or menthol
identified in 341.14(a) (1), (3), (4) and (b) (1) and (2). (a)
''Nonnarcotic cough suppressant for the temporary'' (select one of the
following: ''alleviation,'' ''control,'' ''decrease,'' ''reduction,''
''relief,'' or ''suppression'') ''of cough.''
(b) (Select one of the following: ''Alleviates,'' ''Controls,''
''Decreases,'' ''Reduces,'' ''Relieves,'' or ''Suppresses'') ''cough
impulses without narcotics.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) For oral and topical antitussives. ''A persistent cough may be a
sign of a serious condition. If cough persists for more than 1 week,
tends to recur, or is accompanied by fever, rash, or persistent
headache, consult a doctor.''
(2) For oral and topical antitussives labeled for adults or for
adults and children under 12 years of age. ''Do not take this product
for persistent or chronic cough such as occurs with smoking, asthma, or
emphysema, or if cough is accompanied by excessive phlegm (mucus) unless
directed by a doctor.''
(3) For oral and topical antitussives labeled only for children under
12 years of age. ''Do not give this product for persistent or chronic
cough such as occurs with asthma or if cough is accompanied by excessive
phlegm (mucus) unless directed by a doctor.''
(4) Oral antitussives -- (i) For products containing codeine
ingredients identified in 341.14(a)(2). ''May cause or aggravate
constipation.''
(ii) For products containing codeine ingredients identified in
341.14(a)(2) when labeled only for adults. ''Do not take this product
if you have a chronic pulmonary disease or shortness of breath unless
directed by a doctor.''
(iii) For products containing codeine ingredients identified in
341.14(a)(2) when labeled only for children under 12 years of age. ''Do
not give this product to children who have a chronic pulmonary disease,
shortness of breath, or who are taking other drugs unless directed by a
doctor.''
(iv) For products containing codeine ingredients identified in
341.14(a)(2) when labeled for use in adults and children under 12 years
of age. ''Adults and children who have a chronic pulmonary disease or
shortness of breath, or children who are taking other drugs, should not
take this product unless directed by a doctor.''
(5) Topical antitussives -- (i) For products containing camphor or
menthol identified in 341.14(b) (1) and (2) in a suitable ointment
vehicle. ''For external use only. Do not take by mouth or place in
nostrils.''
(ii) For products containing camphor or menthol identified in
341.14(b) (1) and (2) for steam inhalation use. ''For steam inhalation
only. Do not take by mouth.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) Oral antitussives -- (i) For products containing chlophedianol
hydrochloride identified in 341.14(a)(1). Adults and children 12 years
of age and over: Oral dosage is 25 milligrams every 6 to 8 hours, not
to exceed 100 milligrams in 24 hours, or as directed by a doctor.
Children 6 to under 12 years of age: Oral dosage is 12.5 milligrams
every 6 to 8 hours, not to exceed 50 milligrams in 24 hours, or as
directed by a doctor. Children under 6 years of age: Consult a doctor.
(ii) For products containing codeine ingredients identified in
341.14(a)(2). Adults and children 12 years of age and over: Oral dosage
is 10 to 20 milligrams every 4 to 6 hours, not to exceed 120 milligrams
in 24 hours, or as directed by a doctor. Children 6 to under 12 years
of age: Oral dosage is 5 to 10 milligrams every 4 to 6 hours, not to
exceed 60 milligrams in 24 hours, or as directed by a doctor. Children
under 6 years of age: Consult a doctor. A special measuring device
should be used to give an accurate dose of this product to children
under 6 years of age. Giving a higher dose than recommended by a doctor
could result in serious side effects for your child.
(iii) For products containing dextromethorphan or dextromethorphan
hydrobromide identified in 341.14(a) (3) and (4). The dosage is
equivalent to dextromethorphan hydrobromide. Adults and children 12
years of age and over: Oral dosage is 10 to 20 milligrams every 4 hours
or 30 milligrams every 6 to 8 hours, not to exceed 120 milligrams in 24
hours, or as directed by a doctor. Children 6 to under 12 years of age:
Oral dosage is 5 to 10 milligrams every 4 hours or 15 milligrams every
6 to 8 hours, not to exceed 60 milligrams in 24 hours, or as directed by
a doctor. Children 2 to under 6 years of age: Oral dosage is 2.5 to 5
milligrams every 4 hours or 7.5 milligrams every 6 to 8 hours, not to
exceed 30 milligrams in 24 hours, or as directed by a doctor. Children
under 2 years of age: Consult a doctor.
(2) Topical antitussives -- (i) For products containing camphor
identified in 341.14(b)(1) in a suitable ointment vehicle. The product
contains 4.7 to 5.3 percent camphor. Adults and children 2 to under 12
years of age: Rub on the throat and chest as a thick layer. The area
of application may be covered with a warm, dry cloth if desired.
However, clothing should be left loose about the throat and chest to
help the vapors rise to reach the nose and mouth. Applications may be
repeated up to three times daily or as directed by a doctor. Children
under 2 years of age: consult a doctor.
(ii) For products containing menthol identified in 341.14(b)(2) in a
suitable ointment vehicle. The product contains 2.6 to 2.8 percent
menthol. Adults and children 2 to under 12 years of age: Rub on the
throat and chest as a thick layer. The area of application may be
covered with a warm, dry cloth if desired. However, clothing should be
left loose about the throat and chest to help the vapors rise to reach
the nose and mouth. Applications may be repeated up to three times
daily or as directed by a doctor. Children under 2 years of age:
consult a doctor.
(iii) For products containing menthol identified in 341.14(b)(2) in
a lozenge. The product contains 5 to 10 milligrams menthol. Adults and
children 2 to under 12 years of age: Allow lozenge to dissolve slowly
in the mouth. May be repeated every hour as needed or as directed by a
doctor. Children under 2 years of age: Consult a doctor.
(iv) For products containing camphor identified in 341.14(b)(1) for
steam inhalation use. The product contains 6.2 percent camphor. Adults
and children 2 to under 12 years of age: Add 1 tablespoonful of
solution, for each quart of water, directly to the water in a hot steam
vaporizer, bowl, or wash basin; or add 1 1/2 teaspoonsful of solution,
for each pint of water, to an open container of boiling water. Breathe
in the medicated vapors. May be repeated up to three times daily or as
directed by a doctor. Children under 2 years of age: consult a doctor.
(v) For products containing menthol identified in 341.14(b)(2) for
steam inhalation use. The product contains 3.2 percent menthol. Adults
and children 2 to under 12 years of age: Add 1 tablespoonful of
solution, for each quart of water, directly to the water in a hot steam
vaporizer, bowl, or wash basin; or add 1 1/2 teaspoonsful of solution,
for each pint of water, to an open container of boiling water. Breathe
in the medicated vapors. May be repeated up to three times daily or as
directed by a doctor. Children under 2 years of age: consult a doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(f) Exemption from the general accidental overdose warning. The
labeling for antitussive drug products containing the active ingredient
identified in 341.14(b)(2) marketed in accordance with
341.74(d)(2)(iii) is exempt from the requirement in 330.1(g) of this
chapter that the labeling bear the general warning statement ''In case
of accidental overdose, seek professional assistance or contact a poison
control center immediately.'' The labeling must continue to bear the
first part of the general warning in 330.1(g) of this chapter, which
states, ''Keep this and all drugs out of the reach of children.''
(52 FR 30055, Aug. 12, 1987; 52 FR 35610, Sept. 22, 1987; 53 FR
35809, Sept. 15, 1988; 55 FR 27808, July 6, 1990; 55 FR 40383, Oct.
3, 1990)
21 CFR 341.76 Labeling of bronchodilator drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''bronchodilator.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the phrase listed in paragraph (b)(1) of this
section. Other truthful and nonmisleading statements, describing only
the indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2), subject to
the provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(1) ''For temporary relief of shortness of breath, tightness of
chest, and wheezing due to bronchial asthma.''
(2) In addition to the required information identified in paragraph
(b)(1) of this section, the labeling of the product may contain one or
more of the following statements:
(i) ''For the'' (select one of the following: ''temporary relief''
or ''symptomatic control'') ''of bronchial asthma.''
(ii) ''Eases breathing for asthma patients'' (which may be followed
by: ''by reducing spasms of bronchial muscles'').
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''Do not use this product unless a diagnosis of asthma has been
made by a doctor.''
(2) ''Do not use this product if you have heart disease, high blood
pressure, thyroid disease, diabetes, or difficulty in urination due to
enlargement of the prostate gland unless directed by a doctor.''
(3) ''Do not use this product if you have ever been hospitalized for
asthma or if you are taking any prescription drug for asthma unless
directed by a doctor.''
(4) ''Drug lnteraction precaution. Do not use this product if you
are presently taking a prescription drug for high blood pressure or
depression, without first consulting your doctor.''
(5) For products containing ephedrine, ephedrine hydrochloride,
ephedrine sulfate, or racephedrine hydrochloride identified in 341.16
(a), (b), (c), and (f). (i) ''Do not continue to use this product, but
seek medical assistance immediately if symptoms are not relieved within
1 hour or become worse.''
(ii) ''Some users of this product may experience nervousness, tremor,
sleeplessness, nausea, and loss of appetite. If these symptoms persist
or become worse, consult your doctor.''
(6) For products containing epinephrine, epinephrine bitartrate, or
racepinephrine hydrochloride identified in 341.16 (d), (e), and (g).
(i) ''Do not use this product more frequently or at higher doses than
recommended unless directed by a doctor. (first sentence in boldface
type) Excessive use may cause nervousness and rapid heart beat, and,
possibly, adverse effects on the heart.''
(ii) ''Do not continue to use this product, but seek medical
assistance immediately if symptoms are not relieved within 20 minutes or
become worse.'' (sentence in boldface type)
(iii) For products intended for use in a hand-held rubber bulb
nebulizer. ''Do not use this product if it is brown in color or
cloudy.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For products containing ephedrine, ephedrine hydrochloride,
ephedrine sulfate, or racephedrine hydrochloride identified in 341.16
(a), (b), (c), and (f). Adults and children 12 years of age and over:
Oral dosage is 12.5 to 25 milligrams every 4 hours, not to exceed 150
milligrams in 24 hours, or as directed by a doctor. Do not exceed
recommended dose unless directed by a doctor. Children under 12 years
of age: Consult a doctor.
(2) For products containing epinephrine, epinephrine bitartrate, and
racepinephrine hydrochloride identified in 341.16 (d), (e), and (g) --
(i) For use in a pressurized metered-dose aerosol container. Each
inhalation contains the equivalent of 0.16 to 0.25 milligram of
epinephrine.
(a) Inhalation dosage for adults, children 12 years of age and over,
and children 4 to under 12 years of age: Start with one inhalation,
then wait at least 1 minute. If not relieved, use once more. Do not
use again for at least 3 hours. The use of this product by children
should be supervised by an adult. Children under 4 years of age:
Consult a doctor.
(b) The labeling must include directions for the proper use of the
inhaler and for the proper care and cleaning of the mouthpiece. The
directions must be clear, direct, and provide the consumer with
sufficient information for the safe and effective use of the product.
(ii) For use in a hand-held rubber bulb nebulizer. The ingredient is
used in an aqueous solution at a concentration equivalent to 1 percent
epinephrine. Inhalation dosage for adults, children 12 years of age and
over, and children 4 to under 12 years of age: 1 to 3 inhalations not
more often than every 3 hours. The use of this product by children
should be supervised by an adult. Children under 4 years of age:
Consult a doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(Collection of information requirement approved by the Office of
Management and Budget under control number 0910-0237)
(51 FR 35339, Oct. 2, 1986, as amended at 52 FR 7126, Mar. 9, 1987;
52 FR 7830, Mar. 13, 1987; 53 FR 35810, Sept. 15, 1988)
21 CFR 341.78 Labeling of expectorant drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''expectorant.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''Helps loosen phlegm (sputum)
and thin bronchial secretions to'' (select one or more of the following:
''rid the bronchial passageways of bothersome mucus,'' ''drain
bronchial tubes,'' and ''make coughs more productive''). Other truthful
and nonmisleading statements, describing only the indications for use
that have been established and listed in this paragraph (b), may also be
used, as provided in 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) Warnings. The labeling of the product contains the following
warnings, under the heading ''Warnings'':
(1) ''Do not take this product for persistent or chronic cough such
as occurs with smoking, asthma, chronic bronchitis, or emphysema, or
where cough is accompanied by excessive phlegm (sputum) unless directed
by a doctor.''
(2) ''A persistent cough may be a sign of a serious condition. If
cough persists for more than 1 week, tends to recur, or is accompanied
by a fever, rash, or persistent headache, consult a doctor.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'' for products containing
guaifenesin identified in 341.18: Adults and children 12 years of age
and over: oral dosage is 200 to 400 milligrams every 4 hours not to
exceed 2,400 milligrams in 24 hours. Children 6 to under 12 years of
age: oral dosage is 100 to 200 milligrams every 4 hours not to exceed
1,200 milligrams in 24 hours. Children 2 to under 6 years of age: oral
dosage is 50 to 100 milligrams every 4 hours not to exceed 600
milligrams in 24 hours. Children under 2 years of age: consult a
doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(54 FR 8509, Feb. 28, 1989)
21 CFR 341.90 Professional labeling.
The labeling of the product provided to health professionals (but not
to the general public) may contain the following additional dosage
information for products containing the active ingredients identified
below:
(a) For products containing ephedrine, ephedrine hydrochloride,
ephedrine sulfate, or racephedrine hydrochloride identified in 341.16
(a), (b), (c), and (f). Children 6 to under 12 years of age: oral
dosage is 6.25 to 12.5 milligrams every 4 hours, not to exceed 75
milligrams in 24 hours. Children 2 to under 6 years of age: oral
dosage is 0.3 to 0.5 milligram per kilogram of body weight every 4
hours, not to exceed 2 milligrams per kilogram of body weight in 24
hours.
(b) For products containing chlophedianol hydrochloride identified in
341.14(a)(1). Children 2 to under 6 years of age: oral dosage is 12.5
milligrams every 6 to 8 hours, not to exceed 50 milligrams in 24 hours.
(c) For products containing codeine ingredients identified in
341.14(a)(2). (1) Children 2 to under 6 years of age: Oral dosage is 1
milligram per kilogram body weight per day administered in four equal
divided doses. The average body weight for each age may also be used to
determine dosage as follows: For children 2 years of age (average body
weight, 12 kilograms), the oral dosage is 3 milligrams every 4 to 6
hours, not to exceed 12 milligrams in 24 hours; for children 3 years of
age (average body weight, 14 kilograms), the oral dosage is 3.5
milligrams every 4 to 6 hours, not to exceed 14 milligrams in 24 hours;
for children 4 years of age (average body weight, 16 kilograms), the
oral dosage is 4 milligrams every 4 to 6 hours, not to exceed 16
milligrams in 24 hours: for children 5 years of age (average body
weight, 18 kilograms), the oral dosage is 4.5 milligrams every 4 to 6
hours, not to exceed 18 milligrams in 24 hours. The manufacturer must
relate these dosages for its specific product dosages for its specific
product to the use of the calibrated measuring device discussed in
paragraph (c)(3) of this section. If age is used to determine the dose,
the directions must include instructions to reduce the dose for
low-weight children.
(2) Parents should be instructed to obtain and use a calibrated
measuring device for administering the drug to the child, to use extreme
care in measuring the dosage, and not exceed the recommended daily
dosage.
(3) A dispensing device (such as a dropper calibrated for age or
weight) should be dispensed along with the product when it is intended
for use in children 2 to under 6 years of age to prevent possible
overdose due to improper measuring of the dose.
(4) Codeine is not recommended for use in children under 2 years of
age. Children under 2 years may be more susceptible to the respiratory
depressant effects of codeine, including respiratory arrest, coma, and
death.
(d) The following labeling indication may be used for products
containing guaifenesin identified in 341.18 when used as a single
ingredient product. ''Helps loosen phlegm and thin bronchial secretions
in patients with stable chronic bronchitis.''
(51 FR 35339, Oct. 2, 1986, as amended at 52 FR 30057, Aug. 12, 1987;
54 FR 8509, Feb. 28, 2989)
21 CFR 341.90 PART 344 -- TOPICAL OTIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 341.90 Subpart A -- General Provisions
Sec.
344.1 Scope.
344.3 Definitions.
21 CFR 341.90 Subpart B -- Active Ingredients
344.10 Topical otic active ingredient.
21 CFR 341.90 Subpart C -- Labeling
344.50 Labeling of topical otic drug products.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 51 FR 28660, Aug. 8, 1986, unless otherwise noted:
21 CFR 341.90 Subpart A -- General Provisions
21 CFR 344.1 Scope.
(a) An over-the-counter topical otic drug product in a form suitable
for topical administration is generally recognized as safe and effective
and is not misbranded if it meets each of the conditions in this part in
addition to each of the general conditions established in 330.1.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 344.3 Definitions.
As used in this part:
(a) Anhydrous glycerin. An ingredient that may be prepared by
heating glycerin U.S.P. at 150 C for 2 hours to drive off the moisture
content.
(b) Earwax removal aid. A drug used in the external ear canal that
aids in the removal of excessive earwax.
21 CFR 344.3 Subpart B -- Active Ingredients
21 CFR 344.10 Topical otic active ingredient.
The active ingredient of the product consists of carbamide peroxide
6.5 percent formulated in an anhydrous glycerin vehicle.
21 CFR 344.10 Subpart C -- Labeling
21 CFR 344.50 Labeling of topical otic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''earwax removal aid.''
(b) Indication. The labeling of the product states, under the
heading ''Indication,'' the following: ''For occasional use as an aid
to'' (which may be followed by: ''soften, loosen, and'') ''remove
excessive earwax.'' Other truthful and nonmisleading statements,
describing only the indications for use that have been established and
listed in this paragraph (b), may also be used, as provided in
330.1(c)(2), subject to the provisions of section 502 of the act
relating to misbranding and the prohibition in section 301(d) of the act
against the introduction or delivery for introduction into interstate
commerce of unapproved new drugs in violation of section 505(a) of the
act.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''Do not use if you have ear drainage or discharge, ear pain,
irritation, or rash in the ear or are dizzy; consult a doctor.''
(2) ''Do not use if you have an injury or perforation (hole) of the
ear drum or after ear surgery unless directed by a doctor.''
(3) ''Do not use for more than 4 days; if excessive earwax remains
after use of this product, consult a doctor.''
(4) ''Avoid contact with the eyes.''
(d) Directions. The labeling of the product contains the following
statement under the heading ''Directions'': FOR USE IN THE EAR ONLY.
Adults and children over 12 years of age: tilt head sideways and place
5 to 10 drops into ear. Tip of applicator should not enter ear canal.
Keep drops in ear for several minutes by keeping head tilted or placing
cotton in the ear. Use twice daily for up to 4 days if needed, or as
directed by a doctor. Any wax remaining after treatment may be removed
by gently flushing the ear with warm water, using a soft rubber bulb ear
syringe. Children under 12 years of age: consult a doctor.
(e) Optional wording. The word ''physician'' may be substituted for
the word ''doctor'' in any of the labeling statements in this section.
(51 FR 28660, Aug. 8, 1986; 52 FR 7830, Mar. 13, 1987)
21 CFR 344.50 PART 346 -- ANORECTAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 344.50 Subpart A -- General Provisions
Sec.
346.1 Scope.
346.3 Definitions.
21 CFR 344.50 Subpart B -- Active Ingredients
346.10 Local anesthetic active ingredients.
346.12 Vasoconstrictor active ingredients.
346.14 Protectant active ingredients.
346.16 Analgesic, anesthetic, and antipruritic active ingredients.
346.18 Astringent active ingredients.
346.20 Keratolytic active ingredients.
346.22 Permitted combinations of anorectal active ingredients.
21 CFR 344.50 Subpart C -- Labeling
346.50 Labeling of anorectal drug products.
346.52 Labeling of permitted combinations of anorectal active
ingredients.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 55 FR 31779, Aug. 3, 1990, unless otherwise noted.
21 CFR 344.50 Subpart A -- General Provisions
21 CFR 346.1 Scope.
(a) An over-the-counter anorectal drug product in a form suitable for
external (topical) or intrarectal (rectal) administration is generally
recognized as safe and effective and is not misbranded if it meets each
condition in this part and each general condition established in 330.1
of this chapter.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 212 unless otherwise
noted.
21 CFR 346.3 Definitions.
As used in this part:
(a) Analgesic, anesthetic drug. A topically (externally) applied
drug that relieves pain by depressing cutaneous sensory receptors.
(b) Anorectal drug. A drug that is used to relieve symptoms caused
by anorectal disorders in the anal canal, perianal area, and/or the
lower rectal areas.
(c) Antipruritic drug. A topically (externally) applied drug that
relieves itching by depressing cutaneous sensory receptors.
(d) Astringent drug. A drug that is applied topically (externally)
to the skin or mucous membranes for a local and limited protein
coagulant effect.
(e) External use. Topical application of an anorectal drug product
to the skin of the perianal area and/or the skin of the anal canal.
(f) Intrarectal use. Topical application of an anorectal drug
product to the mucous membrane of the rectum.
(g) Keratolytic drug. A drug that causes desquamation (loosening)
and debridement or sloughing of the surface cells of the epidermis.
(h) Local anesthetic drug. A drug that produces local disappearance
of pain, burning, itching, irritation, and/or discomfort by reversibly
blocking nerve conduction when applied to nerve tissue in appropriate
concentrations.
(i) Protectant drug. A drug that provides a physical barrier,
forming a protective coating over skin or mucous membranes.
(j) Vasoconstrictor. A drug that causes temporary constriction of
blood vessels.
21 CFR 346.3 Subpart B -- Active Ingredients
21 CFR 346.10 Local anesthetic active ingredients.
The active ingredient of the product consists of any of the following
when used in the concentration or within the concentration range
established for each ingredient:
(a) Benzocaine 5 to 20 percent.
(b) Benzyl alcohol 1 to 4 percent.
(c) Dibucaine 0.25 to 1 percent.
(d) Dibucaine hydrochloride 0.25 to 1 percent.
(e) Dyclonine hydrochloride 0.5 to 1 percent.
(f) Lidocaine 2 to 5 percent.
(g) Pramoxine hydrochloride 1 percent.
(h) Tetracaine 0.5 to 1 percent.
(i) Tetracaine hydrochloride 0.5 to 1 percent.
21 CFR 346.12 Vasoconstrictor active ingredients.
The active ingredient of the product consists of any of the following
when used in the concentration or within the concentration range
established for each ingredient.
(a) Ephedrine sulfate 0.1 to 1.25 percent.
(b) Epinephrine 0.005 to 0.01 percent.
(c) Epinephrine hydrochloride 0.005 to 0.01 percent.
(d) Phenylephrine hydrochloride 0.25 percent.
21 CFR 346.14 Protectant active ingredients.
(a) The following active ingredients may be used as the sole
protectant active ingredient in a product if the ingredient as
identified constitutes 50 percent or more by weight of the final
product. In addition, the following active ingredients may be used in
concentrations of less than 50 percent by weight only when used in
combinations in accordance with 346.22 (a), (b), or (n).
(1) Aluminum hydroxide gel.
(2) Cocoa butter.
(3) Glycerin in a 20- to 45-percent (weight/weight) aqueous solution
so that the final product contains not less than 10 and not more than 45
percent glycerin (weight/weight). Any combination product containing
glycerin must contain at least this minimum amount of glycerin.
(4) Hard fat.
(5) Kaolin.
(6) Lanolin.
(7) Mineral oil.
(8) Petrolatum.
(9) Topical starch.
(10) White petrolatum.
(b) The following active ingredients may not be used as a sole
protectant ingredient but may be used in combination with one, two, or
three other protectant active ingredients in accordance with 346.22
(a), (b), (n), and (o) and with the following limitations:
(1) Calamine not to exceed 25 percent by weight per dosage unit
(based on the zinc oxide content of calamine).
(2) Cod liver oil, provided that the product is labeled so that the
amount of the product that is used in a 24-hour period represents a
quantity that provides 10,000 U.S.P. units of vitamin A and 400 U.S.P.
units of cholecalciferol.
(3) Shark liver oil, provided that the product is labeled so that the
amount of the product that is used in a 24-hour period represents a
quantity that provides 10,000 U.S.P. units of vitamin A and 400 U.S.P.
units of cholecalciferol.
(4) Zinc oxide not to exceed 25 percent by weight per dosage unit.
21 CFR 346.16 Analgesic, anesthetic, and antipruritic active
ingredients.
The active ingredient of the product consists of any of the following
when used within the concentration range established for each
ingredient:
(a) Camphor 0.1 to 3 percent.
(b) Juniper tar 1 to 5 percent.
(c) Menthol 0.1 to 1 percent.
21 CFR 346.18 Astringent active ingredients.
The active ingredient of the product consists of any of the following
when used within the concentration range established for each
ingredient:
(a) Calamine, within a concentration range of 5 to 25 percent by
weight per dosage unit (based on the zinc oxide content of calamine).
(b) Hamamelis water, ''The National Formulary XI,'' 10 to 50 percent.
(c) Zinc oxide, within a concentration range of 5 to 25 percent by
weight per dosage unit.
21 CFR 346.20 Keratolytic active ingredients.
The active ingredient of the product consists of any of the following
when used within the concentration range established for each
ingredient:
(a) Alcloxa 0.2 to 2 percent.
(b) Resorcinol 1 to 3 percent.
21 CFR 346.22 Permitted combinations of anorectal active ingredients.
(a) Any two, three, or four protectants identified in (a) 346.14 may
be combined, except aluminum hydroxide gel in 346.14(a)(1) and kaolin
in 346.14(a)(5) may not be combined with any ingredient in 346.14(a)
(2), (4), (6), (7), (8) and (10), and (b) (2) and (3), provided that the
combined percentage by weight of all protectants in the combination is
at least 50 percent of the final product (e.g., 1 gram of a 2-gram
dosage unit). Any protectant ingredient included in the combination
must be present at a level that contributes at least 12.5 percent by
weight (e.g., 0.25 gram of a 2-gram dosage unit), except cod liver oil
and shark liver oil. If an ingredient in 346.14(b) is included in the
combination, it must not exceed the concentration limit specified in
346.14(b).
(b) Any single anorectal ingredient identified in 346.10, 346.12,
346.16, 346.18, or 346.20 may be combined with up to four protectants in
accordance with paragraph (a) of this section.
(c) Any single local anesthetic identified in 346.10 may be combined
with any single vasoconstrictor identified in 346.12.
(d) Any single local anesthetic identified in 346.10 may be combined
with any single astringent identified in 346.18.
(e) Any single local anesthetic identified in 346.10 may be combined
with any single keratolytic identified in 346.20.
(f) Any single vasoconstrictor identified in 346.12 may be combined
with any single astringent identified in 346.18.
(g) Any single analgesic, anesthetic, and antipruritic identified in
346.16 may be combined with any single astringent identified in 346.18.
(h) Any single analgesic, anesthetic, and antipruritic identified in
346.16 may be combined with any single keratolytic identified in
346.20.
(i) Any single astringent identified in 346.18 may be combined with
any single keratolytic identified in 346.20.
(j) Any single local anesthetic identified in 346.10 may be combined
with any single vasoconstrictor identified in 346.12 and with any
single astringent identified in 346.18.
(k) Any single local anesthetic identified in 346.10 may be combined
with any single astringent identified in 346.18 and with any single
keratolytic identified in 346.20.
(l) Any single vasoconstrictor identified in 346.12 may be combined
with any single analgesic, anesthetic, and antipruritic identified in
346.16 and with any single astringent identified in 346.18.
(m) Any single analgesic, anesthetic, and antipruritic identified in
346.16 may be combined with any single astringent identified in 346.18
and with any single keratolytic identified in 346.20.
(n) Any combination of ingredients listed in paragraphs (c) through
(m) of this section may be combined with up to four protectants in
accordance with paragraph (a) of this section.
(o) Any product containing calamine for use as a protectant and/or as
an astringent and/or containing zinc oxide for use as a protectant
and/or as an astringent may not have a total weight of zinc oxide
exceeding 25 percent by weight per dosage unit.
21 CFR 346.22 Subpart C -- Labeling
21 CFR 346.50 Labeling of anorectal drug products.
The labeling of the product contains the following information for
anorectal ingredients identified in 346.10, 346.12, 346.14, 346.16,
346.18, and 346.20, and for combinations of anorectal ingredients
identified in 346.22. Unless otherwise specified, the labeling in this
subpart is applicable to anorectal drug products for both external and
intrarectal use.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as
''anorectal (hemorrhoidal),'' ''hemorrhoidal,'' ''hemorrhoidal
(anorectal) (insert dosage form, e.g., cream, lotion, or ointment).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' any of the phrases listed in paragraph (b) of
this section, as appropriate. Other truthful and nonmisleading
statements, describing only the indications for use that have been
established and listed in this paragraph, may also be used, as provided
in 330.1(c)(2) of this chapter, subject to the provisions of section
502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to
misbranding and the prohibition in section 301(d) of the act against the
introduction or delivery for introduction into interstate commerce of
unapproved new drugs in violation of section 505(a) of the act.
(1) (''For the temporary relief of,'' ''Gives temporary relief of,''
or ''Helps relieve the'') (As an option, select one or both of the
following: ''local'' or ''anorectal'') (select one or more of the
following: ''discomfort,'' ''itching,'' or ''itching and discomfort,''
followed by: ''in the perianal area'' or ''associated with'' (select
one or more of the following: ''hemorrhoids,'' ''anorectal disorders,''
''inflamed hemorrhoidal tissues,'' ''anorectal inflammation,''
''hemorrhoidal tissues,'' or ''piles (hemorrhoids).''))
(2) Additional indications. Indications applicable to each active
ingredient of the product may be combined to eliminate duplicative words
or phrases so that the resulting indication is clear and understandable.
In addition to the indication identified in paragraph (b)(1) of this
section, the labeling of the product intended for external or
intrarectal use may also contain the following indications, as
appropriate.
(i) For products for external use only containing any ingredient
identified in 346.10. ''For the temporary relief of'' (select one or
more of the following: ''pain,'' ''soreness,'' or ''burning'').
(ii) For products containing epinephrine or epinephrine hydrochloride
identified in 346.12 (b) and (c) for external use only, and for
products containing ephedrine sulfate or phenylephrine hydrochloride
identified in 346.12 (a) and (d).
(A) ''Temporarily reduces the swelling associated with'' (select one
of the following: ''irritated hemorrhoidal tissue and other anorectal
disorders'' or ''irritation in hemorrhoids and other anorectal
disorders'').
(B) ''Temporarily shrinks hemorrhoidal tissue.''
(iii) For products for external use only containing glycerin
identified in 346.14(a)(3) and for products for external and/or
intrarectal use containing any protectant identified in 346.14(a) (2),
(4), (6) through (10), and (b) (1) through (4).
(A) ''Temporarily forms a protective coating over inflamed tissues to
help prevent drying of tissues.''
(B) ''Temporarily protects irritated areas.''
(C) ''Temporarily relieves burning.''
(D) ''Provides temporary relief from skin irritations.''
(E) ''Temporarily provides a coating for relief of anorectal
discomforts.''
(F) ''Temporarily protects the inflamed, irritated anorectal
surface'' (select one of the following: ''to help make bowel movements
less painful'' or ''from irritation and abrasion during bowel
movement'').
(G) ''Temporarily protects inflamed perianal skin.''
(H) ''Temporarily relieves the symptoms of perianal skin
irritation.''
(iv) For products containing aluminum hydroxide gel identified in
346.14(a)(1) and for products containing kaolin identified in
346.14(a)(5). ''For the temporary relief of itching associated with
moist anorectal conditions.''
(v) For products for external use only containing any analgesic,
anesthetic, and antipruritic identified in 346.16.
(A) ''For the temporary relief of'' (select one or both of the
following: ''pain'' or ''burning'').
(B) ''Can help distract from pain.''
(C) ''May provide a cooling sensation.''
(vi) For products for external use only containing hamamelis water
identified in 346.18(b), and for products for external use and/or
intrarectal use containing calamine or zinc oxide identified in 346.18
(a) and (c).
(A) ''Aids in protecting irritated anorectal areas.''
(B) ''Temporary relief of'' (select one or both of the following:
''irritation'' or ''burning'').
(vii) For products for external use only containing any ingredient
identified in 346.20. The indication in paragraph (b)(1) of this
section applies.
(c) Warnings. Warnings applicable to each active ingredient of the
product may be combined to eliminate duplicative words or phrases so
that the resulting warning is clear and understandable. The labeling of
the product contains the following warnings under the heading
''Warnings'':
(1) ''If condition worsens or does not improve within 7 days, consult
a doctor.''
(2) ''Do not exceed the recommended daily dosage unless directed by a
doctor.''
(3) ''In case of bleeding, consult a doctor promptly.''
(4) For products for external use only. ''Do not put this product
into the rectum by using fingers or any mechanical device or
applicator.''
(5) For products for intrarectal use to be used with a special
applicator such as a pile pipe or other mechanical device. ''Do not use
this product with an applicator if the introduction of the applicator
into the rectum causes additional pain. Consult a doctor promptly.''
(6) For products for external use only containing any local
anesthetic identified in 346.10, menthol identified in 346.16(c), or
resorcinol identified in 346.20(b). ''Certain persons can develop
allergic reactions to ingredients in this product. If the symptom being
treated does not subside or if redness, irritation, swelling, pain, or
other symptoms develop or increase, discontinue use and consult a
doctor.''
(7) For products containing any vasoconstrictor identified in
346.12. (i) ''Do not use this product if you have heart disease, high
blood pressure, thyroid disease, diabetes, or difficulty in urination
due to enlargement of the prostate gland unless directed by a doctor.''
(ii) ''Drug interaction precaution. Do not use this product if you
are presently taking a prescription drug for high blood pressure or
depression, without first consulting your doctor.''
(iii) For products containing ephedrine sulfate identified in
346.12(a). ''Some users of this product may experience nervousness,
tremor, sleeplessness, nausea, and loss of appetite. If these symptoms
persist or become worse, consult your doctor.''
(8) For products containing aluminum hydroxide gel identified in
346.14(a)(1) and for products containing kaolin identified in
346.14(a)(5). ''Remove petrolatum or greasy ointment before using this
product because they interfere with the ability of this product to
adhere properly to the skin area.''
(9) For products for external use only containinq resorcinol
identified in 346.20(b). ''Do not use on open wounds near the anus.''
(d) Directions. Directions applicable to each active ingredient of
the product may be combined to eliminate duplicative words or phrases so
that the resulting information is clear and understandable. The
labeling of the product contains the following information under the
heading ''Directions'':
(1) ''Adults: When practical, cleanse the affected area'' (select
one or both of the following: ''with mild soap and warm water and rinse
thoroughly'' or ''by patting or blotting with an appropriate cleansing
pad''). ''Gently dry by patting or blotting with toilet tissue or a
soft cloth before application of this product.'' (Other appropriate
directions in this section may be inserted here.) ''Children under 12
years of age: consult a doctor.''
(2) For products for external use only. ''Apply externally to the
affected area'' (insert appropriate time interval of administration as
identified in paragraphs (d)(6), (7), (8), or (9) of this section).
(3) For products for external use that are pads containing anorectal
ingredients. ''Gently apply to the affected area by patting and then
discard.''
(4) For products for intrarectal use that are wrapped suppositories.
''Remove wrapper before inserting into the rectum.''
(5) For products for intrarectal use that are to be used with a
special applicator such as a pile pipe or other mechanical device.
''FOR INTRARECTAL USE: Attach applicator to tube. Lubricate applicator
well, then gently insert applicator into the rectum.''
(6) For products for external use only containing any of the local
anesthetics identified in 346.10; analgesics, anesthetics, and
antipruritics identified in 346.16; or alcloxa or resorcinol
identified in 346.20. Apply to the affected area up to 6 times daily.
(i) For products for external use only containing dibucaine or
dibucaine hydrochloride identified in 346.10 (c) and (d). Apply to the
affected area up to 3 or 4 times daily.
(ii) For products for external use only containing pramoxine
hydrochloride identified in 346.10(g). Apply to the affected area up to
5 times daily.
(7) For products containing vasoconstrictors identified in 346.12.
Apply to the affected area up to 4 times daily.
(8) For products for external use only containing glycerin identified
in 346.14(a)(3) or hamamelis water identified in 346.18(b), and for
products for external and/or intrarectal use containing any protectant
identified in 346.14(a)(1), (2), (4), (5), (6), (7), and (9), and
(b)(1), (2), (3), and (4), or any astringent identified in 346.18(a)
and (c). Apply to the affected area up to 6 times daily or after each
bowel movement.
(9) For products containing petrolatum or white petrolatum identified
in 346.14(a)(8) and (10). Apply liberally to the affected area as
often as necessary.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
21 CFR 346.52 Labeling of permitted combinations of anorectal active
ingredients.
Indications, warnings, and directions for use, respectively,
applicable to each ingredient in the product may be combined to
eliminate duplicative words or phrases so that the resulting information
is clear and understandable.
(a) Statement of identity. For a combination drug product that has
an established name, the labeling of the product states the established
name of the combination drug product, followed by the statement of
identity established in 346.50(a). For a combination drug product that
does not have an established name, the labeling of the product states
the statement of identity established in 346.50(a).
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the indication(s) for each ingredient in the
combination, as established in the indications sections of this subpart.
(c) Warnings. The labeling of the product states, under the heading
''Warnings,'' the warning(s) for each ingredient in the combination, as
established in the warnings sections of this subpart.
(d) Directions. The labeling of the product states, under the
heading ''Directions,'' directions that conform to the directions
established for each ingredient in the directions sections of this
subpart. When the time intervals or age limitations for administration
of the individual ingredients differ, the directions for the combination
product may not exceed any maximum dosage limits established for the
individual ingredients in the applicable OTC drug monograph.
21 CFR 346.52 PART 349 -- OPHTHALMIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 346.52 Subpart A -- General Provisions
Sec.
349.1 Scope.
349.3 Definitions.
21 CFR 346.52 Subpart B -- Active Ingredients
349.10 Ophthalmic astringent.
349.12 Ophthalmic demulcents.
349.14 Ophthalmic emollients.
349.16 Ophthalmic hypertonicity agent.
349.18 Ophthalmic vasoconstrictors.
349.20 Eyewashes.
349.30 Permitted combinations of active ingredients.
21 CFR 346.52 Subpart C -- Labeling
349.50 Labeling of ophthalmic drug products.
349.55 Labeling of ophthalmic astringent drug products.
349.60 Labeling of ophthalmic demulcent drug products.
349.65 Labeling of ophthalmic emollient drug products.
349.70 Labeling of ophthalmic hypertonicity drug products.
349.75 Labeling of ophthalmic vasoconstrictor drug products.
349.78 Labeling of eyewash drug products.
349.79 Labeling of permitted combinations of active ingredients.
349.80 Professional labeling.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 53 FR 7090, Mar. 4, 1988, unless otherwise noted.
21 CFR 346.52 Subpart A -- General Provisions
21 CFR 349.1 Scope.
(a) An over-the-counter ophthalmic drug product in a form suitable
for topical administration is generally recognized as safe and effective
and is not misbranded if it meets each of the conditions in this part
and each of the general conditions established in 330.1.
(b) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 349.3 Definitions.
As used in this part:
(a) Ophthalmic drug product. A drug product, which should be sterile
in accordance with 200.50, to be applied to the eyelid or instilled in
the eye.
(b) Astringent. A locally acting pharmacologic agent which, by
precipitating protein, helps to clear mucus from the outer surface of
the eye.
(c) Buffering agent. A substance which stabilizes the pH of
solutions against changes produced by introduction of acids or bases
from such sources as drugs, body fluids, tears, etc.
(d) Demulcent. An agent, usually a water-soluble polymer, which is
applied topically to the eye to protect and lubricate mucous membrane
surfaces and relieve dryness and irritation.
(e) Emollient. An agent, usually a fat or oil, which is applied
locally to eyelids to protect or soften tissues and to prevent drying
and cracking.
(f) Eyewash, eye lotion, irrigating solution. A sterile aqueous
solution intended for washing, bathing, or flushing the eye.
(g) Hypertonicity agent. An agent which exerts an osmotic gradient
greater than that present in body tissues and fluids, so that water is
drawn from the body tissues and fluids across semipermeable membranes.
Applied topically to the eye, a hypertonicity agent creates an osmotic
gradient which draws water out of the cornea.
(h) Isotonicity. A state or quality in which the osmotic pressure in
two fluids is equal.
(i) Vasoconstrictor. A pharmacologic agent which, when applied
topically to the mucous membranes of the eye, causes transient
constriction of conjunctival blood vessels.
21 CFR 349.3 Subpart B -- Active Ingredients
21 CFR 349.10 Ophthalmic astringent.
The active ingredient and its concentration in the product is as
follows: Zinc sulfate, 0.25 percent.
21 CFR 349.12 Ophthalmic demulcents.
The active ingredients of the product consist of any of the
following, within the established concentrations for each ingredient:
(a) Cellulose derivatives:
(1) Carboxymethylcellulose sodium, 0.2 to 2.5 percent.
(2) Hydroxyethyl cellulose, 0.2 to 2.5 percent.
(3) Hydroxypropyl methylcellulose, 0.2 to 2.5 percent.
(4) Methylcellulose, 0.2 to 2.5 percent.
(b) Dextran 70, 0.1 percent when used with another polymeric
demulcent agent in this section.
(c) Gelatin, 0.01 percent.
(d) Polyols, liquid:
(1) Glycerin, 0.2 to 1 percent.
(2) Polyethylene glycol 300, 0.2 to 1 percent.
(3) Polyethylene glycol 400, 0.2 to 1 percent.
(4) Polysorbate 80, 0.2 to 1 percent.
(5) Propylene glycol, 0.2 to 1 percent.
(e) Polyvinyl alcohol, 0.1 to 4 percent.
(f) Povidone, 0.1 to 2 percent.
21 CFR 349.14 Ophthalmic emollients.
The active ingredients of the product consist of any of the
following:
(a) Lanolin preparations:
(1) Anhydrous lanolin, 1 to 10 percent in combination with one or
more oleaginous emollient agents included in the monograph.
(2) Lanolin, 1 to 10 percent in combination with one or more
oleaginous emollient agents included in the monograph.
(b) Oleaginous ingredients:
(1) Light mineral oil, up to 50 percent in combination with one or
more other emollient agents included in the monograph.
(2) Mineral oil, up to 50 percent in combination with one or more
other emollient agents included in the monograph.
(3) Paraffin, up to 5 percent in combination with one or more other
emollient agents included in the monograph.
(4) Petrolatum, up to 100 percent.
(5) White ointment, up to 100 percent.
(6) White petrolatum, up to 100 percent.
(7) White wax, up to 5 percent in combination with one or more other
emollient agents included in the monograph.
(8) Yellow wax, up to 5 percent in combination with one or more other
emollient agents included in the monograph.
21 CFR 349.16 Ophthalmic hypertonicity agent.
The active ingredient and its concentration in the product is as
follows: Sodium chloride, 2 to 5 percent.
21 CFR 349.18 Ophthalmic vasoconstrictors.
The active ingredient of the product consists of one of the
following, within the established concentration for each ingredient:
(a) Ephedrine hydrochloride, 0.123 percent.
(b) Naphazoline hydrochloride, 0.01 to 0.03 percent.
(c) Phenylephrine hydrochloride, 0.08 to 0.2 percent.
(d) Tetrahydrozoline hydrochloride, 0.01 to 0.05 percent.
21 CFR 349.20 Eyewashes.
These products contain water, tonicity agents to establish
isotonicity with tears, agents for establishing pH and buffering to
achieve the same pH as tears, and a suitable preservative agent.
21 CFR 349.30 Permitted combinations of active ingredients.
The following combinations are permitted provided each active
ingredient is present within the established concentration, and the
product is labeled in accordance with 349.79.
(a) Any single ophthalmic astringent active ingredient identified in
349.10 may be combined with any single ophthalmic vasoconstrictor active
ingredient identified in 349.18.
(b) Any two or three ophthalmic demulcent active ingredients
identified in 349.12 may be combined.
(c) Any single ophthalmic demulcent active ingredient identified in
349.12 or any ophthalmic demulcent combination identified in paragraph
(b) of this section may be combined with any single ophthalmic
vasoconstrictor identified in 349.18.
(d) Any single ophthalmic astringent active ingredient identified in
349.10 may be combined with any single ophthalmic vasoconstrictor active
ingredient identified in 349.18 and any single ophthalmic demulcent
identified in 349.12 or ophthalmic demulcent combination identified in
paragraph (b) of this section.
(e) Any two or more emollient active ingredients identified in
349.14 may be combined as necessary to give the product proper
consistency for application to the eye.
21 CFR 349.30 Subpart C -- Labeling
21 CFR 349.50 Labeling of ophthalmic drug products.
(a) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this part.
(b) Where applicable, indications in this part applicable to each
ingredient in the product may be combined to eliminate duplicative words
or phrases so that the resulting information is clear and
understandable. Other truthful and nonmisleading statements, describing
only the indications for use that have been established and listed in
this part, may also be used, as provided in 330.1(c)(2), subject to the
provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) The labeling of the product contains the following warnings,
under the heading ''Warnings'':
(1) For ophthalmic drug products packaged in multi-use containers.
''To avoid contamination, do not touch tip of container to any surface.
Replace cap after using.''
(2) For ophthalmic drug products packaged in single-use containers.
''To avoid contamination, do not touch tip of container to any surface.
Do not reuse. Once opened, discard.''
(3) For ophthalmic drug products containing mercury compounds used as
a preservative. ''This product contains (name and quantity of
mercury-containing ingredient) as a preservative. Do not use this
product if you are sensitive to'' (select one of the following:
''mercury'' or ''(insert name of mercury-containing ingredient) or any
other ingredient containing mercury).''
21 CFR 349.55 Labeling of ophthalmic astringent drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as an
''astringent'' (select one of the following: ''eye'' or ''ophthalmic'')
''(insert dosage form, e.g., drops).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following phrase: ''For the temporary
relief of discomfort from minor eye irritations.''
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for products containing any ingredient identified in
349.10:
(1) ''If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists for more than 72 hours, discontinue use and consult a doctor.''
(2) ''If solution changes color or becomes cloudy, do not use.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Instill 1 to 2 drops in
the affected eye(s) up to four times daily.
21 CFR 349.60 Labeling of ophthalmic demulcent drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug(s), if any, and identifies the product as a
''lubricant'' or ''demulcent (lubricant)'' (select one of the following:
''eye'' or ''ophthalmic'') ''(insert dosage form, e.g., drops).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' one or more of the following phrases:
(1) ''For the temporary relief of burning and irritation due to
dryness of the eye.''
(2) ''For the temporary relief of discomfort due to minor irritations
of the eye or to exposure to wind or sun.''
(3) ''For use as a protectant against further irritation or to
relieve dryness of the eye.''
(4) ''For use as a lubricant to prevent further irritation or to
relieve dryness of the eye.''
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for products containing any ingredient identified in
349.12:
(1) ''If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists for more than 72 hours, discontinue use and consult a doctor.''
(2) ''If solution changes color or becomes cloudy, do not use.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Instill 1 or 2 drops in
the affected eye(s) as needed.
21 CFR 349.65 Labeling of ophthalmic emollient drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug(s), if any, and identifies the product as a
''lubricant'' or ''emollient (lubricant)'' (select one of the following:
''eye'' or ''ophthalmic'') ''(insert dosage form, e.g., ointment).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' one or more of the following phrases:
(1) ''For the temporary relief of burning and irritation due to
dryness of the eye.''
(2) ''For the temporary relief of discomfort due to minor irritations
of the eye or to exposure to wind or sun.''
(3) ''For use as a protectant against further irritation or to
relieve dryness of the eye.''
(4) ''For use as a lubricant to prevent further irritation or to
relieve dryness of the eye.''
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for products containing any ingredient identified in
349.14: ''If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists for more than 72 hours, discontinue use and consult a doctor.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Pull down the lower lid
of the affected eye and apply a small amount (one-fourth inch) of
ointment to the inside of the eyelid.
21 CFR 349.70 Labeling of ophthalmic hypertonicity drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''hypertonicity'' (select one of the following: ''eye'' or
''ophthalmic'') ''(insert dosage form, e.g., drops).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following phrase: ''For the temporary
relief of corneal edema.''
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for products containing any ingredient identified in
349.16:
(1) ''Do not use this product except under the advice and supervision
of a doctor. If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists, consult a doctor.''
(2) ''This product may cause temporary burning and irritation on
being instilled into the eye.''
(3) ''If solution changes color or becomes cloudy, do not use.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Instill 1 or 2 drops in
the affected eye(s) every 3 or 4 hours, or as directed by a doctor.
21 CFR 349.75 Labeling of ophthalmic vasoconstrictor drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug(s), if any, and identifies the product as a
''redness reliever'' or ''vasoconstrictor (redness reliever)'' (select
one of the following: ''eye'' or ''ophthalmic'') ''(insert dosage form,
e.g., drops).''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following phrase: ''Relieves redness of
the eye due to minor eye irritations.''
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for products containing any ingredient identified in
349.18:
(1) ''If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists for more than 72 hours, discontinue use and consult a doctor.''
(2) ''If you have glaucoma, do not use this product except under the
advice and supervision of a doctor.''
(3) ''Overuse of this product may produce increased redness of the
eye.''
(4) ''If solution changes color or becomes cloudy, do not use.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'': Instill 1 to 2 drops in
the affected eye(s) up to four times daily.
21 CFR 349.78 Labeling of eyewash drug products.
(a) Statement of identity. The labeling of the product identifies
the product with one or more of the following terms: ''eyewash,'' ''eye
lotion,'' or ''eye irrigating solution.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' one of the following phrases:
(1) ''For'' (select one of the following: ''flushing,''
''irrigating,'' ''cleansing,'' ''washing,'' or ''bathing'') ''the eye to
remove'' (select one or more of the following: ''loose foreign
material,'' ''air pollutants (smog or pollen),'' or ''chlorinated
water'').
(2) ''For'' (select one of the following: ''flushing,''
''irrigating,'' ''cleansing,'' ''washing,'' or ''bathing'') ''the eye to
help relieve'' (select one or more of the following: ''irritation,''
''discomfort,'' ''burning,'' ''stinging,'' ''smarting,'' or ''itching'')
''by removing'' (select one or more of the following: ''loose foreign
material,'' ''air pollutants (smog or pollen),'' or ''chlorinated
water'').
(c) Warnings. In addition to the warnings in 349.50, the labeling
of the product contains the following warnings under the heading
''Warnings'' for all eyewash products:
(1) ''If you experience eye pain, changes in vision, continued
redness or irritation of the eye, or if the condition worsens or
persists, consult a doctor.''
(2) ''Obtain immediate medical treatment for all open wounds in or
near the eyes.''
(3) ''If solution changes color or becomes cloudy, do not use.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For eyewash products intended for use with an eyecup. Rinse cup
with clean water immediately before each use. Avoid contamination of
rim and inside surfaces of cup. Fill cup half full and apply the cup to
the affected eye, pressing tightly to prevent the escape of the liquid,
and tilt the head backward. Open eyelids wide and rotate eyeball to
ensure thorough bathing with the wash or lotion. Rinse cup with clean
water after each use.
(2) For eyewash products intended for use with a nozzle applicator.
Flush the affected eye as needed, controlling the rate of flow of
solution by pressure on the bottle.
21 CFR 349.79 Labeling of permitted combinations of active ingredients.
Statements of identity, indications, warnings, and directions for
use, respectively, applicable to each ingredient in the product may be
combined to eliminate duplicative words or phrases so that the resulting
information is clear and understandable.
(a) Statement of identity. For a combination drug product that has
an established name, the labeling of the product states the established
name of the combination drug product, followed by the statement of
identity for each ingredient in the combination, as established in the
statement of identity sections of this part. For a combination drug
product that does not have an established name, the labeling of the
product states the statement of identity for each ingredient in the
combination, as established in the statement of identity sections of
this part.
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the indication(s) for each ingredient in the
combination, as established in the indications sections of this part.
(c) Warnings. The labeling of the product states, under the heading
''Warnings,'' the warning(s) for each ingredient in the combination, as
established in the warnings sections of this part.
(d) Directions. The labeling of the product states, under the
heading ''Directions,'' directions that conform to the directions
established for each ingredient in the directions sections of this part.
When the time intervals or age limitations for administration of the
individual ingredients differ, the directions for the combination
product may not exceed any maximum dosage limits established for the
individual ingredients in the applicable OTC drug monograph.
21 CFR 349.80 Professional labeling.
The labeling of any OTC ophthalmic demulcent drug product provided to
health professionals (but not to the general public) may contain
instructions for the use of these products in professional eye
examinations (i.e. gonioscopy, electroretinography).
21 CFR 349.80 PART 357 -- MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 349.80 Subpart A -- (Reserved)
21 CFR 349.80 Subpart B -- Anthelmintic Drug Products
Sec.
357.101 Scope.
357.103 Definition.
357.110 Anthelmintic active ingredient.
357.150 Labeling of anthelmintic drug products.
357.152 Package inserts for anthelmintic drug products.
357.180 Professional labeling.
21 CFR 349.80 Subpart C -- Cholecystokinetic Drug Products
357.201 Scope.
357.203 Definition.
357.210 Cholecystokinetic active ingredients.
357.250 Labeling of cholecystokinetic drug products.
357.280 Professional labeling.
21 CFR 349.80 Subparts D-H -- (Reserved)
21 CFR 349.80 Subpart I -- Deodorant Drug Products for Internal Use
357.801 Scope.
357.803 Definitions.
357.810 Active ingredients for deodorant drug products for internal
use.
357.850 Labeling of deodorant drug products for internal use.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
21 CFR 349.80 Subpart A -- (Reserved)
21 CFR 349.80 Subpart B -- Anthelmintic Drug Products
Source: 51 FR 27759, Aug. 1, 1986, unless otherwise noted.
21 CFR 357.101 Scope.
(a) An over-the-counter anthelmintic drug product in a form suitable
for oral administration is generally recognized as safe and effective
and is not misbranded if it meets each condition in this subpart and
each general condition established in 330.1.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
21 CFR 357.103 Definition.
As used in this subpart:
Anthelmintic. An agent that is destructive to worms.
21 CFR 357.110 Anthelmintic active ingredient.
The active ingredient of the product is pyrantel pamoate when used
within the dosage limits established in 357.150(d)(1).
21 CFR 357.150 Labeling of anthelmintic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''pinworm treatment.''
(b) Indication. The labeling of the product states, under the
heading ''Indication,'' the following: ''For the treatment of
pinworms.'' Other truthful and nonmisleading statements, describing only
the indications for use that have been established and listed in this
paragraph (b), may also be used, as provided in 330.1(c)(2), subject to
the provisions of section 502 of the act relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) ''Abdominal cramps, nausea, vomiting, diarrhea, headache, or
dizziness sometimes occur after taking this drug. If any of these
conditions persist consult a doctor.''
(2) ''If you are pregnant or have liver disease, do not take this
product unless directed by a doctor.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) Adults, children 12 years of age and over, and children 2 years
to under 12 years of age: Oral dosage is a single dose of 5 milligrams
of pyrantel base per pound, or 11 milligrams per kilogram, of body
weight not to exceed 1 gram. Dosing information should be converted to
easily understood directions for the consumer using the following dosage
schedule:
(2) ''Read package insert carefully before taking this medication.
Take only according to directions and do not exceed the recommended
dosage unless directed by a doctor. Medication should only be taken on
time as a single dose; do not repeat treatment unless directed by a
doctor. When one individual in a household has pinworms, the entire
household should be treated unless otherwise advised. See Warnings. If
any worms other than pinworms are present before or after treatment,
consult a doctor. If any symptoms or pinworms are still present after
treatment, consult a doctor.
(3) ''This product can be taken any time of day, with or without
meals. It may be taken alone or with milk or fruit juice. Use of a
laxative is not necessary prior to, during, or after medication.''
(e) Optional wording. The word ''physician'' may be substituted for
the word ''doctor'' in any of the labeling statements in this section.
(51 FR 27759, Aug. 1, 1986; 52 FR 7831, Mar. 13, 1987, as amended at
53 FR 35810, Sept. 15, 1988)
21 CFR 357.152 Package inserts for anthelmintic drug products.
The labeling of the product contains a consumer package insert which
includes the following information:
(a) A discussion of the symptoms suggestive of pinworm infestation,
including a statement that pinworms must be visually identified before
taking this medication.
(b) A detailed description of how to find and identify the pinworm.
(c) A commentary on the life cycle of the pinworm.
(d) A commentary on the ways in which pinworms may be spread from
person to person and hygienic procedures to follow to avoid such
spreading.
(e) The appropriate labeling information contained in 357.150
(Collection of information requirement approved by the Office of
Management and Budget under control number 0910-0232)
(51 FR 27759, Aug. 1, 1986, as amended at 52 FR 2515, Jan 23, 1987)
21 CFR 357.180 Professional labeling.
The labeling provided to health professionals (but not to the general
public) may contain an additional indication: ''For the treatment of
common roundworm infestation.''
21 CFR 357.180 Subpart C -- Cholecystokinetic Drug Products
21 CFR 357.201 Scope.
(a) An over-the-counter cholecystokinetic drug product in a form
suitable for oral administration is generally recognized as safe and
effective and is not misbranded if it meets each of the conditions in
this subpart in addition to each of the general conditions established
in 330.1.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
(48 FR 27005, June 10, 1983)
21 CFR 357.203 Definition.
As used in this subpart:
Cholecystokinetic drug product. A drug product that causes
contraction of the gallbladder and is used during the course of
diagnostic gallbladder studies (cholecystography).
(48 FR 27005, June 10, 1983)
21 CFR 357.210 Cholecystokinetic active ingredients.
The active ingredient of the product consists of any of the following
when used within the specified concentration and dosage form established
for each ingredient:
(a) 50-percent aqueous emulsion of corn oil.
(b) Hydrogenated soybean oil in a suitable, water-dispersible powder.
The hydrogenated soybean oil is food-grade, partially hydrogenated with
a melting point of 41 to 43.5 C, an iodine value of 65 to 69, and a
fatty acid composition as follows:
(54 FR 8321, Feb. 28, 1989)
21 CFR 357.250 Labeling of cholecystokinetic drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''gallbladder diagnostic agent.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the following: ''For the contraction of the
gallbladder during diagnostic gallbladder studies.'' Other truthful and
nonmisleading statements, describing only the indications for use that
have been established and listed in this paragraph (b), may also be
used, as provided in 330.1(c)(2), subject to the provisions of section
502 of the act relating to misbranding and the prohibition in section
301(d) of the act against the introduction or delivery for introduction
into interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(c) Warnings. (Reserved)
(d) Directions. The labeling of the product contains the following
statements under the heading ''Directions'':
(1) ''Take only when instructed by a doctor:''
(2) For products containing 50-percent aqueous emulsion of corn oil.
(i) ''Shake well before using.''
(ii) Oral dosage is 60 milliliters 20 minutes before diagnostic
gallbladder x-ray or as directed by a doctor.
(3) For products containing hydrogeneated soybean oil. Oral dosage
is 12.4 grams in a suitable, water-dispersible powder in 2 to 3 ounces
of water. Stir briskly to prepare a suspension before using. Drink 20
minutes before diagnostic gallbladder x-ray or as directed by a doctor.
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(48 FR 27005, June 10, 1983, as amended at 51 FR 16267, May 1, 1986;
52 FR 7830, Mar. 13, 1987; 54 FR 8321, Feb. 28, 1989)
21 CFR 357.280 Professional labeling.
The labeling provided to health professionals (but not to the general
public) may contain the following information for ingredients identified
in 357.210: Indication. ''For visualization of biliary ducts during
cholecystography.''
(54 FR 8321, Feb. 28, 1989)
21 CFR 357.280 Subparts D-H -- (Reserved)
21 CFR 357.280 Subpart I -- Deodorant Drug Products for Internal Use
Source: 55 FR 19865, May 11, 1990, unless otherwise noted.
21 CFR 357.801 Scope.
(a) An over-the-counter deodorant drug product for internal use in a
form suitable for oral administration is generally recognized as safe
and effective and is not misbranded if it meets each condition in this
subpart and each general condition established in 330.1 of this
chapter.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21 unless otherwise noted.
21 CFR 357.803 Definitions.
As used in this subpart:
(a) Colostomy. An external operative opening of the colon.
(b) Deodorant for internal use. An ingredient taken internally to
reduce odors arising from conditions such as colostomies, ileostomies,
or fecal incontinence.
(c) Ileostomy. An external operative opening from the ileum.
(d) Incontinence. An inability to retain urine or feces.
21 CFR 357.810 Active ingredients for deodorant drug products for
internal use.
The active ingredient of the product consists of either of the
following when used within the dosage limits established for each
ingredient in 357.850(d):
(a) Bismuth subgallate.
(b) Chlorophyllin copper complex.
21 CFR 357.850 Labeling of deodorant drug products for internal use.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''deodorant for internal use'' or as a ''colostomy or ileostomy
deodorant.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' any of the phrases listed in paragraph (b) of
this section as appropriate. Other truthful and nonmisleading
statements, describing only the indications for use that have been
established and listed in paragraph (b) of this section may also be
used, as provided in 330.1(c)(2) of this chapter, subject to the
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act
(the act) relating to misbranding and the prohibition in section 301(d)
of the act against the introduction or delivery for introduction into
interstate commerce of unapproved new drugs in violation of section
505(a) of the act.
(1) For products containing bismuth subgallate identified in
357.810(a). ''An aid to reduce odor from a colostomy or ileostomy.''
(2) For products containing chlorophyllin copper complex identified
in 357.810(b). (i) ''An aid to reduce odor from a colostomy or
ileostomy.''
(ii) ''An aid to reduce fecal odor due to incontinence.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'': (1) For products containing
chlorophyllin copper complex identified in 357.810(b). (i) ''If cramps
or diarrhea occurs, reduce the dosage. If symptoms persist, consult
your doctor.''
(ii) The warning required by 330.1(g) of this chapter concerning
overdose is not required on products containing chlorophyllin copper
complex identified in 357.810(b).
(2) (Reserved)
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions.''
(1) For products containing bismuth subgallate identified in
357.810(a). Adults and children 12 years of age and over: Oral dosage
is 200 to 400 milligrams up to 4 times daily. Children under 12 years
of age: consult a doctor.
(2) For products containing chlorophyllin copper complex identified
in 357.810(b). Adults and children 12 years of age and over: Oral
dosage is 100 to 200 milligrams daily in divided doses as required. If
odor is not controlled, take up to an additional 100 milligrams daily in
divided doses as required. The smallest effective dose should be used.
Do not exceed 300 milligrams daily. Children under 12 years of age:
consult a doctor.
21 CFR 357.850 PART 358 -- MISCELLANEOUS EXTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
21 CFR 357.850 Subpart A -- (Reserved)
21 CFR 357.850 Subpart B -- Wart Remover Drug Products
Sec.
358.101 Scope.
358.103 Definitions.
358.110 Wart remover active ingredients.
358.150 Labeling of wart remover drug products.
21 CFR 357.850 Subparts C-E -- (Reserved)
21 CFR 357.850 Subpart F -- Corn and Callus Remover Drug Products
358.501 Scope.
358.503 Definitions.
358.510 Corn and callus remover active ingredients.
358.550 Labeling of corn and callus remover drug products.
21 CFR 357.850 Subpart G -- (Reserved)
21 CFR 357.850 Subpart H -- Drug Products for the Control of Dandruff,
Seborrheic Dermatitis, and Psoriasis (Eff. 12-4-92)
358.701 Scope.
358.703 Definitions.
358.710 Active ingredients for the control of dandruff, seborrheic
dermatitis, or psoriasis.
358.720 Permitted combinations of active ingredients.
358.750 Labeling of drug products for the control of dandruff,
seborrheic dermatitis, or psoriasis.
Authority: Sections 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371).
Source: 55 FR 33255, Aug. 14, 1990, unless otherwise noted.
21 CFR 357.850 Subpart A -- (Reserved)
21 CFR 357.850 Subpart B -- Wart Remover Drug Products
21 CFR 358.101 Scope.
(a) An over-the-counter wart remover drug product in a form suitable
for topical application is generally recognized as safe and effective
and is not misbranded if it meets each of the conditions in this subpart
and each of the general conditions established in 330.1 of this
chapter.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21 unless otherwise noted.
21 CFR 358.103 Definitions.
As used in this subpart:
(a) Wart remover drug product. A topical agent used for the removal
of common or plantar warts.
(b) Collodion-like vehicle. A solution containing pyroxylin
(nitrocellulose) in an appropriate nonaqueous solvent that leaves a
transparent cohesive film when applied to the skin in a thin layer.
(c) Plaster vehicle. A fabric, plastic, or other suitable backing
material in which medication is usually incorporated for topical
application to the skin.
21 CFR 358.110 Wart remover active ingredients.
The product consists of any of the following active ingredients
within the specified concentration and in the dosage form established
for each ingredient.
(a) Salicylic acid 12 to 40 percent in a plaster vehicle.
(b) Salicylic acid 5 to 17 percent in a collodion-like vehicle.
(c) Salicylic acid 15 percent in a karaya gum, glycol plaster
vehicle.
21 CFR 358.150 Labeling of wart remover drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''wart remover.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' any of the phrases listed in paragraph (b) of
this section. Other truthful and nonmisleading statements, describing
only the indications for use that have been established in paragraph (b)
of this section, may also be used, as provided in 330.1(c)(2) of this
chapter, subject to the provisions of section 502 of the Federal Food,
Drug, and Cosmetic Act (the act) relating to misbranding and the
prohibition in section 301(d) of the act against the introduction or
delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act.
(1) ''For the removal of common warts. The common wart is easily
recognized by the rough 'cauliflower-like' appearance of the surface.''
(2) ''For the removal of plantar warts on the bottom of the foot.
The plantar wart is recognized by its location only on the bottom of the
foot, its tenderness, and the interruption of the footprint pattern.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) For products containing any ingredient identified in 358.110.
(i) ''For external use only.''
(ii) ''Do not use this product on irritated skin, on any area that is
infected or reddened, if you are a diabetic, or if you have poor blood
circulation.''
(iii) ''If discomfort persists, see your doctor.''
(iv) ''Do not use on moles, birthmarks, warts with hair growing from
them, genital warts, or warts on the face or mucous membranes.''
(2) For any product formulated in a flammable vehicle. (i) The
labeling should contain an appropriate flammability signal word, e.g.
''extremely flammable,'' ''flammable,'' ''combustible,'' consistent with
16 CFR 1500.3(b)(10).
(ii) ''Keep away from fire or flame.''
(3) For any product formulated in a volatile vehicle. ''Cap bottle
tightly and store at room temperature away from heat.''
(4) For any product formulated in a collodion-like vehicle. (i) ''If
product gets into the eye, flush with water for 15 minutes.''
(ii) ''Avoid inhaling vapors.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For products containing salicylic acid identified in 358.110(a).
''Wash affected area.'' (Optional: ''May soak wart in warm water for 5
minutes.'') ''Dry area thoroughly.'' (If appropriate: ''Cut plaster to
fit wart.'') ''Apply medicated plaster. Repeat procedure every 48 hours
as needed (until wart is removed) for up to 12 weeks.''
(2) For products containing salicylic acid identified in 358.110(b).
''Wash affected area.'' (Optional: ''May soak wart in warm water for 5
minutes.'') ''Dry area thoroughly.'' Apply one drop at a time to
sufficiently cover each wart. Let dry. Repeat this procedure once or
twice daily as needed (until wart is removed) for up to 12 weeks.''
(3) For products containing salicylic acid identified in 358.110(c).
''Wash affected area.'' (Optional: ''May soak wart in warm water for 5
minutes.'') ''Dry area thoroughly.'' (If appropriate: ''Cut plaster to
fit wart.'') ''Apply medicated plaster at bedtime, leave in place for at
least 8 hours; in the morning, remove plaster and discard. Repeat
procedure every 24 hours as needed (until wart is removed) for up to 12
weeks.''
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
(f) The phrase ''or podiatrist'' may be used in addition to the word
''doctor'' in any of the labeling statements in this section when a
product is labeled with the indication identified in 358.150(b)(2).
(55 FR 33255, Aug. 14, 1990; 55 FR 37403, Sept. 11, 1990)
21 CFR 358.150 Subparts C-E -- (Reserved)
21 CFR 358.150 Subpart F -- Corn and Callus Remover Drug Products
Source: 55 FR 33261, Aug. 14, 1990, unless otherwise noted.
21 CFR 358.501 Scope.
(a) An over-the-counter corn and callus remover drug product in a
form suitable for topical application is generally recognized as safe
and effective and is not misbranded if it meets each of the conditions
in this subpart and each of the general conditions established in 330.1
of this chapter.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21 unless otherwise noted.
21 CFR 358.503 Definitions.
As used in this subpart:
(a) Corn and callus remover drug product. A topical agent used for
the removal of corns and calluses.
(b) Collodion-like vehicle. A solution containing pyroxylin
(nitrocellulose) in an appropriate nonaqueous solvent that leaves a
transparent cohesive film when applied to the skin in a thin layer.
(c) Plaster vehicle. A fabric, plastic, or other suitable backing
material in which medication is usually incorporated for topical
application to the skin.
21 CFR 358.510 Corn and callus remover active ingredients.
The product consists of any of the following active ingredients
within the specified concentrations and in the dosage form established
for each ingredient.
(a) Salicylic acid 12 to 40 percent in a plaster vehicle.
(b) Salicylic acid 12 to 17.6 percent in a collodion-like vehicle.
21 CFR 358.550 Labeling of corn and callus remover drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
''corn and callus remover.''
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the phrase listed in paragraph (b)(1) of this
section and may contain the additional phrase listed in paragraph (b)(2)
of this section. Other truthful and nonmisleading statements,
describing only the indications for use that have been established in
paragraph (b) of this section, may also be used, as provided in
330.1(c)(2) of this chapter, subject to the provisions of section 502 of
the Federal Food, Drug, and Cosmetic Act (the act) relating to
misbranding and the prohibition in section 301(d) of the act against the
introduction or delivery for introduction into interstate commerce of
unapproved new drugs in violation of section 505(a) of the act.
(1) ''For the removal of corns and calluses.''
(2) In addition to the information identified in paragraph (b)(1) of
this section, the labeling of the product may contain the following
statement: ''Relieves pain by removing corns and calluses.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) For products containing any ingredient identified in 358.510.
(i) ''For external use only.''
(ii) ''Do not use this product on irritated skin, on any area that is
infected or reddened, if you are a diabetic, or if you have poor blood
circulation.''
(iii) ''If discomfort persists, see your doctor or podiatrist.''
(2) For any product formulated in a flammable vehicle. (i) The
labeling should contain an appropriate flammability signal word, e.g.,
''extremely flammable,'' ''flammable,'' ''combustible,'' consistent with
16 CFR 1500.3(b)(10).
(ii) ''Keep away from fire or flame.''
(3) For any product formulated in a volatile vehicle. ''Cap bottle
tightly and store at room temperature away from heat.''
(4) For any product formulated in a collodion-like vehicle. (i) ''If
product gets into the eye, flush with water for 15 minutes.''
(ii) ''Avoid inhaling vapors.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions'':
(1) For products containing salicylic acid identified in 358.510(a).
''Wash affected area and dry thoroughly.'' (If appropriate: ''Cut
plaster to fit corn/callus.'') ''Apply medicated plaster. After 48
hours remove the medicated plaster. Repeat this procedure every 48
hours as needed for up to 14 days (until corn/callus is removed).''
(Optional: ''May soak corn/callus in warm water for 5 minutes to assist
in removal.'')
(2) For products containing salicylic acid identified in 358.510(b).
''Wash affected area and dry thoroughly. Apply one drop at a time to
sufficiently cover each corn/callus. Let dry. Repeat this procedure
once or twice daily as needed for up to 14 days (until corn/callus is
removed).'' (Optional: ''May soak corn/callus in warm water for 5
minutes to assist in removal.'')
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
21 CFR 358.550 Subpart G -- (Reserved)
21 CFR 358.550 Subpart H -- Drug Products for the Control of Dandruff,
Seborrheic Dermatitis, and Psoriasis
Source: 56 FR 63568, Dec. 4, 1991, unless otherwise noted.
Effective Date Note: At 56 FR 63568, Dec. 4, 1991, 358.701 --
358.750 (subpart H) was added effective December 4, 1992.
21 CFR 358.701 Scope.
(a) An over-the-counter dandruff, seborrheic dermatitis, or psoriasis
drug product in a form suitable for topical application is generally
recognized as safe and effective and is not misbranded if it meets each
of the conditions in this subpart and each general condition established
in 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21 unless otherwise noted.
21 CFR 358.703 Definitions.
As used in this subpart:
(a) Coal tar. The tar used for medicinal purposes that is obtained
as a byproduct during the destructive distillation of bituminous coal at
temperatures in the range of 900 C to 1,100 C. It may be further
processed using either extraction with alcohol and suitable dispersing
agents and maceration times or fractional distillation with or without
the use of suitable organic solvents.
(b) Dandruff. A condition involving an increased rate of shedding of
dead epidermal cells of the scalp.
(c) Psoriasis. A condition of the scalp or body characterized by
irritation, itching, redness, and extreme excess shedding of dead
epidermal cells.
(d) Seborrheic dermatitis. A condition of the scalp or body
characterized by irritation, itching, redness, and excess shedding of
dead epidermal cells.
21 CFR 358.710 Active ingredients for the control of dandruff,
seborrheic dermatitis, or psoriasis.
The active ingredient of the product consists of any of the following
within the specified concentration established for each ingredient:
(a) Active ingredients for the control of dandruff. (1) Coal tar,
0.5 to 5 percent. When a coal tar solution, derivative, or fraction is
used as the source of the coal tar, the labeling shall specify the
identity and concentration of the coal tar source used and the
concentration of the coal tar present in the final product.
(2) Pyrithione zinc, 0.3 to 2 percent when formulated to be applied
and then washed off after brief exposure.
(3) Pyrithione zinc, 0.1 to 0.25 percent when formulated to be
applied and left on the skin or scalp.
(4) Salicylic acid, 1.8 to 3 percent.
(5) Selenium sulfide, 1 percent.
(6) Sulfur, 2 to 5 percent.
(b) Active ingredients for the control of seborrheic dermatitis. (1)
Coal tar, 0.5 to 5 percent. When a coal tar solution, derivative, or
fraction is used as the source of the coal tar, the labeling shall
specify the identity and concentration of the coal tar source used and
the concentration of the coal tar present in the final product.
(2) Pyrithione zinc, 0.95 to 2 percent when formulated to be applied
and then washed off after brief exposure.
(3) Pyrithione zinc, 0.1 to 0.25 percent when formulated to be
applied and left on the skin or scalp.
(4) Salicylic acid, 1.8 to 3 percent.
(5) Selenium sulfide, 1 percent.
(c) Active ingredients for the control of psoriasis. (1) Coal tar,
0.5 to 5 percent. When a coal tar solution, derivative, or fraction is
used as the source of the coal tar, the labeling shall specify the
identity and concentration of the coal tar source used and the
concentration of the coal tar present in the final product.
(2) Salicylic acid, 1.8 to 3 percent.
21 CFR 358.720 Permitted combinations of active ingredients.
Salicylic acid identified in 358.710(a) (4) may be combined with
sulfur identified in 358.710(a)(6) provided each ingredient is present
within the established concentration and the product is labeled for the
control of dandruff.
21 CFR 358.750 Labeling of drug products for the control of dandruff,
seborrheic dermatitis, or psoriasis.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product with
one or more of the following, as appropriate:
(1) ''Dandruff (insert product form)'' or ''antidandruff (insert
product form)''.
(2) ''Seborrheic dermatitis (insert product form)''.
(3) ''Psoriasis (insert product form)''.
(b) Indications. The labeling of the product states, under the
heading ''Indications,'' the phrase listed in paragraph (b)(1) of this
section and may contain any of the terms listed in paragraph (b)(2) or
(b)(3) of this section. Other truthful and nonmisleading statements,
describing only the indications for use that have been established and
listed in paragraph (b) of this section, may also be used, as provided
in 330.1(c)(2) of this chapter, subject to the provisions of section
502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to
misbranding and the prohibition in section 301(d) of the act against the
introduction or delivery for introduction into interstate commerce of
unapproved new drugs in violation of section 505(a) of the act.
(1) (''For relief of'' or ''Controls'') ''the symptoms of'' (select
one or more of the following, as appropriate: ''dandruff,''
''seborrheic dermatitis,'' and/or ''psoriasis.'')
(2) The following terms or phrases may be used in place of or in
addition to the words ''For the relief of'' or ''Controls'' in the
indications in paragraph (b)(1) of this section: ''fights,''
''reduces,'' ''helps eliminate,'' ''helps stop,'' ''controls recurrence
of,'' ''fights recurrence of,'' ''helps prevent recurrence of,''
''reduces recurrence of,'' ''helps eliminate recurrence of,'' ''helps
stop recurrence of.''
(3) The following terms may be used in place of the words ''the
symptoms of'' in the indications in paragraph (b)(1) of this section:
(''skin'' and/or ''scalp,'' as appropriate) (select one or more of the
following: ''itching,'' ''irritation,'' ''redness,'' ''flaking,''
''scaling,'') ''associated with.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ''Warnings'':
(1) For products containing any ingredient identified in 358.710.
(i) ''For external use only.''
(ii) ''Avoid contact with the eyes. If contact occurs, rinse eyes
thoroughly with water.''
(iii) ''If condition worsens or does not improve after regular use of
this product as directed, consult a doctor.''
(2) For any product containing coal tar identified in 358.710(a),
(b), or (c). (i) ''Use caution in exposing skin to sunlight after
applying this product. It may increase your tendency to sunburn for up
to 24 hours after application.''
(ii) ''Do not use for prolonged periods without consulting a
doctor.''
(3) For products containing coal tar when formulated to be applied
and left on the skin (e.g., creams, ointments, lotions). ''Do not use
this product in or around the rectum or in the genital area or groin
except on the advice of a doctor.''
(4) For products containing coal tar identified in 358.710(c) for
the control of psoriasis. ''Do not use this product with other forms of
psoriasis therapy such as ultraviolet radiation or prescription drugs
unless directed to do so by a doctor.''
(5) For products containing any ingredient identified in 358.710(b)
or (c) for the control of seborrheic dermatitis or psoriasis. ''If
condition covers a large area of the body, consult your doctor before
using this product.''
(d) Directions. The labeling of the product contains the following
information under the heading ''Directions.'' More detailed directions
applicable to a particular product formulation may also be included.
(1) For products containing active ingredients for the control of
dandruff, seborrheic dermatitis, or psoriasis when formulated to be
applied and then washed off after brief (a few minutes) exposure (e.g,
shampoos, preshampoo rinses, postshampoo rinses). ''For best results
use at least twice a week or as directed by a doctor.''
(2) For products containing active ingredients for the control of
dandruff, seborrheic dermatitis, or psoriasis when formulated so as to
be applied and left on the skin or scalp (e.g., creams, ointments,
lotions, hairgrooms). ''Apply to affected areas one to four times daily
or as directed by a doctor.''
(3) For products containing active ingredients for the control of
seborrheic dermatitis or psoriasis of the skin when formulated as soaps.
''Use on affected areas in place of your regular soap.''
(e) The word ''physician'' may be substituted for the word ''doctor''
in any of the labeling statements in this section.
21 CFR 358.750 PART 361 -- PRESCRIPTION DRUGS FOR HUMAN USE GENERALLY
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED: DRUGS USED IN
RESEARCH
Authority: Secs. 201, 501, 502, 503, 505, 701 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 371); sec.
351 of the Public Health Service Act (42 U.S.C. 262).
21 CFR 361.1 Radioactive drugs for certain research uses.
(a) Radioactive drugs (as defined in 310.3(n) of this chapter) are
generally recognized as safe and effective when administered, under the
conditions set forth in paragraph (b) of this section, to human research
subjects during the course of a research project intended to obtain
basic information regarding the metabolism (including kinetics,
distribution, and localization) of a radioactively labeled drug or
regarding human physiology, pathophysiology, or biochemistry, but not
intended for immediate therapeutic, diagnostic, or similar purposes or
to determine the safety and effectiveness of the drug in humans for such
purposes (i.e., to carry out a clinical trial). Certain basic research
studies, e.g., studies to determine whether a drug localizes in a
particular organ or fluid space and to describe the kinetics of that
localization, may have eventual therapeutic or diagnostic implications,
but the initial studies are considered to be basic research within the
meaning of this section.
(b) The conditions under which use of radioactive drugs for research
are considered safe and effective are:
(1) Approval by Radioactive Drug Research Committee. A Radioactive
Drug Research Committee, composed and approved by the Food and Drug
Administration in accordance with paragraph (c) of this section, has
determined, in accordance with the standards set forth in paragraph (d)
of this section, that:
(i) The pharmacological dose is within the limits set forth in
paragraph (b)(2) of this section;
(ii) The radiation dose is within the limits set forth in paragraph
(b)(3) of this section;
(iii) The radiation exposure is justified by the quality of the study
being undertaken and the importance of the information it seeks to
obtain;
(iv) The study meets the other requirements set forth in paragraph
(d) of this section regarding qualifications of the investigator, proper
licensure for handling radioactive materials, selection and consent of
research subjects, quality of radioactive drugs used, research protocol
design, reporting of adverse reactions, and approval by an appropriate
Institutional Review Committee; and
(v) The use of the radioactive drug in human subjects has the
approval of the Radioactive Drug Research Committee.
(2) Limit on pharmacological dose. The amount of active ingredient
or combination of active ingredients to be administered shall be known
not to cause any clinically detectable pharmacological effect in human
beings. If the same active ingredients (exclusive of the radionuclide)
are to be administered simultaneously, e.g., under a ''Investigational
New Drug Application'' or for a therapeutic use in accordance with
labeling for a drug approved under Part 314 of this chapter, the total
amount of active ingredients including the radionuclide shall be known
not to exceed the dose limitations applicable to the separate
administration of the active ingredients excluding the radionuclide.
(3) Limit on radiation dose. The amount of radioactive material to
be administered shall be such that the subject receives the smallest
radiation dose with which it is practical to perform the study without
jeopardizing the benefits to be obtained from the study.
(i) Under no circumstances may the radiation dose to an adult
research subject from a single study or cumulatively from a number of
studies conducted within 1 year be generally recognized as safe if such
dose exceeds the following:
Whole body, active blood-forming organs, lens of the eye, and gonads:
(ii) For a research subject under 18 years of age at his last
birthday, the radiation dose shall not exceed 10 percent of that set
forth in paragraph (b)(3)(i) of this section.
(iii) All radioactive material included in the drug either as
essential material or as a significant contaminant or impurity shall be
included when determining the total radiation doses and dose
commitments. Radiation doses from x-ray procedures that are part of the
research study (i.e., would not have occurred but for the study) shall
also be included. The possibility of followup studies shall be
considered for inclusion in the dose calculations.
(iv) Numerical definitions of dose shall be based on an absorbed
fraction method of radiation absorbed dose calculation, such as the
system set forth by the Medical Internal Radiation Dose Committee of the
Society of Nuclear Medicine, or the system set forth by the
International Commission on Radiological Protection.
(c) A Radioactive Drug Research Committee, in order to comply with
paragraph (b)(1) of this section, shall be composed, shall function, and
shall obtain and maintain approval of the Food and Drug Administration
in conformity with the following:
(1) Membership. A Radioactive Drug Research Committee shall consist
of at least five individuals. Each committee shall include the
following three individuals: (i) A physician recognized as a specialist
in nuclear medicine, (ii) a person qualified by training and experience
to formulate radioactive drugs, and (iii) a person with special
competence in radiation safety and radiation dosimetry. The remainder
of the committee shall consist of individuals qualified in various
disciplines pertinent to the field of nuclear medicine (e.g., radiology,
internal medicine, clinical pathology, hematology, endocrinology,
radiation therapy, radiation physics, radiation biophysics, health
physics, and radiopharmacy). Membership shall be sufficiently diverse
to permit expert review of the technical and scientific aspects of
proposals submitted to the committee. The addition of consultants in
other pertinent medical disciplines is encouraged. A Radioactive Drug
Research Committee shall be either associated with a medical institution
operated for care of patients and with sufficient scientific expertise
to allow for selection of committee members from its faculty, or with a
committee established by a State authority to provide advice on
radiation health matters. Joint committees involving more than one
medical institution which have been established in order to achieve a
high level and diversity of experience will be acceptable. The Director
of the Center for Drug Evaluation and Research may modify any of the
foregoing requirements in a particular situation where alternative
factors provide substantially the same composition and association.
(2) Function. Each Radioactive Drug Research Committee shall select
a chairman, who shall sign all applications, minutes, and reports of the
committee. Each committee shall meet at least once each quarter in
which research activity has been authorized or conducted. A quorum
consisting of more than 50 percent of the membership must be present
with appropriate representation of the required fields of
specialization. Minutes shall be kept and shall include the numerical
results of votes on protocols involving use in human subjects. No
member shall vote on a protocol in which he is an investigator.
(3) Reports. Each Radioactive Drug Research Committee shall submit
an annual report on or before January 31 of each year to the Food and
Drug Administration, Center for Drug Evaluation and Research, HFD-160,
5600 Fishers Lane, Rockville, MD 20857. The annual report shall include
the names and qualifications of the members of, and of any consultants
used by, the Radioactive Drug Research Committee, and, for each study
conducted during the preceding year, a summary of information presented
in the following format:
1. Title of the research project.
2. Brief description of the purpose of the research project.
3. Name of the investigator responsible.
4. Pharmacological dose:
a. Active ingredients.
b. Maximum amount administered per subject.
5. Name of the radionuclide(s) used, including any present, as
significant contaminants or impurities.
6. Radiation absorbed dose. Provide the maximum dose commitement to
the whole body and each organ specified in 21 CFR 361.1(b)(3)(i) that
was received by a representative subject and the calculations or
references that were used to estimate these maximum dose commitments.
The report shall include the dose contribution of both the administered
radionuclide(s) and any X-ray procedures associated with the study. If
the study elicits data on the uptake or excretion of the radioactive
drug pertinent to the estimation of dose commitment, report the mean
value and range of values. For each subject provide:
(a) Age, sex, and approximate weight.
(b) Total activity of each radionuclide administered for each
radioactive drug used in the study. Report each X-ray procedure used in
conjunction with the study.
(c) If the subject has participated in other radioactive drug
research studies, report the name of the radioactive drug used in these
other studies, the date of administration, and the total activity of
each radionuclide administered. If any X-ray procedures were used,
identify the X-ray procedure(s) and include an estimate of the absorbed
radiation doses.
(d) If more than one administration of a radioactive drug per
subject, cumulative radiation dose and dose commitment, expressed as
whole body, active blood-forming organs, lens of the eye, gonads, and
other organ doses from the administered radionuclides.
7. A claim of confidentiality, if any.
Note: Contents of this report are available for public disclosure
unless confidentiality is requested by the investigator and it is
adequately shown by the investigator that the report constitutes a trade
secret or confidential commercial information as defined in 21 CFR
20.61.
Investigator
Chairman, Radioactive Drug
Research Committee
At any time a proposal is approved which involves exposure either of
more than 30 research subjects, or of any research subject under 18
years of age, the committee shall immediately submit to the Food and
Drug Administration a special summary of information in the format shown
in this paragraph. Contents of these reports are available for public
disclosure, unless confidentiality is requested by the investigator and
it is adequately shown by the investigator that the report constitutes a
trade secret or confidential commercial information as defined in 20.61
of this chapter.
(4) Approval. Each Radioactive Drug Research Committee shall be
specifically approved by the Center for Drug Evaluation and Research of
the Food and Drug Administration. Applications shall be submitted to
the Food and Drug Administration, Center for Drug Evaluation and
Research, HFD-160, 5600 Fishers Lane, Rockville, MD 20857, and shall
contain the names and qualifications of the members of the committee,
and a statement that the committee agrees to comply with the
requirements set forth in this section. Approval shall be based upon an
assessment of the qualifications of the members of the committee, and
the assurance that all necessary fields of expertise are covered.
Approval of a committee may be withdrawn at any time for failure of the
committee to comply with any of the requirements of this section.
Approval of a committee shall remain effective unless and until the FDA
withdraws such approval. Changes in membership and applications for new
members shall be submitted to the Food and Drug Administration as soon
as, or before, vacancies occur on the committee.
(5) Monitoring. The Food and Drug Administration shall conduct
periodic reviews of approved committees. Monitoring of the activities
of the committee shall be conducted through review of its annual report,
through review of minutes and full protocols for certain studies, and
through on-site inspections.
(d) In making the determination required in paragraph (b)(1) of this
section, a Radioactive Drug Research Committee shall consider the
following requirements and assure that each is met:
(1) Radiation dose to subjects. To assure that the radiation dose to
research subjects is as low as practicable to perform the study and meet
the criteria of 361.1(b)(3), the Radioactive Drug Research Committee
shall require that:
(i) The investigator provide absorbed dose calculations based on
biologic distribution data available from published literature or from
other valid studies.
(ii) The investigator provide for an acceptable method of radioassay
of the radioactive drug prior to its use to assure that the dose
calculations actually reflect the administered dose.
(iii) The radioactive drug chosen for the study has that combination
of half-life, types of radiations, radiation energy, metabolism,
chemical properties, etc., which results in the lowest dose to the whole
body or specific organs with which it is possible to obtain the
necessary information.
(iv) The investigator utilize adequate and appropriate
instrumentation for the detection and measurement of the specific
radionuclide.
(2) Pharmacological dosage. To determine that the amount of active
ingredients to be administered does not exceed the limitations set forth
in paragraph (b)(2) of this section, the committee shall require that
the investigator provide pharmacological dose calculations based on data
available from published literature or from other valid human studies.
(3) Qualifications of investigators. Each investigator shall be
qualified by training and experience to conduct the proposed research
studies.
(4) License to handle radioactive materials. The responsible
investigator or institutions shall, in the case of reactor-produced
isotopes, be licensed by the Nuclear Regulatory Commission or Agreement
State to possess and use the specific radionuclides for research use or
be a listed investigator under a broad license, or in the case of
non-reactor-produced isotopes, be licensed by other appropriate State or
local authorities, when required by State or local law, to possess and
use the specific radionuclides for research use.
(5) Human research subjects. Each investigator shall select
appropriate human subjects and shall obtain the review and approval of
an institutional review committee that conforms to the requirements of
Part 56 of this chapter, and shall obtain the consent of the subjects or
their legal representatives in accordance with Part 50 of this chapter.
The research subjects shall be at least 18 years of age and legally
competent. Exceptions are permitted only in those special situations
when it can be demonstrated to the committee that the study presents a
unique opportunity to gain information not currently available, requires
the use of research subjects less than 18 years of age, and is without
significant risk to the subject. Studies involving minors shall be
supported with review by qualified pediatric consultants to the
Radioactive Drug Research Committee. Each female research subject of
childbearing potential shall state in writing that she is not pregnant,
or, on the basis of a pregnancy test be confirmed as not pregnant,
before she may participate in any study.
(6) Quality of radioactive drug. The radioactive drug used in the
research study shall meet appropriate chemical, pharmaceutical,
radiochemical, and radionuclidic standards of identity, strength,
quality, and purity as needed for safety and be of such uniform and
reproducible quality as to give significance to the research study
conducted. The Radioactive Drug Research Committee shall determine that
radioactive materials for parenteral use are prepared in sterile and
pyrogen-free form.
(7) Research protocol. No matter how small the amount of
radioactivity, no study involving administration of a radioactive drug,
as defined in 310.3(n) of this chapter, to research subjects under this
section, shall be permitted unless the Radioactive Drug Research
Committee concludes, in its judgment, that scientific knowledge and
benefit is likely to result from that study. Therefore, the protocol
shall be based upon a sound rationale derived from appropriate animal
studies or published literature and shall be of sound design such that
information of scientific value may result. The radiation dose shall be
both sufficient and no greater than necessary to obtain valid
measurement. The projected number of subjects shall be sufficient but
no greater than necessary for the purpose of the study. The number of
subjects shall also reflect the fact that the study is intended to
obtain basic research information referred to in paragraph (a) of this
section and not intended for immediate therapeutic, diagnostic or
similar purposes or to determine the safety and effectiveness of the
drug in humans for such purposes (i.e., to carry out a clinical trial).
(8) Adverse reactions. The investigator shall immediately report to
the Radioactive Drug Research Committee all adverse effects associated
with the use of the radioactive drug in the research study. All adverse
reactions probably attributable to the use of the radioactive drug in
the research study shall be immediately reported by the Radioactive Drug
Research Committee to the Food and Drug Administration, Center for Drug
Evaluation and Research, HFD-160, 5600 Fishers Lane, Rockville, MD
20857.
(9) Approval by an institutional review board. The investigator
shall obtain the review and approval of an institutional review board
that conforms to the requirements of Part 56 of this chapter.
(e) The results of any research conducted pursuant to this section as
part of the evaluation of a drug pursuant to part 312 of this chapter
shall be included in the submissions required under part 312 of this
chapter.
(f) A radioactive drug prepared, packaged, distributed, and primarily
intended for use in accordance with the requirements of this section
shall be exempt from section 502(f)(1) of the act and 201.5 and
201.100 of this chapter if the packaging, label, and labeling are in
compliance with Federal, State, and local law regarding radioactive
materials and if the label of the immediate container and shielded
container, if any, either separate from or as part of any label and
labeling required for radioactive materials by the Nuclear Regulatory
Commission or by State or local radiological health authorities bear the
following:
(1) The statement ''Caution: Federal law prohibits dispensing
without prescription'';
(2) The statement ''To be administered in compliance with the
requirements of Federal regulations regarding radioactive drugs for
research use (21 CFR 361.1)'';
(3) The established name of the drug, if any;
(4) The established name and quantity of each active ingredient;
(5) The name and half-life of the radionuclide, total quantity of
radioactivity in the drug product's immediate container, and amount of
radioactivity per unit volume or unit mass at a designated referenced
time;
(6) The route of administration, if it is for the other than oral
use;
(7) The net quantity of contents;
(8) An identifying lot or control number from which it is possible to
determine the complete manufacturing history of the package of the drug;
(9) The name and address of the manufacturer, packer, or distributor;
(10) The expiration date, if any;
(11) If the drug is intended for parenteral use, a statement as to
whether the contents are sterile;
(12) If the drug is for other than oral use, the names of all
inactive ingredients, except that:
(i) Trace amounts of harmless substances added solely for individual
product identification need not be named.
(ii) If the drug is intended for parenteral use, the quantity or
proportion of all inactive ingredients, except that ingredients added to
adjust pH or to make the drug isotonic may be declared by name and a
statement of their effect; if the vehicle is water for injection, it
need not be named. Provided, however, That in the case of containers
too small or otherwise unable to accommodate a label with sufficient
space to bear all such information, the information required by
paragraphs (f) (1) and (12) of this section may be placed on the
shielded container only.
(40 FR 31308, July 25, 1975, as amended at 40 FR 44543, Sept. 29,
1975; 42 FR 15674, Mar. 22, 1977; 43 FR 14646, Apr. 7, 1978; 46 FR
8955, Jan. 27, 1981; 49 FR 44460, Nov. 7, 1984; 50 FR 8996, Mar. 6,
1985; 55 FR 11582, Mar. 29, 1990; 56 FR 10806, Mar. 14, 1991)
21 CFR 361.1 PART 369 -- INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND DEVICES FOR OVER-THE-COUNTER SALE
21 CFR 361.1 Subpart A -- Definitions and Interpretations
Sec.
369.1 Purpose of issuance.
369.2 Definitions.
369.3 Warnings required on drugs exempted from
prescription-dispensing requirements of section 503(b)(1)(C).
369.4 Warnings suggested for drugs by formal or informal statements
of policy.
369.5 Warnings required on insulin intended for over-the-counter
sale.
369.6 (Reserved)
369.7 Warnings required by official compendia.
369.8 Warning statements in relation to conditions for use.
369.9 General warnings re accidental ingestion by children.
369.10 Conspicuousness of warning statements.
21 CFR 361.1 Subpart B -- Warning and Caution Statements for Drugs
369.20 Drugs; recommended warning and caution statements.
369.21 Drugs; warning and caution statements required by
regulations.
369.22 Drugs; warning and caution statements specifically required
by law.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353,
355, 356, 357, 371).
Source: 39 FR 11745, Mar. 29, 1974, unless otherwise noted.
21 CFR 361.1 Subpart A -- Definitions and Interpretations
21 CFR 369.1 Purpose of issuance.
The warning and caution statements suggested in Subparts B and C of
this part, for inclusion in the label or labeling of drugs and devices
subject to section 502(d) and (f)(2) and other relevant provisions of
the Federal Food, Drug, and Cosmetic Act are issued for the purpose of
assisting industry in preparing proper labeling for these articles for
over-the-counter sale and in meeting the legal requirements of the act
that the label or labeling of drugs and devices bear adequate warnings,
in such manner and form as are necessary for the protection of users.
Only section 502(d) of the act requires use of the specific language
included in these suggested warning and caution statements. These
suggested warning or caution statements are illustrative of those that
may be necessary or desirable. It is the responsibility of the
manufacturer, packer, shipper, or distributor in interstate commerce to
see that such statements are adequate for compliance with the provisions
of the law. Omission of any article from this suggested list does not
relieve drugs and devices subject to provisions of the act from bearing
adequate warning or caution statements where such statements are
necessary or desirable for the protection of the user.
21 CFR 369.2 Definitions.
(a) As used in this part, the term act means the Federal Food, Drug,
and Cosmetic Act.
(b) The terms drugs and devices are defined in section 201(g) and (k)
of the act.
(c) Official compendia are defined in section 201(j) of the act.
21 CFR 369.3 Warnings required on drugs exempted from
prescription-dispensing requirements of section 503(b)(1)(C).
Drugs exempted from prescription-dispensing requirements under
section 503(b)(1)(C) of the act are subject to the labeling requirements
prescribed in 310.201(a) of this chapter. Although, for convenience,
warning and caution statements for a number of the drugs named in
310.201 of this chapter (cross-referenced in the text of this part) are
included in Subpart B of this part, the inclusion of such drugs in
369.20, 369.21, 369.22 in no way affects the requirements for compliance
with 310.201(a) of this chapter, or the provisions of an effective
application pursuant to section 505(b) of the act.
21 CFR 369.4 Warnings suggested for drugs by formal or informal
statements of policy.
The warning and caution statements included in Subpart B of this part
in no way affect any warning statement suggested for such drugs or
devices by any statement of policy or interpretation in Subchapter C of
this chapter.
(39 FR 11745, Mar. 29, 1974, as amended at 40 FR 13496, Mar. 27,
1975)
21 CFR 369.5 Warnings required on insulin intended for over-the-counter
sale.
Warning and caution statements for insulin products sold over the
counter must comply with the specific labeling provisions of the act and
429.11 of this chapter.
369.6 (Reserved)
21 CFR 369.7 Warnings required by official compendia.
Any drug included in the official compendia defined by the act shall
bear such warning or caution statement as may be required by such
compendia, and no statement in Subpart B or Subpart C of this part is
intended to alter, modify, or permit the omission of any such statement
required by such compendia.
21 CFR 369.8 Warning statements in relation to conditions for use.
The mention in any warning or caution statement included in Subparts
A, B, and C of this part, of a disease condition does not imply a
finding on the part of the Food and Drug Administration that any drug or
device is efficacious in such condition; nor is any drug or device
bearing labeling referring to such disease condition precluded from
regulatory action under the applicable provisions of the act if such
claim is considered to be misbranding.
21 CFR 369.9 General warnings re accidental ingestion by children.
Section 369.20 includes under certain items, but not all medicines,
the statement: ''Warning -- Keep this and all medicines out of
children's reach. In case of accidental overdose, contact a physician
immediately'', or ''Warning -- Keep out of the reach of children''.
However, in view of the possibility of accidental ingestion of drugs, it
is not only suggested but is recommended that one of these statements be
used on the label of all drug products.
21 CFR 369.10 Conspicuousness of warning statements.
Necessary warning statements should appear in the labeling
prominently and conspicuously as compared to other words, statements,
designs, and devices, and in bold type on clearly contrasting
background, in order to comply with the provisions of section 502(c) and
(f)(2) of the act. The warning statements should be placed in the
labeling in juxtaposition with the directions for use and, in any case,
should appear on the label when there is sufficient label space in
addition to mandatory label information.
21 CFR 369.10 Subpart B -- Warning and Caution Statements for Drugs
21 CFR 369.20 Drugs; recommended warning and caution statements.
ACETANILID.
Warning -- Do not exceed recommended dosage. Overdosage or continued
use may result in serious blood disturbances.
ACETOPHENETIDIN CONTAINING PREPARATIONS. (See 201.309 of this
chapter.)
Warning -- This medication may damage the kidneys when used in large
amounts or for a long period of time. Do not take more than the
recommended dosage, nor take regularly for longer than 10 days without
consulting your physician.
ANESTHETICS FOR EXTERNAL USE (LOCAL ANESTHETICS). (See also
310.201(a)(19) and (23) of this chapter.)
Caution -- Do not use in the eyes. Not for prolonged use. If the
condition for which this preparation is used persists or if a rash or
irritation develops, discontinue use and consult physician.
ANTIHISTAMINICS FOR EXTERNAL USE (EXCEPT PREPARATIONS FOR OPHTHALMIC
USE).
Caution -- Do not use in the eyes. If the condition for which this
preparation is used persists or if a rash or irritation develops,
discontinue use and consult physician.
ANTIHISTAMINICS, ORAL. (See also 201.307 and 310.201(a)(4), (6),
(13), (24), and (25) of this chapter.)
Caution -- This preparation may cause drowsiness. Do not drive or
operate machinery while taking this medication. Do not give to children
under 6 years of age or exceed the recommended dosage unless directed by
physician.
The reference to drowsiness is not required on preparations for the
promotion of sleep or on preparations that are shown not to produce
drowsiness.
ANTIPERSPIRANTS.
Do not apply to broken skin. If a rash develops, discontinue use.
ANTIPYRINE.
Warning -- Do not exceed recommended dosage. If skin rash appears,
discontinue use and consult physician.
ANTISEPTICS FOR EXTERNAL USE.
Caution -- In case of deep or puncture wounds or serious burns,
consult physician. If redness, irritation, swelling, or pain persists
or increases or if infection occurs discontinue use and consult
physician.
The reference to wounds and burns is not required on preparations
intended solely for diaper rash.
ARSENIC PREPARATIONS.
Warning -- Frequent or prolonged use may cause serious injury. Do
not exceed recommended dosage. Keep out of the reach of children.
BELLADONNA PREPARATIONS AND PREPARATIONS OF ITS ALKALOIDS (ATROPINE,
HYOSCYAMINE, AND SCOPOLAMINE (HYOSCINE); HYOSCYAMUS, STRAMONIUM, THEIR
DERIVATIVES, AND RELATED DRUG PREPARATIONS.
Warning -- Not to be used by persons having glaucoma or excessive
pressure within the eye, by elderly persons (where undiagnosed glaucoma
or excessive pressure within the eye occurs most frequently), or by
children under 6 years of age, unless directed by a physician.
Discontinue use if blurring of vision, rapid pulse, or dizziness occurs.
Do not exceed recommended dosage. Not for frequent or prolonged use.
If dryness of the mouth occurs, decrease dosage. If eye pain occurs,
discontinue use and see your physician immediately as this may indicate
undiagnosed glaucoma.
In the case of scopolamine or scopolamine aminoxide preparations
indicated for insomnia, the portion of the above warning that reads
''children under 6 years of age'' should read instead ''children under
12 years of age''.
BORIC ACID (POWDERED, CRYSTALLINE, OR GRANULAR).
Warning -- Do not use as a dusting powder, especially on infants, or
take internally. Use only as a solution. Do not apply to badly broken
or raw skin, or to large areas of the body.
BROMIDES.
Caution -- Use only as directed. Do not give to children or use in
the presence of kidney disease. If skin rash appears or if nervous
symptoms persist, recur frequently, or are unusual, discontinue use and
consult physician.
CARBOLIC ACID (PHENOL) PREPARATIONS (MORE THAN 0.5 PERCENT) FOR
EXTERNAL USE.
Warning -- Use according to directions. Do not apply to large areas
of the body. If applied to fingers or toes, do not bandage.
CATHARTICS AND LAXATIVES -- IRRITANTS AND OTHER PERISTALTIC
STIMULANTS.
Warning -- Do not use when abdominal pain, nausea, or vomiting are
present. Frequent or prolonged use of this preparation may result in
dependence on laxatives.
Mercury preparations should have added to the ''frequent use''
statement, the words ''and serious mercury poisoning''.
Phenolphthalein preparations should bear, in addition to the general
warning, the following statement:
Caution -- If skin rash appears, do not use this or any other
preparation containing phenolphthalein.
See also Mineral Oil Laxatives.
CHLORATES: MOUTH WASH OR GARGLE.
Avoid swallowing.
COBALT PREPARATIONS (See also 250.106 of this chapter.)
Warning -- Do not exceed the recommended dosage. Do not administer
to children under 12 years of age unless directed by physician. Do not
use for more than 2 months unless directed by physician.
This warning is not required on articles containing not more than 0.5
milligram of cobalt as a cobalt salt per dosage unit and which recommend
administration of not more than 0.5 milligram per dose and not more than
2 milligrams per 24-hour period.
''COUGH-DUE-TO-COLD'' PREPA- RATIONS. (See also 310.201(a)(20) of
this chapter.)
Warning -- Persons with a high fever or persistent cough should not
use this preparation unless directed by physician.
COUNTERIRRITANTS AND RUBEFACIENTS.
Caution -- Do not apply to irritated skin or if excessive irritation
develops. Avoid getting into the eyes or on mucous membranes.
If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
Caution -- If pain persists for more than 10 days, or redness is
present, or in conditions affecting children under 12 years of age
consult a physician immediately.
See also ''Salicylates'' in this section for additional warnings for
preparations containing methyl salicylate.
CREOSOTE, CRESOLS, GUAIACOL, AND SIMILAR SUBSTANCES IN PREPARATIONS
FOR EXTERNAL USE.
Caution -- Do not apply to large areas of the body.
CREOSOTE, CRESOLS, GUAIACOL, AND SIMILAR SUBSTANCES IN DOUCHE
PREPARATIONS.
Warning -- The use of solutions stronger than those recommended may
result in severe local irritation, burns, or serious poisoning. Mix as
directed before pouring into douche bag. Do not use more often than
twice weekly unless directed by physician.
DENTURE RELINERS, PADS, AND CUSHIONS.
Warning -- For temporary use only. Long-term use of this product may
lead to faster bone loss, continuing irritation, sores, and tumors. For
Use Only Until a Dentist Can Be Seen.
DENTURE REPAIR KITS.
Warning -- For emergency repairs only. Long-term use of
home-repaired dentures may cause faster bone loss, continuing
irritation, sores, and tumors. This kit for emergency use only. See
Dentist Without Delay.
DIARRHEA PREPARATIONS.
Warning -- Do not use for more than 2 days or in the presence of high
fever or in infants or children under 3 years of age unless directed by
a physician.
DOUCHE PREPARATIONS.
Warning -- Do not use more often than twice weekly unless directed by
physician.
See also Creosote * * * Douche for additional warning.
DRESSINGS, PROTECTIVE SPRAY-ON TYPE. (See also 310.201(a) (11) and
(18) of this chapter.)
Warning -- In case of deep or puncture wounds or serious burns
consult physician. If redness, irritation, swelling or pain persists or
increases or if infection occurs consult physician. Keep away from eyes
or other mucous membranes. Avoid inhaling.
See also Dispensers Pressurized by Gaseous Propellants * * * for
additional warnings to be included for products under pressure.
IODINE AND IODIDES (ORAL).
Caution -- If a skin rash appears, discontinue use and consult
physician.
MERCURY PREPARATIONS FOR EXTERNAL USE.
Warning -- Discontinue use if rash or irritation develops or if
condition for which used persists. Frequent or prolonged use, or
application to large areas may cause serious mercury poisoning.
MINERAL OIL LAXATIVES. (See also 201.302 of this chapter.)
Caution -- Take only at bedtime. Avoid prolonged use. Do not
administer to infants or young children, in pregnancy, or to bedridden
or aged patients unless directed by physician.
NASAL PREPARATIONS: OIL BASE.
Warning -- Do not exceed recommended dosage nor use for prolonged
period. Do not administer to infants or children unless directed by
physician. Do not use as a spray.
NASAL PREPARATIONS IN PLASTIC SPRAY CONTAINERS.
Avoid overdosage. Follow directions for use carefully.
NASAL PREPARATIONS: VASOCONSTRICTORS (AMPHETAMINE, EPHEDRINE,
EPINEPHRINE, METHAMPHETAMINE, AND OTHERS OF SIMILAR ACTIVITY). (See
also 310.201(a)(16) of this chapter.)
Caution -- Do not exceed recommended dosage. Overdosage may cause
nervousness, restlessness, or sleeplessness. Do not use for more than 3
or 4 consecutive days unless directed by physician.
NASAL PREPARATIONS: VASOCONSTRICTORS (PHENYLEPH- RINE HYDROCHLORIDE,
HYDROXYAMPHETAMINE, PHENYL- PROPANOLAMINE, AND OTHERS OF SIMILAR
ACTIVITY).
Caution -- Do not exceed recommended dosage.
NUX VOMICA AND STRYCHNINE PREPARATIONS.
Warning -- Do not exceed the recommended dosage. Keep out of the
reach of children.
OPHTHALMIC PREPARATIONS. (See also 200.50 of this chapter.)
Boric acid offered for use in the preparation of ophthalmic solutions
should bear the statement: Prepare solution by boiling in water. Store
in a sterile container. Prepare sufficient for one day's use and
discard unused portion.
PHENACETIN-CONTAINING PREPARATION. (See acetophenetidin.)
PHENYLEPHRINE HYDROCHLO- RIDE PREPARATIONS, ORAL.
Caution -- Individuals with high blood pressure, heart disease,
diabetes, or thyroid disease should use only as directed by physician.
PHENYLPROPANOLAMINE HY- DROCHLORIDE PREPARATIONS, ORAL.
Caution -- Individuals with high blood pressure, heart disease,
diabetes, or thyroid disease should use only as directed by physician.
POTASSIUM PERMANGANATE AQUEOUS SOLUTIONS (CONTAINING NOT MORE THAN
0.04 PERCENT POTASSIUM PERMANGANATE). (See 250.108 of this chapter.)
Warning -- For external use on the skin only. Severe injury may
result from use internally or as a douche. Avoid contact with mucous
membranes.
QUININE AND OTHER CINCHONA DERIVATIVES (EXCEPT FOR USE IN MALARIA).
Caution -- Discontinue use if ringing in the ears, deafness, skin
rash, or visual disturbances occur.
RESINS, OLEORESINS, AND VOLATILE OILS.
Caution -- If nausea, vomiting, abdominal discomfort, diarrhea, or
skin rash occurs, discontinue use and consult physician.
RESORCINOL (NOT THE MONOACETATE) HAIR PREPARATIONS.
Caution -- Excessive use of this preparation may temporarily discolor
blond, white, or red hair.
SALICYLATES, INCLUDING ASPIRIN AND SALICYLAMIDE (EXCEPT METHYL
SALICYLATE, EFFERVESCENT SALICYLATE PREPARATIONS, AND PREPARATIONS OF
AMINOSALICYLIC ACID AND ITS SALTS). (See also 201.314 of this
chapter.)
Warning -- Keep this and all medicines out of children's reach. In
case of accidental overdose, contact a physician immediately; or
Warning -- Keep out of the reach of children.
If the article is an aspirin preparation, it should bear the first of
the above two warning statements. In either case, the above information
should appear on the label.
Caution -- For children under 3 years of age, consult your physician;
or
Caution -- For younger children, consult your physician.
One of the two immediately preceding caution statements is required
on the label of all aspirin tablets, but such a statement is not
required on the labels of other salicylates clearly offered for
administration to adults only.
If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
Caution -- If pain persists for more than 10 days, or redness is
present, or in conditions affecting children under 12 years of age,
consult a physician immediately.
SALICYLATES: METHYL SALICYLATE (WINTERGREEN OIL). See also
201.303 and 201.314 of this chapter.
Warning -- Do not use otherwise than as directed. Keep out of the
reach of children to avoid accidental poisoning.
If the preparation is a counterirritant or rubefacient the statement:
Caution -- Discontinue use if excessive irritation of the skin
develops. Avoid getting into the eyes or on mucous membranes.
If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
Caution -- If pain persists for more than 10 days, or redness is
present, or in conditions affecting children under 12 years of age
consult a physician immediately.
SILVER.
Caution -- Frequent or prolonged use of this preparation may result
in permanent discoloration of skin and mucous membranes.
SODIUM PERBORATE MOUTHWASH AND GARGLE AND TOOTHPASTE.
Caution -- Discontinue use if irritation or inflammation develops, or
increases. Avoid swallowing.
SULFONAMIDE NOSE DROPS.
Caution -- Do not use if a known allergy to sulfonamide drugs exists.
SULFUR PREPARATION FOR EXTERNAL USE.
Caution -- If undue skin irritation develops or increases,
discontinue use and consult physician.
THROAT PREPARATIONS FOR TEMPORARY RELIEF OF MINOR SORE THROAT:
LOZENGES, TROCHES, WASHES, GARGLES, ETC. (See also 201.315 of this
chapter.)
Warning -- Severe or persistent sore throat or sore throat
accompanied by high fever, headache, nausea, and vomiting may be
serious. Consult physician promptly. Do not use more than 2 days or
administer to children under 3 years of age unless directed by
physician.
TOOTHACHE PREPARATIONS.
For temporary use only until a dentist can be consulted.
ZINC STEARATE DUSTING POWDERS.
Warning -- Keep out of the reach of infants and children; avoid
inhaling.
(39 FR 11745, Mar. 29, 1974, as amended at 40 FR 8917, Mar. 3, 1975;
40 FR 13496, Mar. 27, 1975; 41 FR 10885, Mar. 15, 1976; 51 FR 27760,
Aug. 1, 1986; 51 FR 35340, Oct. 2, 1986; 52 FR 15893, Apr. 30, 1987;
52 FR 30057, Aug. 12, 1987; 52 FR 47324, Dec. 11, 1987; 53 FR 7093,
Mar. 4, 1988; 55 FR 31783, Aug. 3, 1990)
21 CFR 369.21 Drugs; warning and caution statements required by
regulations.
ACETAMINOPHEN (N-ACETYL-p-AMINOPHENOL) (See 310.201(a)(1) of this
chapter.)
Warning -- Do not give to children under 3 years of age or use for
more than 10 days unless directed by a physician.
If offered for use in arthritis, or rheumatism, in juxtaposition
therewith, the statement:
Caution -- If pain persists for more than 10 days, or redness is
present, or in conditions affecting children under 12 years of age
consult a physician immediately.
ALCOHOL RUBBING COMPOUND. (See 26 CFR 182.855(a)(5); The National
Formulary, Tenth Edition 1955, pp. 27-28; and section 502(g) of the
act).
Warning -- For external use only. If taken internally serious
gastric distrubances will result.
ANTIHISTAMINICS, ORAL (PHENYLTOLOXAMINE DIHYDROGEN CITRATE,
DOXYLAMINE SUCCINATE, CHLOROTHEN CITRATE, AND CHLORCYCLIZINE
HYDROCHLORIDE PREPARATIONS). (See 201.307 and 310.201(a) (4), (6),
(13), (24), and (25) of this chapter.)
Caution -- This preparation may cause drowsiness. Do not drive or
operate machinery while taking this medication. Do not give to children
under 6 years of age or exceed the recommended dosage unless directed by
physician.
If offered for symptoms of colds, the statement:
Caution -- If relief does not occur within 3 days, discontinue use
and consult physician.
For chlorcyclizine-containing preparations, the statement:
Warning -- Not for use by women who are pregnant or who may possibly
become pregnant, unless directed by a physician, since this drug may
have the potentiality of injuring the unborn child.
CARBETAPENTANE CITRATE PREPARATIONS. (See Cough-Due-to-Cold
Preparations.)
''COUGH-DUE-TO-COLD'' PREPARATIONS (CARBETAPENTANE CITRATE). (See
310.201(a)(20) of this chapter.)
Warning -- Keep out of the reach of children. Do not administer to
children under 2 years of age unless directed by physician. Persistent
cough may indicate the presence of a serious condition. Persons with a
high fever or persistent cough should not use this preparation unless
directed by physician.
DICYCLOMINE HYDROCHLORIDE WITH AN ANTACID. (See 310.201(a)(8) of
this chapter.)
Warning -- Do not exceed the recommended dosage. Do not administer
to children under 12 years of age or use for a prolonged period unless
directed by physician, since persistent or recurring symptoms may
indicate a serious disease requiring medical attention.
DIPHEMANIL METHYLSULFATE FOR EXTERNAL USE. (See 310.201(a)(22) of
this chapter.)
Caution -- If redness, irritation, swelling, or pain persists or
increases, discontinue use and consult physician.
DRUGS IN DISPENSERS PRESSURIZED BY GASEOUS PROPELLANTS. (See also
310.201(a) (11) and (18) of this chapter.)
The warnings herein shall appear prominently and conspicuously, but
in no case may the letters be less than 1/16 inch in height.
If the label of any package is too small to accommodate the warnings,
the Commissioner may establish by regulation an acceptable alternative
method, e.g., a type size smaller than 1/16 inch in height. A petition
requesting such a regulation, as an amendment to this paragraph, shall
be submitted to the Dockets Management Branch in the form established in
Part 10 of this chapter.
Warning -- Avoid spraying in eyes. Contents under pressure. Do not
puncture or incinerate. Do not store at temperature above 120 F. Keep
out of reach of children.
In the case of products packaged in glass containers, the word
''break'' may be substituted for the word ''puncture.''
The words ''Avoid spraying in eyes'' may be deleted from the warning
in the case of a product not expelled as a spray, or that is intended to
be used in the eyes.
In addition to the above warning, the label of a drug packaged in a
self-pressurized container in which the propellant consists in whole or
in part of a halocarbon or hydrocarbon shall bear the following warning:
Warning -- Use only as directed. Intentional misuse by deliberately
concentrating and inhaling the contents can be harmful or fatal.
The warning is not required for the following products:
(a) Products expelled in the form of a foam or cream, which contain
less than ten percent propellant in the container;
(b) Products in a container with a physical barrier that prevents
escape of the propellant at the time of use;
(c) Products of a net quantity of contents of less than 2 ozs. that
are designed to release a measured amount of product with each valve
actuation;
(d) Products of a net quantity of contents of less than 1/2 oz.
In addition to the above warnings, the label on each package of a
drug in a self-pressurized container in which the propellant consists in
whole or in part of a fully halogenated chlorofluoroalkane
(chlorofluorocarbon) shall bear the following warning:
Warning -- Contains a chlorofluorocarbon that may harm the public
health and environment by reducing the ozone in the upper atmosphere.
This required warning for self-pressurized containers that contain a
fully halogenated chlorofluorocarbon shall appear on an appropriate
panel with such prominence and conspicuousness as to render it likely to
be read and understood by ordinary individuals under normal conditions
of purchase. The warning may appear on a firmly affixed tag, tape,
card, or sticker or similar overlabeling attached to the package.
The warning for self-pressurized containers that contain a fully
halogenated chlorofluorocarbon is not required and should not be used
for metered-dose adrenergic bronchodilators for oral inhalation and
contraceptive vaginal foams.
The warning is required only on self-pressurized containers that use
a chlorofluorocarbon in whole or in part as a propellant to expel from
the container liquid or solid material different from the propellant.
DYCLONINE HYDROCHLORIDE. (See 310.201(a)(23) of this chapter.)
Caution -- Do not use in the eyes. Not for prolonged use. Do not
apply to large areas of the body. If redness, irritation, swelling, or
pain persists or increases, discontinue use unless directed by
physician. Do not use, but consult physician for deep or puncture
wounds or serious burns. Do not use in case of rectal bleeding, as this
may indicate serious disease.
HEXADENOL. (See 310.201(a)(11) of this chapter.)
Caution -- Do not use for treatment of serious burns or skin
conditions or for conditions which persist for prolonged periods. In
such cases, consult your physician. Do not spray in vicinity of eyes,
mouth, nose, or ears. Do not store above 120 F.
INSULIN. (See 429.11(c) of this chapter.)
Insulin (40 or 100 U.S.P. units per milliliter):
Caution -- Do not remove stopper. Not for intravenous nor
intramuscular use. Do not use after expiration date shown on outside
wrapper or container. Do not use if drug has become viscous or if its
color has become other than water clear.
In addition to the above warnings, the following statements should be
included in the labeling: ''Keep in a cold place, avoid freezing.
Failure to follow directions for use may lead to infection.'' Potamine
zinc insulin, isophane insulin, lente insulin, semilente insulin, or
ultralente insulin:
Caution -- Do not remove stopper. Not for intravenous nor
intramuscular use. Do not use after expiration date shown on outside
wrapper or container. Do not substitute for any other
insulin-containing drug unless directed by physician. Do not use when
precipitate has become lumped or granular in appearance or has formed a
deposit of solid particles on the wall of the container.
In addition to the above warnings for protamine zinc insulin * * *,
the following statements should be included in the labeling of these
preparations: ''Keep in a cold place, avoid freezing''; ''Shake
carefully'' or ''Shake well before using'' or ''Shake well'' or ''Shake
carefully to suspend all particles''; ''Failure to follow directions
for use may lead to infection''.
Globin zinc insulin:
Caution -- Do not remove stopper. Not for intravenous nor
intramuscular use. Do not use after expiration date shown on outside
wrapper or container. Do not use if any turbidity or precipitate has
developed in the solution. Do not substitute for any other
insulin-containing drug unless directed by physician.
In addition to the above warnings for globin zinc insulin, the
following statements should be included in the labeling: ''Keep in a
cold place, avoid freezing. Failure to follow directions for use may
lead to infection''.
IPECAC SYRUP IN ONE-FLUID OUNCE CONTAINERS FOR EMERGENCY TREATMENT OF
POISONING, TO INDUCE VOMITING. (See 201.308 of this chapter.)
Ipecac syrup packaged for over-the-counter sale must bear statements
to the following effect, in a prominent and conspicuous manner:
The following statement (boxed and in red letters):
''For emergency use to cause vomiting in poisoning. Before using,
call physician, the Poison Control Center, or hospital emergency room
immediately for advice.''
The following warning: Warning -- Keep out of reach of children. Do
not use in unconscious persons. Ordinarily, this drug should not be
used if strychnine, corrosives such as alkalies (lye) and strong acids,
or petroleum distillates such as kerosene, gasoline, coal oil, fuel oil,
paint thinner, or cleaning fluid have been ingested.
ISOAMYLHYRDOCUPREINE AND ZOLAMINE HYDROCHLORIDE RECTAL PREPARATIONS
FOR EXTERNAL USE (See 310.201(a)(3) of this chapter.)
Warning -- Do not use this preparation in case of rectal bleeding, as
this may indicate serious disease.
NEOMYCIN SULFATE WITH A VASOCONSTRICTOR, IN NASAL PREPARATIONS (SPRAY
OR DROPS).
Caution -- Do not exceed recommended dosage. Do not administer to
children under 3 years of age unless directed by physician.
PRAMOXINE HYDROCHLORIDE FOR EXTERNAL USE. (See 310.201(a)(19) of
this chapter.)
Caution -- Do not use in the eyes or nose. Not for prolonged use.
Do not apply to large areas of the body. If redness, irritation,
swelling, or pain persists or increases, discontinue use unless directed
by a physician.
SODIUM FLUORIDE DENTIFRICE POWDER. (See 310.201(a)(10) of this
chapter.)
Caution -- Children under 6 years of age should not use this drug.
SODIUM GENTISATE. (See 201.314, 310.201(a)(2) of this chapter.)
Warning -- Do not give to children under 6 years of age or use for
prolonged period unless directed by physician.
Warning -- Keep this and all medications out of the reach of
children; or
Warning -- Keep out of the reach of children.
If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
Caution -- If pain persists for more than 10 days, or redness is
present, or in conditions affecting children under 12 years of age,
consult a physician immediately.
SODIUM MONOFLUOROPHOS- PHATE DENTIFRICE SOLUTION. (See
310.201(a)(15) of this chapter.)
Caution -- Children under 6 years of age should not use this drug.
TUAMINOHEPTANE SULFATE NASAL PREPARATIONS. (See 310.201(a)(16) of
this chapter.)
Caution -- Do not exceed recommended dosage. Overdosage may cause
nervousness, restlessness, or sleeplessness. Individuals with high
blood pressure, heart disease, diabetes, or thyroid disease should use
only as directed by physician. Do not use for more than 3 or 4
consecutive days unless directed by physician.
VIBESATE PREPARATIONS. (See 310.201(a)(18) of this chapter.)
Caution -- Do not use but consult physician for deep or puncture
wounds or serious burns. If redness, irritation, swelling, or pain
persists or increases, discontinue use and consult physician.
Warning -- Contents under pressure. Do not puncture. Do not use or
store near heat or open flame. Exposure to temperatures above 130
Fahrenheit may cause bursting. Never throw container into fire or
incinerator.
(39 FR 11745, Mar. 29, 1974, as amended at 40 FR 8917, Mar. 3, 1975;
40 FR 13496, Mar. 27, 1975; 41 FR 10885, Mar. 15, 1976; 42 FR 22033,
Apr. 29, 1977; 42 FR 36994, July 19, 1977; 44 FR 22053, Apr. 13,
1979; 44 FR 55170, Sept. 25, 1979; 52 FR 15893, Apr. 30, 1987; 52 FR
30057, Aug. 12, 1987; 52 FR 47324, Dec. 11, 1987; 55 FR 11582, Mar.
29, 1990)
21 CFR 369.22 Drugs; warning and caution statements specifically
required by law.
PREPARATIONS CONTAINING HABIT-FORMING DERIVATIVES OF SUBSTANCES NAMED
IN SECTION 502(d) OF THE ACT. (See 329.1, 329.10, and 329.20 of this
chapter.)
The statement ''Warning -- May be habit forming'' is required to
appear on the labels of all drugs containing derivatives designated in
329.1 of this chapter as habit forming, including exempt narcotic
preparations described in 329.20(a) of this chapter and preparations
containing one or more derivatives of barbituric acid, unless such drug
is not suitable for internal use and is distributed and sold exclusively
for such external use as involves no possibility of habit formation.
21 CFR 369.22 PART 429 -- DRUGS COMPOSED WHOLLY OR PARTLY OF INSULIN
21 CFR 369.22 Subpart A -- General Provisions
Sec.
429.3 Definitions and interpretations.
21 CFR 369.22 Subpart B -- Packaging and Labeling
429.10 Packaging.
429.11 Labeling.
429.12 Distinguishing colors on packages.
21 CFR 369.22 Subpart C -- Product Standards
429.25 Standards of quality and purity for protamine.
429.26 Standards of quality and purity for globin hydrochloride.
21 CFR 369.22 Subpart D -- Tests and Methods
429.30 Tests and methods of assay.
21 CFR 369.22 Subpart E -- Certification
429.40 Requests for certification; samples; storage; approvals
preliminary to certification.
429.41 Certifications.
429.45 Conditions on the effectiveness of certificates.
429.47 Authority to refuse certification service.
21 CFR 369.22 Subpart F -- Administrative Procedures
429.50 Hearing procedure.
429.55 Fees.
21 CFR 369.22 Subpart G -- Records
429.60 Records of distribution.
Authority: Secs. 502, 506, 701 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 352, 356, 371).
Source: 39 FR 11750, Mar. 29, 1974, as amended at 40 FR 13497, Mar.
27, 1975, unless otherwise noted.
Cross References: For other regulations in this chapter concerning
insulin drugs, see also 200.15.
21 CFR 369.22 Subpart A -- General Provisions
21 CFR 429.3 Definitions and interpretations.
For the purpose of the regulations in this part:
(a) The term act means the Federal Food, Drug, and Cosmetic Act, as
amended.
(b) The term Secretary means the Secretary of Health and Human
Services.
(c) The term Commissioner means the Commissioner of Food and Drugs.
(d) The term U.S.P. means the official United States Pharmacopeia,
including supplements thereto.
(e) The term N.F. means the official National Formulary, including
supplements thereto.
(f) The definitions and interpretations of terms contained in section
201 of the act shall be applicable to such terms when used in the
regulations in this part.
(g) The term insulin means the active principle of pancreas which
affects the metabolism of carbohydrate in the animal body and which is
of value in the treatment of diabetes mellitus.
(h) The term insulin injection means the insulin injection recognized
in the U.S.P.
(i) The term protamine zinc insulin suspension means the protamine
zinc insulin suspension recognized in the U.S.P.
(j) The term globin zinc insulin injection means the globin zinc
insulin injection recognized in the U.S.P.
(k) The term isophane insulin suspension means the isophane insulin
suspension recognized in the U.S.P.
(l) The term insulin zinc suspension means the insulin zinc
suspension recognized in the U.S.P.
(m) The term prompt insulin zinc suspension means the prompt insulin
zinc suspension recognized in the U.S.P.
(n) The term extended insulin zinc suspension means the extended
insulin zinc suspension recognized in the U.S.P.
(o) The term master lot means a quantity (which is purified and which
has been mixed in one container so as to be homogeneous) of:
(1) A concentrated solution of insulin; or
(2) The insulin-containing solids, in amorphous or crystalline form,
derived from one or more such solutions.
(p) Except as provided in 429.41(c), the term batch means a quantity
of a drug, in labeled packages, of uniform composition and intended for
administration without further change, in which the sole
insulin-containing ingredient is a single dilution (which has been mixed
in one container so as to be homogeneous) of:
(1) A single master lot or part thereof; or
(2) A mixture of two or more master lots or parts thereof; except
that such term means a portion of such quantity when certification of
such portion is requested.
(q) The term master lot mark means an identifying mark or other
identifying device assigned to a master lot by the manufacturer thereof.
(r) The term batch mark means an identifying mark or other
identifying device assigned to a batch by the manufacturer thereof.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40285, Nov. 15,
1974)
21 CFR 429.3 Subpart B -- Packaging and Labeling
21 CFR 429.10 Packaging.
Each batch shall be packaged in immediate containers of colorless
transparent glass. Such containers shall be closed with a substance
through which successive doses may be withdrawn by hypodermic needle
without removing the closure or destroying its effectiveness. The
containers and closures shall be sterile at the time the containers are
filled and closed. The composition of the containers and closures shall
be such as will not cause any change in the strength, quality, or purity
of the contents beyond any limit therefor prescribed in applicable
standards of strength, quality, and purity. The shape of the containers
shall be cylindrical, except that the cross-section of the containers
for isophane insulin suspension containing less than 100 U.S.P. Units of
insulin per milliliter shall be a rounded square, and the shoulder of
the containers for insulin zinc suspension, prompt insulin zinc
suspension, or extended insulin zinc suspension containing less than 100
U.S.P. Units of insulin per milliliter shall be hexagonal.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40285, Nov. 15,
1974)
21 CFR 429.11 Labeling.
Each package from a batch that has been certified in accordance with
the regulations in this part shall bear, on its label or labeling as
hereinafter indicated, the following:
(a) On the outside wrapper or container and the immediate container
of the retail package:
(1) The batch mark of such batch;
(2) The potency of the drug in terms of the U.S.P. Units of insulin
per milliliter; and
(3) The statement ''Expiration date -------- ,'' the blank being
filled in with the date on which the certificate applicable to such
batch expires with respect to such package, as provided in
429.45(b)(1).
(b) On the outside container or wrapper of the retail package, the
statement ''Keep in a cold place, avoid freezing.''
(c) If the batch contains 40 or 100 U.S.P. Units of insulin per
milliliter, on the circular or other labeling of the retail package:
(1) A statement that the treatment of diabetes mellitus is an
individual problem and that the use of the drug, the time of its
administration, and the number of daily doses and the quantity of each,
as well as diet and exercise, are problems which require direct and
continuous medical supervision;
(2) A statement explaining that the volume of the dose depends on the
number of units of insulin per milliliter stated on the label, and that
the patient should understand the meaning of the volume markings on the
syringe;
(3) A description of a practicable method for sterilizing the needle
and syringe before use;
(4) A description of the technique of withdrawal from the vial and
the use of an antiseptic on the stopper, and a caution against the
removal of the stopper;
(5) A description of the technique for cleansing, and the use of an
antiseptic on the site of injection;
(6) A statement that failure to comply with the techniques described
in paragraphs (c) (3), (4), and (5) of this section may lead to
infection of the patient;
(7) A statement that injection should be subcutaneous, at a different
site from that of the preceding injection, and a caution against
intravenous or intramuscular use;
(8) An explanation of hypoglycemia and its relation to overdosage,
omission of meals, illness, and infection;
(9) A statement of the significance of sugar in the urine and of the
necessity of tests therefor; and
(10) A caution against use after the expiration date shown on the
outside wrapper or container.
(d) On the circular or other labeling of the retail package, if the
batch is insulin injection (in addition to the information required by
paragraphs (a), (b), and (c) or (i) of this section), a caution against
use if the drug has become viscous or if its color has become other than
water clear.
(e) On the outside wrapper or container and immediate container of
the retail package, if the batch is protamine zinc insulin suspension,
isophane insulin suspension, insulin zinc suspension, prompt insulin
zinc suspension, or extended insulin zinc suspension (in addition to the
information required by paragraphs (a), (b), and (c) of this section),
the statement ''Shake carefully,'' or ''Shake well before using,'' or
''Shake well,'' or ''Shake carefully to suspend all particles.''
(f) On the circular or other labeling of the retail package, if the
batch is protamine zinc insulin suspension, isophane insulin suspension,
insulin zinc suspension, prompt insulin zinc suspension, or extended
insulin zinc suspension (in addition to the information required by
paragraphs (a), (b), (c), and (e) of this section):
(1) An explanation of the difference, as compared with other
insulin-containing drugs, in onset of action, duration, and the time and
frequency of administration;
(2) A caution that it is not to be substituted for any other
insulin-containing drug except on the advice and direction of a
physician;
(3) A statement that a uniform suspension of the preparation is
necessary and is brought about by careful shaking before use; and
(4) A caution against use when the precipitate has become lumped or
granular in appearance or has formed a deposit of solid particles on the
wall of the container.
(g) On the circular or other labeling of the retail package, if the
batch is globin zinc insulin injection (in addition to the information
required by paragraphs (a), (b), and (c) of this section):
(1) An explanation of the difference, as compared with other
insulin-containing drugs, in onset of action, duration, and the time and
frequency of administration;
(2) A caution that it is not to be substituted for any other
insulin-containing drug, except on the advice and direction of a
physician; and
(3) A caution against use if any turbidity or precipitate has
developed in the solution.
(h) If the batch contains 500 U.S.P. Units of insulin per milliliter,
on the outside container or wrapper and the immediate container of the
retail package:
(1) The statement ''Caution: Federal law prohibits dispensing
without prescription''; 2003 and
(2) The statement ''Warning -- High potency -- Not for ordinary
use''.
(i) If the batch contains 500 U.S.P. Units of insulin per milliliter,
on the circular or other labeling of the retail package:
(1) Information adequate for the safe and effective use of the drug,
by practitioners licensed by law to administer it, in insulin shock
therapy and for the treatment of diabetic patients with high insulin
resistance (daily requirement more than 200 units);
(2) A prominently placed and conspicuous statement: ''Warning --
This insulin preparation contains 500 units of insulin in each
milliliter. Extreme caution must be observed in measurement of dosage
because inadvertent overdose may result in irreversible insulin shock.
Serious consequences may result if it is used other than under constant
medical supervision'';
(3) A caution against intravenous use; and
(4) A caution against use after the expiration date shown on the
outside wrapper or container.
(39 FR 11750, Mar. 29, 1974, as amended at 40 FR 13497, Mar. 27,
1975; 41 FR 6912, Feb. 13, 1976; 44 FR 55170, Sept. 25, 1979)
0032For the Spanish-language version of the required labeling
statement, see 201.16(a), 801.16 and 290.6 of this chapter.
21 CFR 429.12 Distinguishing colors on packages.
(a) The outside containers or wrappers of the packages, and the
labels on the immediate containers of each potency of insulin injection
shall be distinguished by the following colors:
Red, if it contains 40 U.S.P. Units of insulin per milliliter.
White, if it contains 100 U.S.P. Units of insulin per milliliter.
Narrow (at least 5 but not more than 20 to each inch) brown and white
diagonal stripes, if it contains 500 U.S.P. Units of insulin per
milliliter.
But if the master lot used was in crystalline form, the
distinguishing colors, instead of those prescribed above, may be the
following:
Red and gray, if it contains 40 U.S.P. Units of insulin per
milliliter.
(b) The outside containers or wrappers of the packages, and the
labels on the immediate containers of each potency of protamine zinc
insulin suspension shall be distinguished by the following colors:
Red and white, if it contains 40 U.S.P. Units of insulin per
milliliter.
Black and white, if it contains 100 U.S.P. Units of insulin per
milliliter.
(c) The outside containers or wrappers of the packages, and the
labels of the immediate containers of each potency of globin zinc
insulin injection shall be distinguished by the following colors:
Red and brown, if it contains 40 U.S.P. Units of insulin per
milliliter.
Black and white, if it contains 100 U.S.P. Units of insulin per
milliliter.
(d) The outside containers or wrappers of the packages, and the
labels of the immediate containers of each potency of isophane insulin
suspension shall be distinguished by the following colors:
Red and blue, if it contains 40 U.S.P. Units of insulin per
milliliter.
Black and white, if it contains 100 U.S.P. Units of insulin per
milliliter.
(e) The outside containers or wrappers of the packages, and the
labels of the immediate containers, of insulin zinc suspension, prompt
insulin zinc suspension, and extended insulin zinc suspension shall bear
a mark or design to distinguish each drug, and each potency of these
drugs shall be distinguished by the following colors:
Red and lavender, if it contains 40 U.S.P. Units of insulin per
milliliter.
Black and white, if it contains 100 U.S.P. Units of insulin per
milliliter.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40286, Nov. 15,
1974; 44 FR 55170, Sept. 25, 1979)
21 CFR 429.12 Subpart C -- Product Standards
21 CFR 429.25 Standards of quality and purity for protamine.
When protamine is dried to constant weight at 100 C., its total
nitrogen content is not less than 22.5 percent and not more than 25.5
percent, and its sulfate content, calculated as SO4, is not less than 16
percent and not more than 19 percent.
21 CFR 429.26 Standards of quality and purity for globin hydrochloride.
The ash content of globin hydrochloride is not more than 0.3 percent;
its nitrogen content, calculated to moisture, ash, and hydrochloric
acid free basis, is not less than 16.0 percent and not more than 17.5
percent.
21 CFR 429.26 Subpart D -- Tests and Methods
21 CFR 429.30 Tests and methods of assay.
The following tests and methods of assay are prescribed for the
purposes of the regulations in this Part 429. (All reagents specified
in this section shall be of U.S.P. quality or better.)
(a) Tests and methods of assay for insulin injection, protamine zinc
insulin suspension, globin zinc insulin injection, isophane insulin
suspension, insulin zinc suspension, prompt insulin zinc suspension, and
extended insulin zinc suspension. The tests and methods of assay for
insulin injection, protamine zinc insulin suspension, globin zinc
insulin injection, isophane insulin suspension, insulin zinc suspension,
prompt insulin zinc suspension, and extended insulin zinc suspension
shall be those set forth therefor in the U.S.P. or N.F., except that
alternative test procedures may be employed when such have been
authorized by the Commissioner.
(b) (Reserved)
(c) Isophane ratio. The isophane ratio shall be expressed as
milligrams of protamine per 100 U.S.P. Units of insulin.
(1) Reagents -- (i) The stock buffer solution. Dissolve in water the
quantities of metacresol, phenol, glycerin, and disodium phosphate
required to make 10 liters of the batch of isophane insulin and dilute
to 1,000 milliliters.
(ii) The insulin solution. From a sample of the zinc-insulin
crystals to be used in making the batch weigh a quantity which contains
10,000 U.S.P. Units of insulin. Dissolve the crystals in 15 milliliters
of 0.1 percent hydrochloric acid. The resulting solution must be clear.
Add it to 25 milliliters of the stock buffer solution (paragraph
(c)(1)(i) of this section). Dilute with water to approximately 200
milliliters. Adjust the pH to 7.2 using hydrochloric acid or sodium
hydroxide. The solution must be clear at this stage. If sodium
chloride is to be used in preparing the batch add 25 milliliters of 4.2
percent (w/v) sodium chloride solution. Dilute to 250 milliliters with
water. The pH must be between 7.1 and 7.4.
(iii) The protamine solution. Weigh 500 milligrams of the protamine
to be used in making the batch and dissolve in 10 milliliters of the
stock buffer solution (paragraph (c)(1)(i) of this section). If sodium
chloride is to be used in preparing the batch add 10 milliliters of 4.2
percent (w/v) sodium chloride solution. Dilute with water to
approximately 80 milliliters. Adjust the pH to 7.2 using hydrochloric
acid or sodium hydroxide. Dilute with water to 100 milliliters. The pH
must be between 7.2 and 7.4 and the solution must be clear.
(2) Conduct of the test. Measure six 25-milliliter samples of the
insulin solution (paragraph (c)(1)(ii) of this section) into six tubes.
To the first tube add 0.60 milliliter of the protamine solution
(paragraph (c)(1)(iii) of this section), to the second add 0.72
milliliter, to the third add 0.84 milliliter, to the fourth add 0.96
milliliter, to the fifth add 1.08 milliliters, and to the sixth add 1.20
milliliters. Mix the contents of each tube and let stand for at least 30
minutes. Centrifuge. (Do not filter.) From each supernatant fluid
remove two 10-milliliter samples, thus creating two series of samples.
To each of one series add 1 milliliter of the insulin solution
(paragraph (c)(1)(ii) of this section). To each of the other series add
1 milliliter of the protamine solution (paragraph (c)(1)(iii) of this
section). Mix each sample and let stand 10 minutes. Measure the
turbidity of each sample by means of a photometer or nephelometer. Plot
the readings of the two series of samples, using the amount of protamine
originally added in milligrams per 100 U.S.P. Units of insulin as
abscissas, and the photometer or nephelometer readings as ordinates.
The abscissa of the intersection of the two curves indicates the
isophane ratio of the protamine to the zinc-insulin crystals. In order
to increase the precision of the test, when the approximate isophane
ratio is known, the quantities of protamine solution to be added to the
six tubes may be so chosen that the range (0.60 to 1.20 milliliters) is
reduced, and the approximate isophane ratio is near the middle of the
range.
The isophane ratio found is not more than 100 percent nor less than
90 percent of the ratio of protamine to insulin used in the trial
mixture referred to in 429.40(d)(7).
(d)-(e) (Reserved)
(f) Chloride in globin hydrochloride -- (1) Conduct of the test.
Weigh accurately approximately 0.5 gram of globin hydrochloride into a
small beaker and dissolve in 10-15 milliliters of distilled water. Add
10 milliliters of tenth-normal silver nitrate, 5 milliliters of nitric
acid, and 5 milliliters of a saturated solution of potassium
permanganate. Stir and place on a steam bath for approximately 1 hour.
If any brown color remains, stir again, rinse the sides of the beaker
with distilled water and place on the steam bath until the brown color
disappears. Transfer quantitatively to a 50-milliliter volumetric flask
and fill the flask to the mark with distilled water. Mix and filter
through a dry filter paper into a dry vessel. Transfer exactly 40
milliliters of the filtrate to a flask, add 2 milliliters of ferric
ammonium sulfate test solution and titrate with tenth-normal ammonium
thiocyanate. To obtain the percent chloride as HCl, subtract 1.25 times
the number of milliliters of ammonium thiocyanate used from 10;
multiply this difference by 0.365 and divide by the weight of the sample
in grams.
(2) Reagents. The reagents used are those described in the U.S.P.
(g) Sulfate in protamine -- (1) Conduct of the test. Weigh
accurately about 250 milligrams of protamine and dissolve it in about
100 milliliters of approximately tenth-normal hydrochloric acid. Heat
to boiling and add 5 milliliters of barium chloride test solution.
Digest on a steam bath for 1 hour; allow to cool. Filter through an
ignited and weighed Gooch crucible; wash free of chlorides. Dry,
ignite, and weight. The weight of barium sulfate thus obtained
multiplied by 41.15 and divided by the weight of sample is the percent
sulfate (SO4) in the sample. Calculate the results to a moisture-free
basis.
(2) Reagents. The reagents used are those described in the U.S.P.
(h) Nitrogen. Determine total nitrogen by the method described in
the U.S.P., for insulin U.S.P.
(i) Zinc in insulin-containing solutions or suspensions. Use the
method described in the U.S.P. for insulin injection.
(j) Zinc in insulin-containing solids. Dissolve 10 to 20 milligrams,
accurately weighed, of insulin-containing solids in 5 to 10 milliliters
of distilled water containing one drop of 5N hydrochloric acid, and
proceed as directed in the U.S.P. under the test for zinc in insulin
injection.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40286, Nov. 15,
1974)
21 CFR 429.30 Subpart E -- Certification
21 CFR 429.40 Requests for certification; samples; storage;
approvals preliminary to certification.
(a) A request for certification of a batch is to be addressed to the
Food and Drug Administration, Division of Research and Testing
(HFD-470), 200 C St. SW., Washington, DC 20204.
(b) The initial request for certification submitted by any person
shall be preceded or accompanied by a full statement of the facilities
and controls used to maintain the identity, strength, quality, and
purity of each batch, including a description of:
(1) The equipment, methods, and processes used in diluting master
lots and parts thereof, and in maintaining the identity, strength,
quality, and purity of master lots and dilutions therefrom;
(2) The tests and assays made on master lots and mixtures thereof, on
dilutions and batches therefrom, and on ingredients used in such
dilutions and batches; and
(3) The laboratory facilities used in such controls.
Such initial request shall also be preceded or accompanied by the
keys to the master lot marks and batch marks used by such person. When
any change is made in any of such facilities or controls, or in any such
key, the next request for certification thereafter shall be accompanied
by a full statement of such change.
(c) A person who requests certification of a batch shall submit in
connection with his request statements showing:
(1) The master lot mark of each master lot used or to be used wholly
or partly as an ingredient or component of an ingredient of the batch;
(2) The quantity of each such master lot so used;
(3) The original quantity of each such master lot (unless such
information has been previously submitted);
(4) The quantity of the batch; and
(5) The batch mark.
(d) Except as otherwise provided in paragraphs (g) and (h) of this
section, a person who requests certification of a batch shall submit in
connection with his request and in the quantities hereinafter indicated,
accurately representative samples of the following:
(1) The single master lot or the mixture of two or more master lots
or parts thereof, to be used as ingredients of the batch; in a quantity
containing approximately 10,000 U.S.P. Units of insulin, except that, if
the batch is to be isophane insulin suspension, the quantity shall
contain not less than 20,000 U.S.P. Units of insulin.
(2) If the batch is to be insulin injection, a trial dilution made
from such master lot or mixture, glycerin, phenol or cresol, and
hydrochloric acid, which dilution conforms to the standard of identity,
strength, quality, and purity for insulin injection, except that it may
contain approximately 40, 80, or 100 units of insulin per milliliter in
a quantity containing approximately 5,000 U.S.P. units of insulin.
(3) If the batch is to be protamine zinc insulin suspension, a trial
mixture which is intended to be accurately representative of the mixture
which will constitute the finished batch; in a quantity containing
approximately 10,000 U.S.P. units of insulin.
(4) If the batch is to be protamine zinc insulin suspension or
isophane insulin suspension, the lot of protamine used as an ingredient
of the trial mixture referred to in paragraph (d)(3) or (7) of this
section; in a quantity of approximately 2 grams.
(5) If the batch is to be globin zinc insulin injection, a trial
mixture made from the master lot or mixture referred to in paragraph
(d)(1) of this section, globin, zinc chloride, hydrochloric acid,
glycerin, and phenol or cresol, which mixture is intended to be
accurately representative of the mixture which will constitute the
finished batch; in a quantity containing approximately 10,000 U.S.P.
units of insulin.
(6) If the batch is to be globin zinc insulin injection, the lot of
globin hydrochloride from which the globin is to be prepared for use as
an ingredient of the trial mixture referred to in paragraph (d)(5) of
this section; in a quantity of approximately 5 grams.
(7) If the batch is to be isophane insulin suspension, a trial
mixture which is intended to be accurately representative of the
finished batch; in a quantity of approximately 10,000 U.S.P. units of
insulin.
(8) If the batch is to be insulin zinc suspension, prompt insulin
zinc suspension, or extended insulin zinc suspension, a trial mixture
which is intended to be accurately representative of the finished batch;
in a quantity of approximately 50 milliliters.
(9) The finished batch; for all tests except sterility, not less
than 10 retail packages.
(10) The finished batch for sterility testing, 20 retail packages,
collected at approximately equal intervals throughout each filling
operation (as defined by the U.S.P.), except that if it is insulin
injection containing 500 U.S.P. Units of insulin per milliliter, in lieu
of the volume contained in the retail package each such container may
contain an amount of drug that is less than that contained in the retail
package but in no case less than 5 milliliters.
(e) Except as otherwise provided by paragraphs (g) and (h) of this
section, a person who requests certification shall submit in connection
with his request results of the tests and assays listed after each of
the following materials, made by him on a sample of such material:
(1) The master lot or mixture, referred to in paragraph (d)(1) of
this section: Ash, nitrogen, potency, pH, sterility, and zinc, if such
master lot or mixture is a solution; ash, moisture, nitrogen, potency,
and zinc, if such master lot or mixture is a solid.
(2) A trial dilution of such master lot or mixture, of the potency of
the trial dilution referred to in paragraph (d)(2) of this section:
Nitrogen, pH, and potency.
(3) If the batch is to be protamine zinc insulin suspension, the
trial mixture referred to in paragraph (d)(3) of this section:
Nitrogen, pH, zinc, and biological reaction (by the test prescribed in
the U.S.P.).
(4) If the batch is to be protamine zinc insulin suspension or
isophane insulin suspension, the protamine referred to in paragraph
(d)(4) of this section: Moisture, nitrogen, and sulfate.
(5) If the batch is to be globin zinc insulin injection the trial
mixture referred to in paragraph (d)(5) of this section: Nitrogen, pH,
zinc, and biological reaction (by the test prescribed in the U.S.P.).
(6) If the batch is to be globin zinc insulin injection, the globin
hydrochloride referred to in paragraph (d)(6) of this section:
Moisture, nitrogen, chloride, and ash.
(7) If the batch is to be isophane insulin suspension, the trial
mixture referred to in paragraph (d)(7) of this section: Nitrogen, pH,
zinc, isophane ratio of the protamine to the master lot or mixture (by
the test prescribed in 429.30(c)), and biological activity of the
supernatant liquid (by the test prescribed in the U.S.P.).
(8) If the batch is to be insulin zinc suspension, prompt insulin
zinc suspension, or extended insulin zinc suspension, the trial mixture
referred to in paragraph (d)(8) of this section: Nitrogen, pH, zinc,
zinc in the supernatant liquid and insulin not extracted by buffered
acetone solution.
(9) The finished batch: Nitrogen, pH, sterility; and if the batch
is protamine zinc insulin suspension, globin zinc insulin injection,
isophane insulin suspension, insulin zinc suspension, prompt insulin
zinc suspension, or extended insulin zinc suspension, zinc.
(f) The results of tests and assays for the following shall be
reported in the terms indicated:
(1) Ash (except globin hydrochloride) -- milligrams per 1,000 U.S.P.
Units of insulin.
(2) Ash in globin hydrochloride -- percent by weight.
(3) Chloride -- percent by weight as HCl.
(4) Insulin not extracted by buffered acetone solution -- percent of
total nitrogen of the preparation not extracted by buffered acetone
solution.
(5) Isophane ratio -- milligrams of protamine per 100 U.S.P. Units of
insulin.
(6) Moisture -- percent by weight.
(7) Nitrogen (except in globin hydrochloride and protamine) --
milligrams per milliliter in the cases of solutions and suspensions, and
percent by weight in the case of solids.
(8) Nitrogen in globin hydrochloride -- percent by weight, calculated
to a moisture-free, ash-free, chloride-free basis.
(9) Nitrogen in protamine -- percent by weight, calculated to a
moisture-free basis.
(10) Potency -- U.S.P. Units of insulin per milliliter in the case of
solutions, and U.S.P. Units of insulin per milligram in the case of
solids.
(11) pH.
(12) Sulfate -- percent by weight as SO4, calculated to a
moisture-free basis.
(13) Zinc -- milligrams per milliliter in the cases of solutions and
suspensions, and percent by weight in the case of solids.
(g)(1) No sample referred to in paragraphs (d) (1) to (3), inclusive,
of this section, and no result referred to in paragraphs (c) (1) to (8),
inclusive of this section, is required if such sample or result has been
submitted in connection with a previous request for certification.
Except for paragraphs (d) (9), (10), and (e)(9), the samples referred to
in paragraph (d) of this section and the results referred to in
paragraph (e) of this section for insulin injection, protamine zinc
insulin suspension, globin zinc insulin injection, or isophane insulin
suspension are not required if the Commissioner has previously approved
a trial mixture containing 40, 100 units of insulin per milliliter or
trial dilution containing approximately 40, 100 units of insulin per
milliliter and the mixture or dilution was prepared from the same
materials and in the same manner, except for adjustment of pH of the
buffer solution.
(2) Each sample submitted pursuant to this section shall be so
packaged as to maintain its representative character, and in the case of
any solution or suspension, shall be collected and packaged under
aseptic conditions. Each package shall be clearly identified as to its
contents and shall bear the name and post office address of the person
submitting the request.
(3) The packages constituting the samples submitted pursuant to
paragraph (d)(9) of this section shall be collected at such intervals
that the quantities packaged between collections are approximately
equal; in no case shall any such quantity be more than 10,000 packages.
The collections shall cover the entire period of packaging.
(4) Each sample submitted pursuant to paragraphs (d) (2), (3), (5),
(7), and (8) of this section shall be accompanied by a statement showing
the identity, quality, and quantity of each substance used as an
ingredient or as a component of an ingredient in the material from which
the sample was taken.
(5) If the tests and assays, results of which are submitted pursuant
to paragraph (e)(2) of this section, were not made on the same trial
dilution as that from which the sample submitted pursuant to paragraph
(d)(2) of this section was taken, such sample shall be accompanied by a
statement showing the identity, quality, and quantity of each substance
used as an ingredient or as a component of an ingredient of the trial
dilution on which such tests and assays were made.
(6) The value for nitrogen submitted pursuant to paragraphs (e) (1)
and (2) of this section may be calculated from the result of a test
therefor submitted pursuant to either paragraph (e) (1) or (2) of this
section. The result on potency required under paragraph (e)(1) of this
section may be calculated from an assay therefor submitted pursuant to
paragraph (e)(2) of this section. The value of each of the components
nitrogen and zinc, to the extent required under paragraph (e)(9) of this
section, may be calculated from the result of a test therefor submitted
pursuant to paragraph (e) (3), or (5), or (7) or (8) of this section or
from the result of a test of the bulk dilution from which the batch was
prepared. The value for nitrogen required under paragraph (e)(9) of
this section may, if the batch is insulin injection, insulin zinc
suspension, prompt insulin zinc suspension, or extended insulin zinc
suspension, be calculated from a test therefor submitted pursuant to
either paragraph (e) (1) or (2) of this section. Each calculated value
shall be indicated as such.
(7) The information required under paragraphs (c) (1), (2), and (3)
of this section, and the samples and results of tests and assays
required under paragraphs (d) (1) and (2) and (e) (1) and (2) of this
section, should be submitted before submission of the samples and
results required in paragraphs (d) (3) to (8), inclusive, of this
section and (e) (3) to (8), inclusive, of this section; and the samples
and results required under paragraphs (d) (3) to (8), inclusive, and (e)
(3) to (8), inclusive, should be submitted before submission of the
information, samples, and results required under paragraphs (c) (4) and
(5), (d) (9) and (10), and (e)(9) of this section. All information,
including results of tests and assays (except results of tests for
sterility), required under this section should be submitted at the same
time as the samples to which they relate are submitted.
(h) The person who requests certifications shall submit such
information additional to that submitted pursuant to paragraphs (b),
(c), (e), and (g) of this section, such additional samples of any
substance referred to in paragraph (d) of this section, and such samples
of any other substance used or to be used as an ingredient or as a
component of an ingredient in the batch, as the Commissioner may require
for the purpose of investigations to determine whether or not such batch
complies with the requirements set forth by 429.41 for the issuance of
a certificate.
(i) After a sample required by paragraph (d) of this section is taken
from any master lot or mixture of part of two or more master lots, such
master lot or master lots and all parts thereof, and all dilutions and
batches and all parts thereof in which any such master lot is used as an
ingredient or as a component of an ingredient, shall be stored at the
establishment where manufactured until used up or shipped or otherwise
delivered, at a temperature above freezing but not above 15 C. (59
F.), and under such other conditions as prevent, so far as practicable,
any change in composition; except that master lots and parts thereof
which are solids may be stored at ordinary room temperatures.
(j) As promptly as practicable after the samples submitted pursuant
to paragraphs (d) (1) and (2) of this section, and any other material or
information relative thereto that may be required under this section,
are received by the Commissioner, he shall notify the person who
submitted such samples of his approval or refusal to approve the use of
the master lot or mixture for the making of bulk dilutions. In case of
a refusal to approve, the Commissioner shall state his reasons therefor.
(k) In like manner, the Commissioner shall notify the person who
submits samples pursuant to paragraphs (d) (3) to (8), inclusive, of
this section of his approval or refusal to approve the use of the
materials represented by such samples in completing the manufacture of
the batch. In case of a refusal to approve, the Commissioner shall
state his reasons therefor.
(l) If, under the provisions of paragraph (j) or (k) of this section,
the Commissioner has refused to approve any material for use in a
subsequent operation, he shall examine no other sample required
hereunder which includes such material as an ingredient or component of
an ingredient, unless and until the person requesting certification
makes an adequate showing that the cause for such refusal no longer
exists.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40286, Nov. 15,
1974; 44 FR 48968, Aug. 21, 1979; 44 FR 55170, Sept. 25, 1979; 45 FR
40111, June 13, 1980; 50 FR 8996, Mar. 6, 1985; 55 FR 11582, Mar. 29,
1990)
21 CFR 429.41 Certifications.
(a) If it appears to the Commissioner, after such investigation as he
considers necessary, that:
(1) The information (including results of tests and assays) and the
samples required by or pursuant to 429.40 have been submitted, and such
information contains no untrue statement of a material fact;
(2) The batch complies with the regulations in this Part 429 and
conforms to the standards of identity, quality, strength, and purity for
insulin injection, protamine zinc insulin suspension, globin zinc
insulin injection, isophane insulin suspension, insulin zinc suspension,
prompt insulin zinc suspension, or extended insulin zinc suspension;
the Commissioner shall certify that such batch is safe and
efficacious for use, subject to such conditions on the effectiveness of
such certifications as are set forth in 429.45, and shall issue to the
person who requested it a certificate to that effect.
(b) If the Commissioner determines, after such investigation as he
considers to be necessary, that the information submitted pursuant to
429.40 or the batch covered by such request, does not comply with the
requirements set forth in paragraph (a) of this section for the issuance
of a certificate, the Commissioner shall refuse to certify such batch
and shall give notice thereof to the person who requested certification,
stating his reasons for refusal.
(c) Upon the request of the manufacturer, the Commissioner shall
certify as a ''batch'' a master lot, which has been approved in
accordance with 429.40(j) as safe and efficacious for use in
preparation of an insulin-containing drug, subject to the conditions on
the effectiveness of such certifications as are set forth in 429.45(a)
(1) and (b) (4).
(d) For the purposes of his investigations under the authority of
this section, the Commissioner may accept, when he is satisfied as to
the completeness and accuracy thereof, the results of any tests or
assays made by the control laboratory of the Insulin Committee of the
University of Toronto.
21 CFR 429.45 Conditions on the effectiveness of certificates.
(a) A certificate shall not become effective:
(1) If it is obtained through fraud, or through misrepresentation or
concealment of a material fact.
(2) With respect to any package, unless its immediate container
complies with the requirements of 429.10 and such package or such
immediate container has been so sealed that its contents cannot be used
without destroying such package or seal.
(3) With respect to any package, unless its label and labeling bear
all words, statements, and other information, and are distinguished by
the color or colors, required by 429.11 and 429.12.
(b) A certificate shall cease to be effective: (1) With respect to
any package of insulin injection, protamine zinc insulin suspension,
globin zinc insulin injection, isophane insulin suspension, insulin zinc
suspension, prompt insulin zinc suspension, or extended insulin zinc
suspension on the expiration date specified in the U.S.P.
(2) With respect to any package, when such package or the seal
thereof or the immediate container therein or the seal of the immediate
container is broken, or when its label or labeling ceases to conform to
any requirement of 429.11 or 429.12.
(3) With respect to any package, when the drug therein so changes
that it fails to meet the standards of identity, strength, quality, and
purity upon the basis of which the batch was certified; except that
those minor changes in potency (not exceeding 10 percent from the
potency stated on the label, in the case of insulin injection) which
occur before the expiration date, and which are normal and unavoidable
in good storage and distribution practice, shall be disregarded.
(4) With respect to a master lot of insulin, 5 years after date of
issue if the master lot is a solution, or 10 years after date of issue
if the master lot is a solid.
(39 FR 11750, Mar. 29, 1974, as amended at 39 FR 40286, Nov. 15,
1974)
21 CFR 429.47 Authority to refuse certification service.
When the Commissioner finds, after giving notice and opportunity for
hearing, that a person has:
(a) Obtained or attempted to obtain a certificate through fraud, or
through misrepresentation or concealment of a material fact;
(b) Falsified the records required to be kept by 429.60; or
(c) Failed to keep such records or to make them available, or to
accord full opportunity to make an inventory of stocks on hand or
otherwise to check the correctness of such records, as required by such
section;
the Commissioner may immediately suspend service to such person under
the regulations in this part, and may continue such suspension unless
and until such person shows adequate cause why such suspension should be
terminated.
21 CFR 429.47 Subpart F -- Administrative Procedures
21 CFR 429.50 Hearing procedure.
Hearings pursuant to 429.47 shall be governed by Part 16 of this
chapter.
(41 FR 48267, Nov. 2, 1976, as amended at 42 FR 15674, Mar. 22, 1977)
21 CFR 429.55 Fees.
(a)(1) Fees for the services rendered under the regulations in this
part shall be such as are necessary to provide, equip, and maintain an
adequate certification service.
(2) Whenever in the judgment of the Commissioner the ratio between
fees collected (which are based upon experience and the best estimate of
costs and the best estimate of earnings) and the costs of providing the
service during an elapsed period of time, in the light of all
circumstances and contingencies, warrants a refund from the fund
collected during such period, he shall make ratable refunds to those
persons to whom the services were rendered and charged.
(b) The fees for insulin samples submitted for certification services
under 429.40(d) are as follows:
(1) $3,900 for each master lot or mixture of two or more master lots
or parts thereof.
(2) $2,800 for each dosage form batch.
(3) The fees established in this paragraph will increase as Federal
salary costs increase. The rate of increase will be equal to Federal
salary increases, commencing with pay raises on or after January 1,
1993. Notification of the exact fees established after adjustment will
be communicated directly to the manufacturers of insulin products.
Except as otherwise provided by paragraph (c) of this section, each
request for certification submitted, or the initial sample or samples
submitted in connection therewith pursuant to 429.40(d), whichever is
sent first to the Commissioner, shall be accompanied by such fees as are
prescribed in specific amounts for the samples. If the Commissioner
considers that investigations or additional samples are necessary to
determine whether or not such batch complies with the requirements of
429.41 for the issuance of a certificate, the fee shall include the cost
of such investigations.
(c) A person requiring continuing certification services may maintain
an advance deposit of the estimated costs of such services for a period
of 2 months or more. Such deposits shall be debited with fees for
services rendered, but shall not be debited for any fee the amount of
which is not definitely specified in these regulations unless the
depositor has previously requested the performance of the services to be
covered by such fee. A monthly statement for each such advance deposit
shall be rendered.
(d) The unearned portion of any advance deposit made pursuant to
paragraph (b) or (c) of this section shall be refunded to the depositor
upon his application.
(e) All advance deposits required by the regulations in this Part 429
shall be paid by money order, bank draft, or certified check drawn to
the order of the Food and Drug Administration, collectible at par at
Washington, D.C. All deposits shall be forwarded to the Food and Drug
Administration, Department of Health and Human Services, Washington, DC
20204, whereupon after making appropriate record thereof they will be
transmitted to the Chief Disbursing Officer, Division of Disbursement,
Treasurer of the United States, for deposit to the special account
''Salaries and Expenses, Certification, Inspection and Other Services,
Food and Drug Administration.''
(39 FR 11750, Mar. 29, 1974, as amended at 42 FR 27227, May 27, 1977;
48 FR 788, Jan. 7, 1983; 56 FR 50249, Oct. 4, 1991)
21 CFR 429.55 Subpart G -- Records
21 CFR 429.60 Records of distribution.
(a) The person to whom a certificate is issued shall keep complete
records showing each shipment and other delivery (including exports) of
each batch or part thereof, by the person requesting certification, and
showing each such shipment and delivery into, or from any place in, any
State or Territory, made by any person subject to his control, including
records showing the date and quantity of each such shipment and delivery
and the name and post office address of the person to whom such shipment
or delivery was made.
(b) Upon the request of any officer or employee of the Food and Drug
Administration or of any other officer or employee of the United States,
acting on behalf of the Secretary, the person to whom a certificate is
issued, at all reasonable hours within 2 years after disposal of all the
batch covered by such certificate, shall make such records available to
any such officer or employee, and shall accord to such officer or
employee full opportunity to make inventory of stocks of such batch on
hand and otherwise to check the correctness of such records.
21 CFR 429.60 PART 430 -- ANTIBIOTIC DRUGS; GENERAL
21 CFR 429.60 Subpart A -- General Provisions
Sec.
430.3 Definitions applicable to all certifiable antibiotic drugs.
430.4 Definitions of antibiotic substances.
430.5 Definitions of master and working standards.
430.6 Definitions of the terms ''unit'' and ''microgram'' as applied
to antibiotic substances.
21 CFR 429.60 Subpart B -- Antibiotic Drugs affected by the Drug
Amendments of 1962
430.10 Certification or release of antibiotic drugs affected by the
drug amendments of 1962.
Authority: Secs. 201, 501, 502, 503, 505, 507, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 357,
371); secs. 215, 301, 351 of the Public Health Service Act (42 U.S.C.
216, 241, 262).
21 CFR 429.60 Subpart A -- General Provisions
21 CFR 430.3 Definitions applicable to all certifiable antibiotic
drugs.
(a) The definitions and interpretations contained in section 201 of
the Federal Food, Drug, and Cosmetic Act shall be applicable to such
terms when used in the regulations in this chapter covering the
certification of antibiotic and antibiotic-containing drugs.
(b) The term Commissioner means the Commissioner of Food and Drugs
and any other officer of the Food and Drug Administration whom he may
designate to act in his behalf for the purpose of the regulations for
the certification of antibiotic and antibiotic-containing drugs.
(c) The term act means the Federal Food, Drug, and Cosmetic Act and
amendments thereto. (52 Stat. 1040 et seq.; 21 U.S.C. 301-392).
(d) The term U.S.P. means the official Pharmacopeia of the United
States, including supplements thereto. The term N.F. means the official
National Formulary, including supplements thereto.
(e) The term batch means a specific homogeneous quantity of a drug.
(f) The term batch mark means an identifying mark or other
identifying device assigned to a batch by the manufacturer or packer
thereof.
(g) The term manufacture does not include the use of a drug as an
ingredient in compounding any prescription issued by a practitioner
licensed by law to administer such drug.
(39 FR 18925, May 30, 1974)
21 CFR 430.4 Definitions of antibiotic substances.
(a) The following are definitions of antibiotic substances:
(1) Penicillin. Each of the several antibiotic substances (e.g.,
penicillin F, penicillin G, penicillin X) produced by the growth of
Penicillium notatum or Penicillium chrysogenum, and each of the same
substances produced by any other means, is a kind of penicillin.
(2) Streptomycin. Each of the several antibiotic substances produced
by the growth of Streptomyces griseus, and each of the same substances
produced by any other means, is a kind of streptomycin.
(3) Dihydrostreptomycin. Each of the antibiotic substances produced
by hydrogenation of streptomycin, and each of the same substances
produced by any other means, is a kind of dihydrostreptomycin.
(4) Chlortetracycline. Each of the several antibiotic substances
produced by the growth of Streptomyces aureofaciens, and each of the
same substances produced by any other means is a kind of
chlortetracycline.
(5) Tetracycline. Each of the several antibiotic substances produced
by the hydrogenation of chlortetracycline, and each of the same
substances produced by any other means, is a kind of tetracycline.
(6) Chloramphenicol. Each of the several antibiotic substances
produced by the growth of Streptomyces venezuelae, and each of the same
substances produced by any other means, is a kind of chloramphenicol.
(7) Bacitracin. Each of the several antibiotic substances produced
by the growth of Bacillus subtilis var. Tracy, and each of the same
substances produced by any other means, is a kind of bacitracin.
(8) (Reserved)
(9) Amphotericin. Each of the antibiotic substances produced by the
growth of Streptomyces nodosus, and each of the same substances produced
by any other means, is a kind of amphortericin.
(10) Colistin. Each of the antibiotic substances produced by the
growth of Bacillus polymyxa var. colistinus, and each of the same
substances produced by any other means, is a kind of colistin.
(11) Cycloserine. Each of the antibiotic substances produced by the
growth of Streptomyces orchidaceus, and each of the same substances
produced by any other means, is a kind of cycloserine.
(12) Erythromycin. Each of the antibiotic substances produced by the
growth of Streptomyces erythreus, and each of the same substances
produced by any other means, is a kind of erythromycin.
(13) Gramicidin. Each of the antibiotic substances produced by the
growth of Bacillus brevis, and each of the same substances produced by
any other means, is a kind of gramicidin.
(14) Griseofulvin. Each of the antibiotic substances produced by the
growth of Penicillium patulum or Penicillium griseofulvum, and each of
the same substances produced by any other means, is a kind of
griseofulvin.
(15) Kanamycin. Each of the antibiotic substances produced by the
growth of Streptomyces kanamyceticus, and each of the same substances
produced by any other means, is a kind of kanamycin.
(16) Neomycin. Each of the antibiotic substances produced by the
growth of Streptomyces fradiae, and each of the same substances produced
by any other means, is a kind of neomycin.
(17) Novobiocin. Each of the antibiotic substances produced by the
growth of Streptomyces niveus (known also as Streptomyces spheroides),
and each of the same substances produced by any other means, is a kind
of novobiocin.
(18) Nystatin. Each of the antibiotic substances produced by the
growth of Streptomyces noursei, and each of the same substances produced
by any other means, is a kind of nystatin.
(19) Oleandomycin. Each of the antibiotic substances produced by the
growth of Streptomyces antibioticus, and each of the same substances
produced by any other means, is a kind of oleandomycin.
(20) Troleandomycin. Each of the antibiotic substances produced by
the triacetylation of oleandomycin, and each of the same substances
produced by any other means, is a kind of troleandomycin.
(21) Oxytetracycline. Each of the antibiotic substances produced by
the growth of Streptomyces rimosus, and each of the same substances
produced by any other means, is a kind of oxytetracycline.
(22) Paromomycin. Each of the antibiotic substances produced by the
growth of Streptomyces rimosus var. paromomycinus, and each of the same
substances produced by any other means, is a kind of paromomycin.
(23) Polymyxin. Each of the antibiotic substances produced by the
growth of Bacillus polymyxa, and each of the same substances produced by
any other means, is a kind of polymyxin.
(24) Plicamycin. Each of the antibiotic substances produced by the
growth of a variant of Streptomyces plicatus, and each of the same
substances produced by any other means, is a kind of plicamycin.
(25) Tyrothricin. Each of the mixtures of antibiotic substances
produced by the growth of Bacillus brevis, and each of the same mixtures
of substances produced by any other means, is a kind of tyrothricin.
(26) Vancomycin. Each of the antibiotic substances produced by the
growth of Streptomyces orientalis, and each of the same substances
produced by any other means, is a kind of vancomycin.
(27) (Reserved)
(28) Gentamicin. Each of the antibiotic substances produced by the
growth of Micromonospora purpurea, and each of the same substances
produced by any other means, is a kind of gentamicin.
(29) Dactinomycin. Dactinomycin is a specific kind of actinomycin
produced by the growth of Streptomyces parvullus or the same antibiotic
produced by any other means.
(30) Candicidin. Each of the heptaene antibiotic substances produced
by the growth of Streptomyces griseus and each of the same substances
produced by any other means is a kind of candicidin.
(31) Cephalosporin. Each of the antibiotic substances produced by
the growth of Cephalosporium acremonium, and each of the same substances
produced by any other means, is a kind of cephalosporin.
(32) Lincomycin. Each of the antibiotic substances produced by the
growth of Streptomyces lincolnensis var. lincolnensis, and each of the
same substances produced by any other means, is a kind of lincomycin.
(33) Demeclocycline. Each of the antibiotic substances produced by
removal of the 6-methyl group from chlortetracycline, and each of the
same substances produced by any other means, is a kind of
demeclocycline.
(34) Clindamycin. Each of the antibiotic substances produced by the
7-chloro-substitution of the 7(R)hydroxyl group of lincomycin, and each
of the same substances produced by any other means, is a kind of
clindamycin.
(35) (Reserved)
(36) Capreomycin. Each of the antibiotic substances produced by the
growth of Streptomyces capreolus, and each of the same substances
produced by any other means, is a kind of capreomycin.
(37) Rifamycin. Each of the several antibiotic substances (e.g.,
rifamycin A, rifamycin B, rifamycin SV) produced by the growth of
Streptomyces mediterranei, and each of the same substances produced by
any other means, is a kind of rifamycin.
(38) Spectinomycin. Each of the antibiotic substances produced by
the growth of Streptomyces spectabilis, and each of the same substances
produced by any other means, is a kind of spectinomycin.
(39) Mitomycin. Mitomycin is the antibiotic substance produced by
the growth of Streptomyces caespitosus, and each of the same substances
produced by any other means is a kind of mitomycin.
(40) Doxorubicin. Each of the antibiotic substances produced by the
growth of Streptomyces peucetius var. caesius, and each of the same
substances produced by any other means, is a kind of doxorubicin.
(41) Bleomycin. Each of the antibiotic substances produced by the
growth of Streptomyces verticillus and each of the same substances
produced by any other means is a kind of bleomycin.
(42) Tobramycin. A specific one of the antibiotic substances
produced by the growth of Streptomyces tenebrarius, and the same
substance produced by any other means, is tobramycin.
(43) Amikacin. Each of the antibiotic substances produced by the
acylation of the 1-amino group of the 2-deoxy-streptamine moiety of
kanamycin A with L-(-)- )amino- -hydroxybuyric acid, and each of the
same substances produced by any other means is a kind of amikacin.
(44) Vidarabine. Vidarabine is a purine glycoside antibiotic
substance produced by the growth of Streptomyces antibioticus, and each
of the same substances produced by any other means is a kind of
vidarabine.
(45) Natamycin. Each of the antibiotic substances produced by the
growth of Streptomyces natalensis, and each of the same substances
produced by any other means, is a kind of natamycin.
(46) Daunorubicin. Each of the antibiotic substances produced by the
growth of Streptomyces coeruleorubidus and each of the same substances
produced by any other means is a kind of daunorubicin.
(47) Sisomicin. A specific one of the antibiotic substances produced
by the growth of Micromonospora inyoensis, and the same substance
produced by any other means, is a kind of sisomicin.
(48) Moxalactam. 5-oxa-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic
acid,
7-((carboxy(4-hydroxyphenyl)acetyl)-aminl-1H-tetrazol-5-yl)thio)-methyl
)-8-oxo-, disodium salt.
(49) Cefoperazone. Cefoperazone is a semi-synthetic antibiotic
substance produced by the acylation of the amino group at the 7 position
of 7-aminocephalosporanic acid with
a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetic
acid and introduction of a methylthiotetrazol group at the 3 position.
(50) Netilmicin. Netilmicin is a semi-synthetic antibiotic of the
aminoglycoside group derived from sisomicin, and each of the same
substances produced by any other means is a kind of netilmicin. It is
d-Streptamine,
4-O-(3-amino-6-(aminomethyl)-3,4-dihydro2-deoxy-6-O-(3-deoxy-4-C-methyl
-3-(methylamino)- -l-arabinopyranosyl)-N1-ethyl-, (2S-cis)-.
(51) Cyclosporine. Cyclosporine is a specific cyclic polypeptide
consisting of 11 amino acids produced by the growth of Cylindrocarpon
lucidum Booth or Tolypocladium inflatum Gams.
(52) Cefonicid. 5-Thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic
acid, 7-((hydroxyphenylacetyl)amino)-8-oxo-3((zol-5yl)-thio)methyl)-,
disodium salt, (6R-(6 7b(R*))).
(53) Clavulanic acid. Clavulanic acid is an antibiotic substance
produced by the growth of Streptomyces clavuligerus having the structure
described as follows: Z-(2R,
5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo(3.2.0)heptane-2-ca
rboxylic acid, and each of the same substances produced by any other
means, is a kind of clavulanic acid.
(54) Ceftriaxone. Ceftriaxone is a semi-synthetic antibiotic
substance produced by the addition of
S-2-benzothiazolyl-2-(2-aminothiazol-4-yl)-2-methoxyiminothioacetate to
the 7 amino group of 7-amino-3-(2,5-dihydro-2
methyl-5,6-dioxo-1,2,4-triazin-3-yl)-thiomethyl-3-cephem-4-carboxylic
acid.
(55) Imipenem monohydrate. Imipenem monohydrate is an antibiotic
substance having the chemical structure described by the following name:
(5R-(5a,6a,(R*)))-6-(1-hydroxyethyl)-3-(thyl)thio)-7-oxo-1-azabicyclo(3.
2.0)-hept-2-ene-2-carboxylic acid monohydrate.
(56) Aztreonam.
(2S(2alpha,3beta(Z)))-2-(((1-(2-amino-4--2-((2-methyl-4-oxo-1-sulfo-3-a
zetidinyl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid.
(57) Sulbactam. Sulbactam is a semi-synthetic antibiotic substance
produced by the oxidation of the sulfur atom at the 4 position to its
dioxide and the deamination at the 6 position of
(2S,5R)-6-amino-3,3-dimethyl-7-oxo-4
thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid (6-APA).
(58) Cefmenoxime. Cefmenoxime is
5-thia-1-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid,
7-(((2-amino-4-thiazolyl)
(methoxyimino)acetyl)amino)-3-(((1-methytetrazol-5-yl)thio)methyl)-8-ox
o-, (6R-(6-a,7-b(Z)))-.
(59) Cefixime. Cefixime is a semisynthetic antibiotic substance
produced by the acylation of the amino group at the 7 position of
7-aminocephalosporanic acid with a b-((2-amino-4-thiazolyl)
(carboxymethoxy)imino) acetyl group and the introduction of a vinyl
group at the 3 position.
(60) Cefotiam. Cefotiam is an antibiotic substance having the
chemical structure described by the following name:
7-(R)-(2-(2-amino-4-thiazol)acetamido)-3-(((1-(2-dimethylamino)ethyl)-1H
-tetrazol-5-y1) thio) methyl)-3-cephem-4-carboxylic acid.
(61) Mupirocin. Each of the antibiotic substances produced by the
growth of Pseudomonas fluorescens, and each of the same substances
produced by any other means, is a kind of mupirocin.
(62) Cefmetazole. Cefmetazole is an antibiotic substance having the
chemical structure described by the following name: (6R-cis)-7-
(((cyanomethyl)thio)acetyl)amino)-7- methoxy-3-(((1-methyl-1H-
tetrazol-5-yl)thio)methyl)-8-oxo-5- thia-1-azabicyclo(4.2.0)oct-2-
ene-2-carboxylic acid.
(63) Cefpiramide. Cefpiramide is an antibiotic substance having the
chemical structure described by the following name: (6R,
7R)-7-((R)-2-(4-hydroxy-6- methyl-nicotinamido)-2-(p-
hydroxyphenyl)acetamido)-3-(((1- methyl-1H-tetrazol-5-yl)thio)methyl)-8-
oxo-5-thia-1-azabicyclo(4.2.0)oct-2-ene- 2-carboxylic acid.
(b) (Reserved)
(39 FR 18925, May 30, 1974)
Editorial Note: For Federal Register citations affecting 430.4, see
the List of CFR Sections Affected in the Finding Aids section of this
volume.
21 CFR 430.5 Definitions of master and working standards.
(a) Master standards -- (1) Penicillinand salts of penicillin -- (i)
Penicillin G The term ''penicillin G master standard' means a specific
lot of crystalline penicillin G that is designated by the Commissioner
as the standard of comparison in determining the potency of the
penicillin G working standard.
(ii) (Reserved)
(iii) Penicillin V. The term ''penicillin V master standard'' means
a specific lot of crystalline penicillin V that is designated by the
Commissioner as the standard of comparison in determining the potency of
the penicillin V working standard.
(iv) -- (v) (Reserved)
(vi) Methicillin. The term ''methicillin master standard'' means a
specific lot of crystalline methicillin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the methicillin working standard.
(vii) Oxacillin. The term ''oxacillin master standard'' means a
specific lot of crystalline oxacillin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the oxacillin working standard.
(viii) Ampicillin. The term ''ampicillin master standard'' means a
specific lot of crystalline ampicillin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the ampicillin working standard.
(ix) Nafcillin. The term ''nafcillin master standard'' means a
specific lot of crystalline nafcillin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the nafcillin working standard.
(x) Cloxacillin. The term ''cloxacillin master standard'' means a
specific lot of crystalline cloxacillin that is designated as the
standard of comparison in determining the potency of the cloxacillin
working standard.
(xi) Dicloxacillin. The term ''dicloxacillin master standard'' means
a specific lot of dicloxacillin that is designated by the Commissioner
as the standard of comparison in determining the potency of the
dicloxacillin working standard.
(xii) The term ''hetacillin working standard'' means a specific lot
of homogenous preparation of hetacillin.
(2) Streptomycin. The term ''streptomycin master standard'' means a
specific lot of streptomycin that is designated by the Commissioner as
the standard of comparison in determining the potency of the
streptomycin working standard.
(3) Dihydrostreptomycin. The term ''dihydrostreptomycin master
standard'' means a specific lot of crystalline dihydrostreptomycin that
is designated by the Commissioner as the standard of comparison in
determining the potency of the dihydrostreptomycin working standard.
(4) Chlortetracycline. The term ''chlortetracyclin master standard''
means a specific lot of crystalline chlortetracycline hydrochloride that
is designated by the Commissioner as the standard of comparison in
determining the potency of the chlortetracycline working standard.
(5) Demeclocycline. The term ''demeclocycline master standard''
means a specific lot of crystalline demeclocycline hydrochloride that is
designated by the Commissioner as the standard of comparison in
determining the potency of the demeclocycline working standard.
(6) Tetracycline. The term ''tetracycline master standard'' means a
specific lot of crystalline tetracycline hydrochloride that is
designated by the Commissioner as the standard of comparison in
determining the potency of the tetracycline working standard.
(7) Rolitetracycline. The term ''rolitetracycline master standard''
means a specific lot of crystalline rolitetracycline that is designated
by the Commissioner as the standard of comparison in determining the
potency of the rolitetracycline working standard.
(8) Chloramphenicol. The term ''chloramphenicol master standard''
means a specific lot of crystalline chloramphenicol that is designated
by the Commissioner as the standard of comparison in determining the
potency of the chloramphenicol working standard.
(9) Bacitracin The term ''bacitracin master standard'' means a
specific lot of bacitracin that is designated by the Commissioner as the
standard of comparison in determining the potency of the bacitracin
working standard.
(10) (Reserved)
(11) Amphotericin. The term ''amphotericin A master standard'' means
a specific lot of amphotericin A designated by the Commissioner as the
standard of comparison in determining the potency of the amphotericin A
working standard. The term ''amphotericin B master standard'' means a
specific lot of amphotericin B designated by the Commissioner as the
standard of comparison in determining the potency of the amphotericin B
working standard.
(12) Colistin. The term ''colistin master standard'' means a
specific lot of colistin designated by the Commissioner as the standard
of comparison in determining the potency of the colistin working
standard.
(13) Colistimethate. The term ''colistimethate master standard''
means a specific lot of colistimethate designated by the Commissioner as
the standard of comparison in determining the potency of the
colistimethate working standard.
(14) Cycloserine. The term ''cycloserine master standard'' means a
specific lot of cycloserine designated by the Commissioner as the
standard of comparison in determining the potency of the cycloserine
working standard.
(15) Erythromycin. The term ''erythromycin master standard'' means a
specific lot of erythromycin designated by the Commissioner as the
standard of comparison in determining the potency of the erythromycin
working standard.
(16) Gramicidin. The term ''gramicidin master standard'' means a
specific lot of gramicidin designated by the Commissioner as the
standard of comparison in determining the potency of the gramicidin
working standard.
(17) Griseofulvin. The term ''griseofulvin master standard'' means a
specific lot of griseofulvin designated by the Commissioner as the
standard of comparison in determining the potency of the griseofulvin
working standard.
(18) Kanamycin. The term ''kanamycin master standard'' means a
specific lot of kanamycin designated by the Commissioner as the standard
of comparison in determining the potency of the kanamycin working
standard.
(19) Neomycin. The term ''neomycin master standard'' means a
specific lot of neomycin designated by the Commissioner as the standard
of comparison in determining the potency of the neomycin working
standard.
(20) Novobiocin. The term ''novobiocin master standard'' means a
specific lot of novobiocin designated by the Commissioner as the
standard of comparison in determining the potency of the novobiocin
working standard.
(21) Nystatin. The term ''nystatin master standard'' means a
specific lot nystatin designated by the Commissioner as the standard of
comparison in determining the potency of the nystatin working standard.
(22) Oleandomycin. The term ''oleandomycin master standard'' means a
specific lot of oleandomycin designated by the Commissioner as the
standard of comparison in determining the potency of the oleandomycin
working standard.
(23) Oxytetracycline. The term ''oxytetracycline master standard''
means a specific lot of oxytetracycline designated by the Commissioner
as the standard of comparison in determining the potency of the
oxytetracycline working standard.
(24) Paromomycin. The term ''paromomycin master standard'' means a
specific lot of paromomycin designated by the Commissioner as the
standard of comparison in determining the potency of the paromomycin
working standard.
(25) Polymyxin B. The term ''polymyxin B master standard'' means a
specific lot of polymyxin B designated by the Commissioner as the
standard of comparison in determining the potency of the polymyxin B
working standard.
(26) (Reserved)
(27) Vancomycin. The term ''vancomycin master standard'' means a
specific lot of vancomycin designated by the Commissioner as the
standard of comparison in determining the potency of the vancomycin
working standard.
(28) (Reserved)
(29) Troleandomycin. The term ''troleandomycin master standard''
means a specific lot of troleandomycin designated by the Commissioner as
the standard of comparison in determiing the potency of the
troleandomycin working standard.
(30) Gentamicin. The term ''gentamicin master standard'' means a
specific lot of gentamicin designated by the Commissioner as the
standard of comparison in determining the potency of the gentamicin
working standard.
(31) Dactinomycin. The term ''dactinomycin master standard'' means a
specific lot of dactinomycin designated by the Commissioner as the
standard of comparison in determining the potency of the dactinomycin
working standard.
(32) Candicidin. The term ''candicidin master standard'' means a
specific lot of candicidin that is designated by the Commissioner as the
standard of comparison in determining the potency of the candicidin
working standard.
(33) Cephalothin. The term ''cephalothin master standard'' means a
specific lot of cephalothin designated by the Commissioner as the
standard of comparison in determining the potency of the cephalothin
working standard.
(34) Lincomycin. The term ''lincomycin master standard'' means a
specific lot of lincomycin designated by the Commissioner as the
standard of comparison in determining the potency of the lincomycin
working standard.
(35) Methacycline. The term ''methacycline master standard'' means a
specific lot of methacycline designated by the Commissioner as the
standard of comparison in determining the potency of the methacycline
working standard.
(36) Doxycycline. The term ''doxycycline master standard'' means a
specific lot of -6-deoxyoxytetracycline designated by the Commissioner
as the standard of comparison in determining the potency of the
doxycycline working standard.
(37) Cephaloridine. The term ''cephaloridine master standard'' means
a specific lot of cephaloridine that is designated by the Commissioner
as the standard of comparison in determining the potency of the
cephaloridine working standard.
(38) Plicamycin. The term ''plicamycin master standard'' means a
specific lot of plicamycin designated by the Commissioner as the
standard of comparison in determining the potency of the plicamycin
working standard.
(39) Clindamycin. The term ''clindamycin master standard'' means a
specific lot of clindamycin designated by the Commissioner as the
standard of comparison in determining the potency of the clindamycin
working standard.
(40) Cephaloglycin. The term ''cephaloglycin master standard'' means
a specific lot of cephaloglycin designated by the Commissioner as the
standard of comparison in determining the potency of the cephaloglycin
working standard.
(41) Carbenicillin. The term ''carbenicillin master standard'' means
a specific lot of carbenicillin designated by the Commissioner as the
standard of comparison in determining the potency of the carbenicillin
working standard.
(42) Cephalexin. The term ''cephalexin master standard'' means a
specific lot of cephalexin that is designated by the Commissioner as the
standard of comparison in determining the potency of the cephalexin
working standard.
(43) (Reserved)
(44) Capreomycin. The term ''capreomycin master standard'' means a
specific lot of capreomycin designated by the Commissioner as the
standard of comparison in determining the potency of the capreomycin
working standard.
(45) Rifampin. The term ''rifampin master standard'' means a
specific lot of rifampin designated by the Commissioner as the standard
of comparison in determining the potency of the rifampin working
standard.
(46) Minocycline. The term ''minocycline master standard'' means a
specific lot of minocycline designated by the Commissioner as the
standard of comparison in determining the potency of the minocycline
working standard.
(47) Spectinomycin. The term ''spectinomycin master standard'' means
a specific lot of spectinomycin designated by the Commissioner as the
standard of comparison in determining the potency of the spectinomycin
working standard.
(48) Clindamycin palmitate hydrochloride. The term ''clindamycin
palmitate hydrochloride master standard'' means a specific lot of
clindamycin palmitate hydrochloride designated by the Commissioner as
the standard of comparison in determining the potency of the clindamycin
palmitate hydrochloride working standard.
(49) Carbenicillin indanyl. The term ''carbenicillin indanyl master
standard'' means a specific lot of carbenicillin indanyl designated by
the Commissioner as the standard of comparison in determining the
potency of the carbenicillin indanyl working standard.
(50) Cephapirin. The term ''cephapirin master standard'' means a
specific lot of cephapirin that is designated by the Commissioner as the
standard of comparison in determining the potency of the cephapirin
working standard.
(51) Cefazolin. The term ''cefazolin master standard'' means a
specific lot of cefazolin that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefazolin
working standard.
(52) Mitomycin. The term ''mitomycin master standard'' means a
specific lot of crystalline mitomycin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the mitomycin working standard.
(53) Amoxicillin. The term ''amoxicillin master standard'' means a
specific lot of amoxicillin that is designated by the Commissioner as
the standard of comparison in determining the potency of the amoxicillin
working standard.
(54) (Reserved)
(55) Cephradine. The term ''cephradine master standard'' means a
specific lot of cephradine that is designated by the Commissioner as the
standard of comparison in determining the potency of the cephradine
working standard.
(56) Doxorubicin. The term ''doxorubicin master standard'' means a
specific lot of crystalline doxorubicin that is designated by the
Commissioner as the standard of comparison in determining the potency of
the doxorubicin working standard.
(57) Bleomycin. The term ''bleomycin master standard'' means a
specific lot of bleomycin designated by the Commissioner as the standard
of comparison in determining the potency of the bleomycin working
standard.
(58) Tobramycin. The term ''tobramycin master standard'' means a
specific lot of tobramycin designated by the Commissioner as the
standard of comparison in determining the potency of the tobramycin
working standard.
(59) Amikacin. The term ''amikacin master standard'' means a
specific lot of amikacin designated by the Commissioner as the standard
of comparison in determining the potency of the amikacin working
standard.
(60) Vidarabine. The term ''vidarabine master standard'' means a
specific lot of vidarabine that is designated by the Commissioner as the
standard of comparison in determining the potency of the vidarabine
working standard.
(61) Ticarcillin. The term ''ticarcillin master standard'' means a
specific lot of ticarcillin designated by the Commissioner as the
standard of comparison in determining the potency of the ticarcillin
working standard.
(62) Cefadroxil. The term ''cefadroxil master standard'' means a
specific lot of cefadroxil that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefadroxil
working standard.
(63) Natamycin. The term ''natamycin master standard'' means a
specific lot of natamycin designated by the Commissioner as the standard
of comparison in determining the potency of the natamycin working
standard.
(64) Cefoxitin. The term ''cefoxitin master standard'' means a
specific lot of cefoxitin that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefoxitin
working standard.
(65) Cefamandole. The term ''cefamandole master standard'' means a
specific lot of cefamandole that is designated by the Commissioner as
the standard of comparison in determining the potency of the cefamandole
working standard.
(66) Cefaclor. The term ''cefaclor master standard'' means a
specific lot of cefaclor that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefaclor
working standard.
(67) Cyclacillin. The term ''cyclacillin master standard'' means a
specific lot of cyclacillin that is designated by the Commissioner as
the standard of comparison in determining the potency of the cyclacillin
working standard.
(68) Daunorubicin. The term ''daunorubicin master standard'' means a
specific lot of daunorubicin that is designated by the Commissioner as
the standard of comparison in determining the potency of the
daunorubicin working standard.
(69) Sisomicin. The term ''sisomicin master standard'' means a
specific lot of sisomicin that is designated by the Commissioner as the
standard of comparison in determining the potency of the sisomicin
working standard.
(70) Meclocycline. The term ''meclocycline master standard'' means a
specific lot of meclocycline that is designated by the Commissioner as
the standard of comparison in determining the potency of the
meclocycline working standard.
(71) Cefotaxime. The term ''cefotaxime master standard'' means a
specific lot of cefotaxime that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefotaxime
working standard.
(72) Mezlocillin. The term ''mezlocillin master standard'' means a
specific lot of mezlocillin that is designated by the Commissioner as
the standard of comparison in determining the potency of the mezlocillin
working standard.
(73) Moxalactam. The term ''moxalactam master standard'' means a
specific lot of moxalactam that is designated by the Commissioner as the
standard of comparison in determining the potency of the moxalactam
working standard.
(74) Piperacillin. The term ''piperacillin master standard'' means a
specific lot of piperacillin that is designated by the Commissioner as
the standard of comparison in determining the potency of the
piperacillin working standard.
(75) Azlocillin. The term ''azlocillin master standard'' means a
specific lot of azlocillin that is designated by the Commissioner as the
standard of comparison in determining the potency of the azlocillin
working standard.
(76) Cefoperazone. The term ''cefoperazone master standard'' means a
specific lot of cefoperazone that is designated by the Commissioner as
the standard of comparison in determining the potency of the
cefoperazone working standard.
(77) Netilmicin. The term ''netilmicin master standard'' means a
specific lot of netilmicin that is designated by the Commissioner as the
standard of comparison in determining the potency of the netilmicin
working standard.
(78) Cefuroxime. The term ''cefuroxime master standard'' means a
specific lot of cefuroxime that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefuroxime
working standard.
(79) Ceftizoxime. The term ''ceftizoxime master standard'' means a
specific lot of ceftizoxime that is designated by the Commissioner as
the standard of comparison in determining the potency of the ceftizoxime
working standard.
(80) Cyclosporine. The term ''cyclosporine master standard'' means a
specific lot of cyclosporine that is designated by the Commissioner as
the standard of comparison in determining the potency of the
cyclosporine working standard.
(81) Ceforanide. The term ''ceforanide master standard'' means a
specific lot of ceforanide that is designated by the Commissioner as the
standard of comparison in determining the potency of the ceforanide
working standard.
(82) Cefonicid. The term ''cefonicid master standard'' means a
specific lot of cefonicid that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefonicid
working standard.
(83) Clavulanic acid. The term ''clavulanic acid master standard''
means a specific lot of clavulanic acid or a salt thereof that is
designated by the Commissioner as the standard of comparison in
determining the potency of the clavulanic acid working standard.
(84) Amdinocillin. The term ''amdinocillin master standard'' means a
specific lot of amdinocillin that is designated by the Commissioner as
the standard of comparison in determining the potency of the
amdinocillin working standard.
(85) Ceftriaxone. The term ''ceftriaxone master standard'' means a
specific lot of ceftriaxone that is designated by the Commissioner as
the standard of comparison in determining the potency of the ceftriaxone
working standard.
(86) Ceftazidime. The term ''ceftazidime master standard'' means a
specific lot of ceftazidime that is designated by the Commissioner as
the standard of comparison in determining the potency of the ceftazidime
working standard.
(87) Imipenem. The term ''imipenem master standard'' means a
specific lot of imipenem that is designated by the Commissioner as the
standard of comparison in determining the potency of the imipenem
working standard.
(88) Cefotetan. The term ''cefotetan master standard'' means a
specific lot of cefotetan that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefotetan
working standard.
(89) Aztreonam. The term ''aztreonam master standard'' means a
specific lot of aztreonam that is designated by the Commissioner as the
standard of comparison in determining the potency of the aztreonam
working standard.
(90) Sulbactam. The term ''sulbactam master standard'' means a
specific lot of sulbactam that is designated by the Commissioner as the
standard of comparison in determining the potency of the sulbactam
working standard.
(91) Cefuroxime axetil. The term ''cefuroxime axetil master
standard'' means a specific lot of cefuroxime axetil that is designated
by the Commissioner as the standard of comparison in determining the
potency of the cefuroxime axetil working standard.
(92) Cefmenoxime. The term ''cefmenoxime master standard'' means a
specific lot of cefmenoxime that is designated by the Commissioner as
the standard of comparison in determining the potency of the cefmenoxime
working standard.
(93) Cefixime. The term ''cefixime master standard'' means a
specific lot of cefixime that is designated by the Commissioner as the
standard of comparison in determining the potency of the cefixime
working standard.
(94) Cefotiam. The term ''cefotiam master standard'' means a
specific lot of cefotiam that is designed by the Commissioner as the
standard of comparison in determining the potency of the cefotiam
working standard.
(95) Clindamycin phosphate. The term ''clindamycin phosphate master
standard'' means a specific lot of clindamycin phosphate that is
designed by the Commissioner as the standard for comparison in
determining the potency of the clindamycin phosphate standard.
(96) Mupirocin. The term ''mupirocin master standard'' means a
specific lot of mupirocin or a salt thereof that is designated by the
Commissioner as the standard of comparison in determining the potency of
the mupirocin working standard.
(97) Cefmetazole. The term ''cefmetazole master standard'' means a
specific lot of cefmetazole that is designated by the Commissioner as
the standard of comparison in determining the potency of the cefmetazole
working standard.
(98) Cefpiramide. The term ''cefpiramide master standard'' means a
specific lot of cefpiramide that is designated by the Commissioner as
the standard of comparison in determining the potency of the cefpiramide
working standard.
(b) Working standards. The potency or purity of each preparation has
been determined by comparison with its master standard , and each has
been designated by the Commissioner as working standards for use in
determining the potency or purity of antibiotic substances subject to
the regulations in this chapter.Unless otherwise noted, the working
standard and the U.S.P. reference standard for the antibiotic drug named
are identical.
(1) Penicillin. (i) The term ''penicillin G working standard'' means
a specific lot of a homogeneous preparation of penicillin G.
(ii) (Reserved)
(iii) The term ''penicillin V working standard'' means a specific lot
of a homogeneous preparation of penicillin V.
(iv) (Reserved)
(v) The term ''methicillin working standard'' means a specific lot of
a homogeneous preparation of methicillin.
(vi) The term ''oxacillin working standard'' means a specific lot of
a homogeneous preparation of oxacillin.
(vii) The term ''ampicillin working standard'' means a specific lot
of a homogeneous preparation of ampicillin.
(viii) The term ''nafcillin working standard'' means a specific lot
of a homogeneous preparation of nafcillin.
(ix) The term ''cloxacillin working standard'' means a specific lot
of a homogeneous preparation of cloxacillin.
(x) The term ''penicillin G procaine working standard'' means a
specific lot of a homogeneous preparation of penicillin G procaine.
(xi) The term ''dicloxacillin working standard'' means a specific lot
of a homogeneous preparation of dicloxacillin.
(xii) The term ''bacampicillin hydrochloride working standard'' means
a specific lot of a homogeneous preparation of bacampicillin
hydrochloride.
(2) Amphotericin A. The term ''amphotericin A working standard''
means a specific lot of a homogeneous preparation of amphotericin A.
(3) Amphotericin B. The term ''amphotericin B working standard''
means a specific lot of a homogeneous preparation of amphotericin B.
(4) Streptomycin. The term ''streptomycin working standard'' means a
specific lot of a homogeneous preparation of streptomycin.
(5) Dihydrostreptomycin. The term ''dihydrostreptomycin working
standard'' means a specific lot of a homogeneous preparation of
dihydrostreptomycin.
(6) Chlortetracycline. The term ''chlortetracycline working
standard'' means a specific lot of a homogeneous preparation of
chlortetracycline.
(7) Demeclocycline. The term ''demeclocycline working standard''
means a specific lot of a homogeneous preparation of demeclocycline.
(8) Tetracycline. The term ''tetracycline working standard'' means a
specific lot of a homogeneous preparation of tetracycline.
(9) Rolitetracycline. The term ''rolitetracycline working standard''
means a specific lot of a homogeneous preparation of rolitetracycline.
(10) Chloramphenicol. The term ''chloramphenicol working standard''
means a specific lot of a homogeneous preparation of chloramphenicol.
(11) Bacitracin. The term ''bacitracin working standard'' means a
specific lot of a homogeneous preparation of bacitracin.
(12) (Reserved)
(13) Colistin. The term ''colistin working standard'' means a
specific lot of a homogeneous preparation of colistin.
(14) Colistimethate. The term ''colistimethate working standard''
means a specific lot of a homogeneous preparation of colistimethate.
(15) Cycloserine. The term ''cycloserine working standard'' means a
specific lot of a homogeneous preparation of cycloserine.
(16) Erythromycin. The term ''erythromycin working standard'' means
a specific lot of a homogeneous preparation of erythromycin.
(17) Gramicidin. The term ''gramicidin working standard'' means a
specific lot of a homogeneous preparation of gramicidin.
(18) Griseofulvin. The term ''griseofulvin working standard'' means
a specific lot of a homogeneous preparation of griseofulvin.
(19) Kanamycin. The term ''kanamycin working standard'' means a
specific lot of a homogeneous preparation of kanamycin.
(20) Neomycin. The term ''neomycin working standard'' means a
specific lot of a homogeneous preparation of neomycin.
(21) Novobiocin. The term ''novobiocin working standard'' means a
specific lot of a homogeneous preparation of novobiocin.
(22) Nystatin. The term ''nystatin working standard'' means a
specific lot of a homogeneous preparation of nystatin.
(23) Oleandomycin. The term ''oleandomycin working standard'' means
a specific lot of a homogeneous preparation of oleandomycin.
(24) Troleandomycin. The term ''troleandomycin working
standard''means a specific lot of a homogeneous preparation of
troleandomycin.
(25) Oxytetracycline. The term ''oxytetracycline working standard''
means a specific lot of a homogeneous preparation of oxytetracycline.
(26) Paromomycin. The term ''paromomycin working standard'' means a
specific lot of a homogeneous preparation of paromomycin.
(27) Polymyxin B. The term ''polymyxin B working standard'' means a
specific lot of a homogeneous preparation of polymyxin B.
(28) Vancomycin. The term ''vancomycin working standard'' means a
specific lot of a homogeneous preparation of vancomycin.
(29) (Reserved)
(30) Gentamicin. The term ''gentamicin working standard'' means a
specific lot of a homogeneous preparation of gentamicin.
(31) Dactinomycin. The term ''dactinomycin working standard'' means
a specific lot of a homogeneous preparation of dactinomycin.
(32) Candicidin. The term ''candicidin working standard'' means a
specific lot of a homogeneous preparation of candicidin.
(33) Cephalothin. The term ''cephalothin working standard'' means a
specific lot of a homogeneous preparation of cephalothin.
(34) Lincomycin. The term ''lincomycin working standard'' means a
specific lot of a homogeneous preparation of lincomycin.
(35) Methacycline. The term ''methacycline working standard'' means
a specific lot of homogeneous preparation of methacycline.
(36) Doxycycline. The term ''doxycycline working standard'' means a
specific lot of homogeneous preparation of -6-deoxyoxytetracycline.
(37) Cephaloridine. The term ''cephaloridine working standard''
means a specific lot of homogeneous preparation of cephaloridine.
(38) Plicamycin. The term ''plicamycin working standard'' means a
specific lot of a homogeneous preparation of plicamycin.
(39) Clindamycin. The term ''clindamycin working standard'' means a
specific lot of a homogeneous preparation of clindamycin.
(40) Cephaloglycin. The term ''cephaloglycin working standard''
means a specific lot of homogeneous preparation of cephaloglycin.
(41) Carbenicillin. The term ''carbenicillin working standard''
means a specific lot of homogeneous preparation of carbenicillin.
(42) Cephalexin. The term ''cephalexin working standard'' means a
specific lot of a homogeneous preparation of cephalexin.
(43) (Reserved)
(44) Capreomycin. The term ''capreomycin working standard'' means a
specific lot of a homogeneous preparation of capreomycin.
(45) Rifampin. The term ''rifampin working standard'' means a
specific lot of a homogeneous preparation of rifampin.
(46) Minocycline. The term ''minocycline working standard'' means a
specific lot of a homogeneous preparation of minocycline.
(47) Spectinomycin. The term ''spectinomycin working standard''
means a specific lot of a homogeneous preparation of spectinomycin.
(48) Clindamycin palmitate hydrochloride. The term ''clindamycin
palmitate hydrochloride working standard'' means a specific lot of a
homogeneous preparation of clindamycin palmitate hydrochloride.
(49) Carbenicillin indanyl. The term ''carbenicillin indanyl working
standard'' means a specific lot of a homogeneous preparation of
carbenicillin indanyl.
(50) Cephapirin. The term ''cephapirin working standard'' means a
specific lot of a homogeneous preparation of cephapirin.
(51) Cefazolin. The term ''cefazolin working standard'' means a
specific lot of a homogeneous preparation of cefazolin.
(52) Mitomycin. The term ''mitomycin working standard'' means a
specific lot of a homogeneous preparation of mitomycin.
(53) Amoxicillin. The term ''amoxicillin working standard'' means a
specific lot of a homogeneous preparation of amoxicillin.
(54) (Reserved)
(55) Cephradine. The term ''cephradine working standard'' means a
specific lot of a homogeneous preparation of cephradine.
(56) Doxorubicin. The term ''doxorubicin working standard'' means a
specific lot of a homogeneous preparation of doxorubicin.
(57) Bleomycin. The term ''bleomycin working standard'' means a
specific lot of a homogeneous preparation of bleomycin.
(58) Tobramycin. The term ''tobramycin working standard'' means a
specific lot of a homogeneous preparation of tobramycin.
(59) Amikacin. The term ''amikacin working standard'' means a
specific lot of a homogeneous preparation of amikacin.
(60) Vidarabine. The term ''vidarabine working standard'' means a
specific lot of a homogeneous preparation of vidarabine.
(61) Ticarcillin. The term ''ticarcillin working standard'' means a
specific lot of a homogeneous preparation of ticarcillin.
(62) Cefadroxil. The term ''cefadroxil working standard'' means a
specific lot of a homogeneous preparation of cefadroxil.
(63) Natamycin. The term ''natamycin working standard'' means a
specific lot of a homogeneous preparation of natamycin.
(64) Cefoxitin. The term ''cefoxitin working standard'' means a
specific lot of a homogeneous preparation of cefoxitin.
(65) Cefamandole. The term ''cefamandole working standard'' means a
specific lot of a homogeneous preparation of cefamandole.
(66) Cefaclor. The term ''cefaclor working standard'' means a
specific lot of a homogeneous preparation of cefaclor.
(67) Cyclacillin. The term ''cyclacillin working standard'' means a
specific lot of a homogeneous preparation of cyclacillin.
(68) Daunorubicin. The term ''daunorubicin working standard'' means
a specific lot of a homogeneous preparation of daunorubicin.
(69) Sisomicin. The term ''sisomicin working standard'' means a
specific lot of a homogeneous preparation of sisomicin.
(70) Meclocycline. The term ''meclocycline working standard'' means
a specific lot of a homogeneous preparation of meclocycline.
(71) Cefotaxime. The term ''cefotaxime working standard'' means a
specific lot of a homogeneous preparation of cefotaxime.
(72) Mezlocillin. The term ''mezlocillin working standard'' means a
specific lot of a homogeneous preparation of mezlocillin.
(73) Moxalactam. The term ''moxalactam working standard'' means a
specific lot of a homogeneous preparation of moxalactam.
(74) Piperacillin. The term ''piperacillin working standard'' means
a specific lot of a homogeneous preparation of piperacillin.
(75) Azlocillin. The term ''azlocillin working standard'' means a
specific lot of a homogeneous preparation of azlocillin.
(76) Cefoperazone. The term ''cefoperazone working standard'' means
a specific lot of a homogeneous preparation of cefoperazone.
(77) Netilmicin. The term ''netimicin working standard'' means a
specific lot of a homogeneous preparation of netilmicin.
(78) Cefuroxime. The term ''cefuroxime working standard'' means a
specific lot of a homogeneous preparation of cefuroxime.
(79) Ceftizoxe. The term ''ceftizoxime working standard'' means a
specific lot of a homogeneous preparation of ceftizoxime.
(80) 4-Epitetracycline. The term ''4-epitetracycline working
standard'' means a specific lot of a homogeneous preparation of
4-epitetracycline.
(81) Chloramphenicol palmitate. The term ''chloramphenicol palmitate
working standard'' means a specific lot of a homogeneous preparation of
chloramphenicol palmitate.
(82) Cyclosporine. The term ''cyclosporine working standard'' means
a specific lot of a homogeneous preparation of cyclosporine.
(83) Ceforanide. The term ''ceforanide working standard'' means a
specific lot of a homogeneous preparation of ceforanide.
(84) Cefonicid. The term ''cefonicid working standard'' means a
specific lot of a homogeneous preparation of cefonicid.
(85) Clavulanic acid. The term ''clavulanic acid working standard''
means a specific lot of a homogeneous preparation of clavulanic acid or
a salt thereof.
(86) Amdinocillin. The term ''amdinocillin working standard'' means
a specific lot of a homogeneous preparation of amdinocillin.
(87) Ceftriaxone. The term ''ceftriaxone working standard'' means a
specific lot of a homogeneous preparation of ceftriaxone.
(88) Ceftazidime. The term ''ceftazidime working standard'' means a
specific lot of a homogeneous preparation of ceftazidime.
(89) Imipenem. The term ''imipenem working standard'' means a
specific lot of a homogeneous preparation of imipenem.
(90) Cefotetan. The term ''cefotetan working standard'' means a
specific lot of a homogeneous preparation of cefotetan.
(91) Aztreonam. The term ''aztreonam working standard'' means a
specific lot of a homogeneous preparation of aztreonam.
(92) Sulbactam. The term ''sulbactam working standard'' means a
specific lot of a homogeneous preparation of sulbactam.
(93) Cefuroxime axetil. The term ''cefuroxime axetil working
standard'' means a specific lot of a homogeneous preparation of
cefuroxime axetil.
(94) Cefmenoxime. The term ''cefmenoxime working standard'' means a
specific lot of a homogeneous preparation of cefmenoxime.
(95) Cefixime. The term ''cefixime working standard'' means a
specific lot of a homogeneous preparation of cefixime.
(96) Cefotiam. The term ''cefotiam working standard'' means a
specific lot of a homogenous preparation of cefotiam.
(97) Clindamycin phosphate. The term ''clindamycin phosphate working
standard'' means a specific lot of a homogenous preparation of
clindamycin phosphate.
(98) Mupirocin. The term ''mupirocin working standard'' means a
specific lot of a homogeneous preparation of mupirocin or a salt
thereof.
(99) Cefmetazole. The term ''cefmetazole working standard'' means a
specific lot of a homogeneous preparation of cefmetazole.
(100) Cefpiramide. The term ''cefpiramide working standard'' means a
specific lot of a homogeneous preparation of cefpiramide.
(39 FR 18925, May 30, 1974)
Editorial Note: For Federal Register citations affecting 430.5, see
the List of CFR Sections Affected appearing in the Finding Aids section
of this volume.
21 CFR 430.6 Definitions of the terms ''unit'' and ''microgram'' as
applied to antibiotic substances.
Unless it has been otherwise specified in the individual definitions
in this section, the activity assigned to each ''unit'' or ''microgram''
is equivalent to an International Unit, if such has been defined by the
World Health Organization.
(a) ''Unit'' (1) Penicillin -- (i) Penicillin G. The term ''unit''
applies to penicillin G means the penicillin activity (potency)
contained in 0.600 microgram of the penicillin G master standard.
(ii) (Reserved)
(iii) Penicillin V. The term ''unit'' applied to penicillin V means
the penicillin activity (potency) contained in 0.590 microgram of the
penicillin V master standard.
(2) Bacitracin. The term ''unit'' applied to bacitracin means a
bacitracin activity (potency) contained in 13.51 micrograms of the
bacitracin master standard, except that when the activity (potency) of
bacitracin is expressed in terms of its weight, as in the feed and
drinking water of animals, 1 gram of activity is equivalent to 42,000
units.
(3) Nystatin. The term ''unit'' applied to nystatin means the
nystatin activity (potency) contained in 0.2817 microgram of the
nystatin master standard when dried for 2 hours at 40 C. and a
pressure of 5 millimeters or less.
(4) Polymyxin B. The term ''unit'' applied to polymyxin B means the
polymyxin activity (potency) contained in 0.1274 microgram of the
polymyxin B master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(5) Bleomycin. The term ''unit'' applied to bleomycin means the
bleomycin activity (potency) contained in 0.637 milligram of the
bleomycin master standard.
(b) ''Microgram'' -- (1) Streptomycin. The term ''microgram''
applied to streptomycin means the streptomycin activity (potency)
contained in 1.250 micrograms of the streptomycin master standard after
it is dried for 3 hours at 60 C. and a pressure of 5 millimeters or
less.
(2) Dihydrostreptomycin. The term ''microgram'' applied to
dihydrostreptomycin means the dihydrostreptomycin activity (potency)
contained in 1.25 micrograms of the dihydrostreptomycin master standard
after it is dried for 4 hours at 100 C. and a pressure of 50 microns
or less.
(3) Chlortetracycline. The term ''microgram'' applied to
chlortetracycline means the chlortetracycline activity (potency)
contained in 1.0 microgram of the chlortetracycline master standard.
(4) Demeclocycline. The term ''microgram'' applied to demeclocycline
means the demeclocycline activity (potency) contained in 1.0 microgram
of the demeclocycline master standard after it is dried for 3 hours at
60 C. and a pressure of 5 millimeters or less.
(5) Tetracycline. The term ''microgram'' applied to tetracycline
means the tetracycline activity (potency) contained in 1.0 microgram of
tetracycline master standard.
(6) Rolitetracycline. The term ''microgram'' applied to
rolitetracycline means the rolitetracycline activity (potency) contained
in 1.0 microgram of the rolitetracycline master standard when dried for
3 hours at 60 C. and a pressure of 5 millimeters or less.
(7) Chloramphenicol. The term ''microgram'' applied to
chloramphenicol means the chloramphenicol activity (potency) contained
in 1.0 microgram of the chloramphenicol master standard.
(8) Methicillin. The term ''microgram'' applied to methicillin means
the methicillin activity (potency) contained in 1.105 micrograms of the
methicillin master standard.
(9) Oxacillin. The term ''microgram'' applied to oxacillin means the
oxacillin activity (potency) contained in 1.111 micrograms of the
oxacillin master standard.
(10) (Reserved)
(11) Amphotericin A. The term ''microgram'' applied to amphotericin
A means the amphotericin A activity (potency) contained in 1.0 microgram
of the amphotericin A master standard when dried for 3 hours at 60 C.
and a pressure of 5 millimeters or less.
(12) Amphotericin B. The term ''microgram'' applied to amphotericin
B means the amphotericin B activity (potency) contained in 1.014
micrograms of the amphotericin B master standard when dried for 3 hours
at 60 C. and a pressure of 5 millimeters or less.
(13) Colistin. The term ''microgram'' applied to colistin means the
colistin base activity (potency) contained in 1.495 micrograms of the
colistin master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less. The numerical value of a microgram
of colistin is not equivalent to the International Unit.
(14) Colistimethate. The term ''microgram'' applied to
colistimethate means the activity (potency) calculated as colistin base
that is contained in 1.938 micrograms of the colistimethate master
standard when dried for 3 hours at 60 C. and a pressure of 5
millimeters or less. The numerical value of a microgram of
colistimethate is not equivalent to the International Unit.
(15) Cycloserine. The term ''microgram'' applied to cycloserine
means the cycloserine activity (potency) contained in 1.0 microgram of
the cycloserine master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(16) Erythromycin. The term ''microgram'' applied to erythromycin
means the erythromycin base activity (potency) contained in 1.02
micrograms of the erythromycin master standard when dried for 3 hours at
60 C. and a pressure of 5 millimeters or less.
(17) Gramicidin. The term ''microgram'' applied to gramicidin means
the gramicidin activity (potency) contained in 1.0 microgram of the
gramicidin master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(18) Griseofulvin. The term ''microgram'' applied to griseofulvin
means the griseofulvin activity (potency) contained in 1.0 microgram of
the griseofulvin master standard.
(19) Kanamycin. The term ''microgram'' applied to kanamycin means
the kanamycin base activity (potency) contained in 1.299 micrograms of
the kanamycin master standard.
(20) Neomycin. The term ''microgram'' applied to neomycin means the
neomycin base activity (potency) contained in 1.429 micrograms of the
neomycin master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(21) Novobiocin. The term ''microgram'' applied to novobiocin means
the novobiocin acid activity (potency) contained in 1.033 micrograms of
the novobiocin master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(22) Oleandomycin. The term ''microgram'' applied to oleandomycin
means the oleandomycin base activity (potency) contained in 1.176
micrograms of the oleandomycin master standard.
(23) Troleandomycin. The term ''microgram'' applied to
troleandomycin means the activity (potency), calculated as the molecular
equivalent of the oleandomycin base, contained in 1.2315 micrograms of
the troleandomycin master standard.
(24) Oxytetracycline. The ''microgram'' applied to oxytetracycline
means the oxytetracycline base activity (potency) contained in 1.13
micrograms of the oxytetracycline master standard.
(25) Paromomycin. The term ''microgram'' applied to paromomycin
means the paromomycin activity (potency) contained in 1.333 micrograms
of the paromomycin master standard when dried for 3 hours at 60 C. and
a pressure of 5 millimeters or less.
(26) Tyrothricin. The term ''microgram'' applied to tyrothricin
means the activity (potency) contained in 0.2 microgram of the
gramicidin master standard when dried for 3 hours at 60 C. and a
pressure of 5 millimeters or less.
(27) Vancomycin. The term ''microgram'' applied to vancomycin means
the vancomycin base activity (potency) contained in 1.25 micrograms of
the vancomycin master standard.
(28) (Reserved)
(29) Ampicillin. The term ''microgram'' applied to ampicillin means
the ampicillin activity (potency) contained in 1.1764 micrograms of the
ampicillin master standard.
(30) Nafcillin. The term ''microgram'' applied to nafcillin means
the nafcillin activity (potency) contained in 1.0989 micrograms of the
nafcillin master standard.
(31) Gentamicin. The term ''microgram'' applied to gentamicin means
the gentamicin activity (potency) contained in 1.56 micrograms of the
gentamicin master standard when dried for 3 hours at 110 C. and a
pressure of 5 millimeters or less.
(32) Dactinomycin. The term ''microgram'' applied to dactinomycin
means the dactinomycin activity (potency) contained in 1.000 microgram
of the dactinomycin master standard when dried for 3 hours at 60 C.
and a pressure of 5 millimeters or less.
(33) Candicidin. The term ''microgram'' applied to candicidin means
the candicidin activity (potency) contained in 1.0 microgram of the
candicidin master standard when dried for 3 hours at 40 C. and a
pressure of 5 millimeters or less.
(34) Cephalothin. The term ''microgram'' applied to cephalothin
means the cephalothin activity (potency) contained in 1.056 micrograms
of the cephalothin master standard when dried for 3 hours at 60 C. and
a pressure of 5 millimeters or less.
(35) Lincomycin. The term ''microgram'' applied to lincomycin means
the lincomycin base activity (potency) contained in 1.156 micrograms of
the lincomycin master standard.
(36) Cloxacillin. The term ''microgram'' applied to cloxacillin
means the cloxacillin activity (potency) contained in 1.135 micrograms
of the cloxacillin master standard.
(37) Methacycline. The term ''microgram'' applied to methacycline
means the methacycline activity (potency) contained in 1.082 micrograms
of the methacycline master standard when dried for 3 hours at 60 C.
and a pressure of 5 millimeters or less.
(38) Doxycycline. The term ''microgram'' applied to doxycycline
means the doxycycline activity (potency) contained in 1.155 micrograms
of the doxycycline master standard.
(39) Cephaloridine. The term ''microgram'' applied to cephaloridine
means the cephaloridine activity (potency) contained in 1.00806
micrograms of the cephaloridine master standard when dried for 3 hours
at 60 C. and a pressure of 5 millimeters or less.
(40) Dicloxacillin. The term ''microgram'' applied to dicloxacillin
means the dicloxacillin activity (potency) contained in 1.087 micrograms
of the dicloxacillin master standard.
(41) Plicamycin. The term ''microgram'' applied to plicamycin means
the plicamycin activity (potency) contained in 1.000 microgram of the
plicamycin master standard when dried for 4 hours at 25 C. and a
pressure of 5 millimeters or less.
(42) Clindamycin. The term ''microgram'' applied to clindamycin
means the clindamycin activity (potency) contained in 1.139 micrograms
of the clindamycin master standard.
(43) Cephaloglycin. The term ''microgram'' applied to cephaloglycin
means the cephaloglycin activity (potency) contained in 1.02564
micrograms of the cephaloglycin master standard.
(44) Carbenicillin. The term ''microgram'' applied to carbenicillin
means the carbenicillin activity (potency) contained in 1.135 micrograms
of the carbenicillin master standard.
(45) Cephalexin. The term ''microgram'' applied to cephalexin means
the cephalexin activity (potency) contained in 1.0707 micrograms of the
cephalexin master standard.
(46) (Reserved)
(47) Capreomycin. The term ''microgram'' applied to capreomycin
means the capreomycin activity (potency) contained in 1.0870 micrograms
of the capreomycin master standard when dried for 4 hours at 100 C.
and a pressure of 5 millimeters or less.
(48) Rifampin. The term ''microgram'' applied to rifampin means the
rifampin activity (potency) contained in 1.0101 micrograms of the
rifampin master standard.
(49) Minocycline. The term ''microgram'' applied to minocycline
means the minocycline activity (potency) contained in 1.1588 micrograms
of the minocycline master standard.
(50) Spectinomycin. The term ''microgram'' applied to spectinomycin
means the spectinomycin activity (potency) contained in 1.490 micrograms
of the spectinomycin master standard.
(51) Clindamycin palmitate hydrochloride. The term ''microgram''
applied to clindamycin palmitate hydrochloride means the clindamycin
activity (potency) contained in 1.661 micrograms of the clindamycin
palmitate hydrochloride master standard.
(52) Carbenicillin indanyl. The term ''microgram'' applied to
carbenicillin indanyl means the carbenicillin activity (potency)
contained in 1.4514 micrograms of the carbenicillin indanyl master
standard.
(53) Cephapirin. The term ''microgram'' applied to cephapirin means
the cephapirin activity (potency) contained in 1.0616 micrograms of the
cephapirin master standard.
(54) Cefazolin. The term ''microgram'' applied to cefazolin means
the cefazolin activity (potency) contained in 1.005 micrograms of the
cefazolin master standard.
(55) Mitomycin. The term ''microgram'' applied to mitomycin means
the mitomycin activity (potency) contained in 1.0416 micrograms of the
mitomycin master standard.
(56) Amoxicillin. The term ''microgram'' applied to amoxicillin
means the amoxicillin activity (potency) contained in 1.17647 micrograms
of the amoxicillin master standard.
(57) (Reserved)
(58) Cephradine. The term ''microgram'' applied to cephradine means
the cephradine activity (potency) contained in 1.1111 micrograms of the
cephradine master standard.
(59) Doxorubicin. The term ''microgram'' applied to doxorubicin
means the activity (potency) calculated as doxorubicin hydrochloride
contained in 1.0204 micrograms of the doxorubicin master standard.
(60) Tobramycin. The term ''microgram'' applied to tobramycin means
the tobramycin activity (potency) contained in 1.126 micrograms of the
tobramycin master standard.
(61) Amikacin. The term ''microgram'' applied to amikacin means the
amikacin activity (potency) contained in 1.091 micrograms of the
amikacin master standard.
(62) Vidarabine. The term ''microgram'' applied to vidarabine means
the vidarabine activity (potency) contained in 1.0674 micrograms of the
vidarabine master standard.
(63) Ticarcillin. The term ''microgram'' applied to ticarcillin
means the ticarcillin activity (potency) contained in 1.136 micrograms
of the ticarcillin master standard.
(64) Cefadroxil. The term ''microgram'' applied to cefadroxil means
the cefadroxil activity (potency) contained in 1.0537 micrograms of the
cefadroxil master standard.
(65) Natamycin. The term ''microgram'' applied to natamycin means
the natamycin activity (potency) contained in 1.0846 micrograms of the
natamycin master standard.
(66) Cefoxitin. The term ''microgram'' applied to cefoxitin means
the cefoxitin activity (potency) contained in 1.072 micrograms of the
cefoxitin master standard.
(67) Cefamandole. The term ''microgram'' applied to cefamandole
means the cefamandole activity (potency) contained in 1.1364 micrograms
of cefamandole master standard.
(68) Cefaclor. The term ''microgram'' applied to cefaclor means the
cefaclor activity (potency) contained in 1.0493 micrograms of cefaclor
master standard.
(69) Cyclacillin. The term ''microgram'' applied to cyclacillin
means the cyclacillin activity (potency) contained in 1.01 micrograms of
the cyclacillin master standard.
(70) Daunorubicin. The term ''microgram'' applied to daunorubicin
means the daunorubicin activity (potency) contained in 1.0965 micrograms
of the daunorubicin master standard.
(71) Sisomicin. The term ''microgram'' applied to sisomicin means
the sisomicin activity (potency) contained in 1.00 microgram of the
sisomicin master standard expressed on an anhydrous basis.
(72) Meclocycline. The term ''microgram'' applied to meclocycline
means the meclocycline activity (potency) contained in 1.0493 micrograms
of the meclocycline master standard.
(73) Cefotaxime. The term ''microgram'' applied to cefotaxime means
the cefotaxime activity (potency) contained in 1.089 micrograms of
cefotaxime master standard.
(74) Mezlocillin. The term ''microgram'' applied to mezlocillin
means the mezlocillin activity (potency) contained in 1.1086 micrograms
of the mezlocillin master standard.
(75) Moxalactam. The term ''microgram'' applied to moxalactam means
the moxalactam activity (potency) contained in 1.1173 micrograms of the
moxalactam master standard.
(76) Piperacillin. The term ''microgram'' applied to piperacillin
means the piperacillin activity (potency) contained in 1.0460 micrograms
of the piperacillin master standard.
(77) Cefoperazone. The term ''microgram'' applied to cefoperazone
means the cefoperazone activity (potency) contained in 1.056 micrograms
of the cefoperazone master standard.
(78) Azlocillin. The term ''microgram'' applied to azlocillin means
the azlocillin activity (potency) contained in 1.128 micrograms of the
azlocillin master standard.
(79) Netilmicin. The term ''microgram'' applied to netilmicin means
the netilmicin activity (potency) contained in 1.000 microgram of the
netilmicin master standard expressed on an anhydrous basis.
(80) Cefuroxime. The term ''microgram'' applied to cefuroxime means
the cefuroxime activity (potency) contained in 1.0893 micrograms of the
cefuroxime master standard.
(81) Ceftizoxime. The term ''microgram'' applied to ceftizoxime
means the ceftizoxime activity (potency) contained in 1.011 micrograms
of the ceftizoxime master standard.
(82) Cyclosporine. The term ''microgram'' applied to cyclosporine
means the cyclosporine activity (potency) contained in 1.0173 micrograms
of cyclosporine master standard.
(83) Ceforanide. The term ''microgram'' applied to ceforanide means
the ceforanide activity (potency) contained in 1.005 micrograms of the
ceforanide master standard.
(84) Cefonicid. The term ''microgram'' applied to cefonicid means
the cefonicid activity (potency) contained in 1.150 micrograms of the
cefonicid master standard.
(85) Clavulanic acid. The term ''microgram'' applied to clavulanic
acid means the clavulanic acid activity (potency) contained in 1.053
micrograms of clavulanic acid master standard.
(86) Amdinocillin. The term ''microgram'' applied to amdinocillin
means the amdinocillin activity (potency) contained in 1.004 micrograms
of the amdinocillin master standard.
(87) Ceftriaxone. The term ''microgram'' applied to ceftriaxone
means the ceftriaxone activity (potency) contained in 1.19 micrograms of
the ceftriaxone master standard.
(88) Ceftazidime. The term ''microgram'' applied to ceftazidime
means the ceftazidime activity (potency) contained in 1.1834 micrograms
of the ceftazidime master standard.
(89) Imipenem. The term ''microgram'' applied to imipenem
monohydrate means the imipenem activity (potency) contained in 1.07
micrograms of the imipenem master standard.
(90) Cefotetan. The term ''microgram'' applied to cefotetan means
the cefotetan activity (potency) contained in 1.012 micrograms of the
cefotetan master standard.
(91) Aztreonam. The term ''microgram'' applied to aztreonam means
the aztreonam activity (potency) contained in 1.05 micrograms of the
aztreonam master standard.
(92) Sulbactam. The term ''microgram'' applied to sulbactam means
the sulbactam activity (potency) contained in 1.002 micrograms of the
sulbactam master standard.
(93) Cefuroxime axetil. The term ''microgram'' applied to cefuroxime
axetil means the cefuroxime activity (potency) contained in 1.246
micrograms of the cefuroxime axetil master standard.
(94) Cefmenoxime. The term ''microgram'' applied to cefmenoxime
means the cefmenoxime activity (potency) contained in 1.0482 micrograms
of the cefmenoxime master standard.
(95) Cefixime. The term ''microgram'' applied to cefixime means the
cefixime activity (potency) contained in 1.126 micrograms of the
cefixime master standard.
(96) Cefotiam. The term ''microgram'' applied to cefotiam means the
cefotiam (potency) contained in 1.144 micrograms of the cefotiam master
standard.
(97) Clindamycin phosphate. The term ''microgram'' applied to
clindamycin phosphate means the clindamycin phosphate (potency)
contained in 1.252 micrograms of the clindamycin phosphate master
standard.
(98) Mupirocin. The term ''microgram'' applied to mupirocin means
the activity (potency) calculated as mupirocin activity (potency)
contained in 1.075 micrograms of the mupirocin master standard.
(99) Cefmetazole. The term ''microgram'' applied to cefmetazole
means the cefmetazole (potency) contained in 1.002 micrograms of the
cefmetazole master standard.
(100) Cefpiramide. The term ''microgram'' applied to cefpiramide
means the cefpiramide (potency) contained in 0.994 microgram of the
cefpiramide master standard.
(39 FR 18925, May 30, 1974)
Editorial Note: For Federal Register citations affecting 430.6, see
the List of CFR Sections Affected appearing in the Finding Aids section
of this volume.
21 CFR 430.6 Subpart B -- Antibiotic Drugs Affected by the Drug Amendments of 1962
21 CFR 430.10 Certification or release of antibiotic drugs affected by
the drug amendments of 1962.
(a) Before the 1962 amendments to it, the Federal Food, Drug, and
Cosmetic Act only permitted the Food and Drug Administration to provide
for the certification of batches of antibiotic drugs containing
penicillin, streptomycin, chlortetracycline, chloramphenicol, or
bacitracin, or any derivative of them. FDA certified those drugs under
regulations promulgated on the basis of scientific proof of the drugs'
safety and effectiveness. Most drugs containing an antibiotic other
than one of those listed were subject to the new drug provisions of the
act, which required that an applicant show that the drug was safe and
obtain FDA approval of a new drug application before marketing it. An
affirmative showing of effectiveness was not then required to obtain
approval. Some antibiotic drugs that were not subject to certification,
however, were also not subject to the new drug provisions of the act
under informal FDA opinions that the drug was ''not a new drug'' or ''no
longer a new drug.'' FDA revoked those opinions under 310.100 of this
chapter.
(b) The 1962 amendments amended section 507 of the act to require the
certification, release without certification, or exemption from
certification, of all antibiotic drugs on the basis of scientific proof
of safety and effectiveness. The amendments provided that FDA implement
them for antibiotic drugs that were marketed on April 30, 1963 and were
not subject to the certification provisions on that date. FDA is
implementing the amendments with respect to antibiotic drugs formerly
subject to the new drug provisions of the act through its Drug Efficacy
Study Implementation (DESI) program under which the agency is evaluating
those antibiotic drugs for efficacy. Until FDA completes that
evaluation it will permit continued marketing of those antibiotic drugs
under paragraph (c) of this section. The agency is also implementing
the 1962 amendments with respect to antibiotic drugs formerly not
subject to either the certification or new drug provisions of the act
and the agency is evaluating those antibiotic drugs for both safety and
efficacy. Until FDA completes that evaluation, it will permit continued
marketing of those antibiotic drugs under paragraph (d) of this section.
(c) Unless exempted from certification, FDA will certify or release
antibiotic drugs which on April 30, 1963 were the subject of an approved
new drug application under section 505 of the act, under regulations
providing for certification of the drugs. Although the initial
regulation for each of these drugs established under section 507(h) of
the act was not conditioned upon an affirmative finding of the
effectiveness of the drug, FDA is proceeding under its DESI program to
amend or repeal those regulations to provide for certification of those
drugs only if they had been shown to be both safe and effective.
(d) Unless exempted from certification, FDA will release without
certification an antibiotic drug that was marketed on April 30, 1963,
but not subject to certification, and not subject to an approved new
drug application on that date, unless FDA has made a determination that
the drug has not been shown to be safe or lacks substantial evidence of
effectiveness under the DESI program. FDA is proceeding under its DESI
program to establish regulations under section 507 to provide for
certification of those drugs only if they have been shown to be safe and
effective.
(50 FR 7516, Feb. 22, 1985)
21 CFR 430.10 PART 431 -- CERTIFICATION OF ANTIBIOTIC DRUGS
21 CFR 430.10 Subpart A -- General Provisions
Sec.
431.1 Requests for certification, check tests and assays, and working
standards; information and samples required.
431.5 Samples for sterility testing.
431.10 Certification.
431.11 Conditions on the effectiveness of certificates.
431.12 Certification of antibiotic drugs after shipment in bulk
containers.
431.17 Request to provide for certification of an antibiotic drug.
431.20 Disposition of outdated drugs.
21 CFR 430.10 Subpart B -- Administrative Procedures
431.50 Forms for certification or exemption of antibiotic drugs.
431.51 Suspension of certification service.
431.52 Hearings.
431.53 Fees.
21 CFR 430.10 Subpart C -- Records and Reports
431.61 Records of distribution.
431.62 Records retention.
21 CFR 430.10 Subpart D -- Confidentiality of Information
431.70 Confidentiality of data and information in an investigational
new drug notice for an antibiotic drug.
Authority: Secs. 501, 502, 503, 505, 507, 706 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 351, 352, 353, 355, 357, 376); secs.
215, 301, 351 of the Public Health Service Act (42 U.S.C. 216, 241,
262); 5 U.S.C. 552.
Source: 39 FR 18934, May 30, 1974, unless otherwise noted.
21 CFR 430.10 Subpart A -- General Provisions
21 CFR 431.1 Requests for certification, check tests and assays, and
working standards; information and samples required.
(a) A request for certification of a batch (antibiotic Form 7/Form
FDA-1677) is to be addressed to the Food and Drug Administration,
Division of Research and Testing (HFD-470), 200 C St. SW., Washington,
DC 20204.
(b) (Reserved)
(c) A person who requests certification or check tests and assays of
a batch shall submit with his request the following information and
samples:
(1) The batch mark of the drug.
(2) The quantity of each ingredient used in making the batch and a
statement that each such ingredient conforms to the requirements or
standards prescribed therefor, if any, by specific regulations or
official compendium or otherwise approved by the Commissioner.
(3) The size of the batch, including the number of containers of each
size in the batch.
(4) The date of the latest assay of the batch.
(5) The results of the latest tests and assays made by or for him on
the batch as required for the drug by specific regulations.
(6) The batch mark(s) of the antibiotic(s) used in making the batch.
(7) Unless previously submitted, the results and dates of the latest
tests and assays made by or for him on the antibiotic(s) used in making
the batch as required by specific regulations.
(8) The number of accurately representative samples that are required
for the batch by specific regulations:
(i) In the case of drugs such as dry powders, solutions, ointments,
and suspensions, the sample shall be collected by taking single
immediate containers, before or after labeling, at such intervals
throughout the entire time of packaging the batch that the quantities
packaged during the intervals are approximately equal. In no case,
however, shall more than 5,000 immediate containers have been packaged
during each such interval of sampling, except for a sample collected for
sterility testing.
(ii) In the case of drugs in unit dosage forms, such as tablets,
capsules, or suppositories, samples shall be collected as follows:
(a) From batches exceeding 500,000 units, a representative sample
consisting of 100 units shall be collected by taking single units at
approximately equal intervals throughout the final production of the
batch. If the person packaging the units into dispensing-size
containers is not the manufacturer, the representative sample consisting
of 100 units shall be collected by taking single units at approximately
equal intervals during packaging.
(b) From batches of 500,000 units or less, a representative sample
consisting of not more than 100 units shall be collected by taking
single units at approximately equal intervals throughout the final
production of the batch. If the person packaging the units into
dispensing-size containers is not the manufacturer, the samples shall be
collected by taking single units at approximately equal intervals during
packaging. In no case shall more than 5,000 units be produced or
packaged during a sampling interval. The minimum acceptable sample size
shall be as specified in the appropriate monograph.
(c) When the manufacturing process is such that it is not feasible to
collect the samples throughout the final production of the batch (e.g.,
if tablets undergo further processing, such as polishing or coating,
after being compressed), the samples may be collected from bulk
containers of the finished product, according to the following
requirements:
(1) For batches exceeding 500,000 units: If the batch is in more
than 100 containers, the sample is 1 unit from each container. If the
batch is in 100 containers or less, the sample is 100 units, taken in
approximately equal amounts from each container.
(2) For batches of 500,000 units or less: If the batch is in more
than 100 containers, the sample is 1 unit from each container. If the
batch is in 100 containers or less, the sample is at least 1 unit for
every 5,000 units in the batch taken in approximately equal amounts from
each container. The sample shall not be less than the minimum number of
units specified in the appropriate monograph.
(iii) In the case of drugs packaged for repacking or for use in the
manufacture of another drug, the sample must be representative of the
batch. Such samples may be taken from a composite composed of portions
taken from a representative number of bulk containers, the composite
consisting of no more than 10 times the amount required for conducting
the required tests and assays. Such samples are not required if they
have been previously submitted.
(iv) In the case of a sterile drug packaged in combination with
containers of a sterile diluent, the sample shall be collected by taking
20 immediate containers of the diluent collected at regular intervals
throughout each filling operation, except that if the diluent is
sterilized after filling into containers, the representative sample
shall consist of 20 immediate containers collected from each sterilizer
load and each container shall be taken from a different part of each
such sterilizer load. In the case of sterile drugs packaged in
combination with sterile dispensers, the sample shall be collected by
taking 20 dispensers from each sterilizer load, and each dispenser shall
be taken from a different part of such sterilizer load.
(9) In the case of an initial request for certification, each
ingredient used in making the batch other than ingredients required by
specific regulations: 1 package of each containing approximately 5
grams. Results and dates of the latest tests and assays made by or for
him on such ingredients shall precede or accompany the submission.
(10) The results and dates of tests and assays made by or for him on
the nonantibiotic active ingredients in the batch.
(11) If such batch or any part thereof is to be packaged with a
sterile diluent or sterile dispenser, such request shall also be
accompanied by a statement that such diluent or dispenser is sterile and
conforms to the requirements prescribed therefor by specific
regulations.
(d) Each sample submitted pursuant to the regulations in this chapter
shall be addressed to the Commissioner. Its package shall be clearly
identified as to its contents and shall bear the name and post-office
address of the person submitting it.
(e) In addition to the information and samples specifically required
to be submitted to the Commissioner by the regulations in this chapter,
the person who requests certification of a batch shall submit such
further information and samples as the Commissioner may require for the
purpose of investigations to determine whether or not such batch
complies with the requirements of 431.10 for the issuance of a
certificate.
(f) Reference standards identical to working standards are available
from: U.S.P. Reference Standards, 12601 Twinbrook Parkway, Rockville,
Md. 20857, 301-881-0666.
(39 FR 18934, May 30, 1974, as amended at 41 FR 46852, Oct. 26, 1976;
43 FR 41195, 41197, Sept. 15, 1978; 45 FR 40111, June 30, 1980; 50 FR
7516, Feb. 22, 1985; 50 FR 8997, Mar. 6, 1985; 55 FR 11582, Mar. 29,
1990)
21 CFR 431.5 Samples for sterility testing.
(a) ''Filling operation'' and ''sample'' defined. (1) The term
''filling operation'' when used in connection with samples of a batch
required for sterility testing refers to that period of time not longer
than 24 consecutive hours during which a homogeneous quantity of drug is
being filled continuously into market-size containers and during which
no changes are made in the equipment used for filling. (Short rest
periods for operators of the filling equipment and the time required to
change operators between consecutive shifts are not considered as a
break in continuity of the filling operation.) If more than one filling
device is used during the filling operation, the samples shall include
immediate containers filled by each device, and each such container
shall be identified with a mark corresponding to that assigned to the
filling device. If more than one filling operation is required to fill
a batch, each container in the sample shall be identified with the
number of the operation.
(2) For the purpose of sterility testing, the term ''sample'' means
the total number of containers taken from each filling operation.
(b) Packaging requirements for samples. If a batch of a sterile
antibiotic is packaged for repacking or for use as an ingredient in the
manufacture of another drug, the sample required for sterility testing
may be packaged in one container, in lieu of 20 containers, or in two
containers in lieu of 40 containers, under the following conditions:
(1) The weight or volume of the sample is equivalent to the composite
weight or volume required for a multiple container sample;
(2) The sample is a composite of samples taken from all parts of the
batch; and
(3) The sterility test method prescribed for the drug by the
regulations in this chapter is ''Bacterial membrane filter method''
described in 436.20(e)(1) of this chapter.
21 CFR 431.10 Certification.
(a) If it appears to the Commissioner, after such investigation as he
considers necessary, that:
(1) The information (including results of tests and assays) and
samples required by or pursuant to the regulations in this chapter have
been submitted, and the request for certification contains no untrue
statement of a material fact; and
(2) The batch complies with the regulations in this chapter and
conforms to the applicable standards of identity, strength, quality, and
purity prescribed by the regulations in this chapter;
the Commissioner shall certify that such batch is safe and
efficacious for use, subject to such conditions on the effectiveness of
certificates as are prescribed by 431.11 and shall issue to the person
who requested it a certificate to that effect.
(b) If the Commissioner determines, after such investigation as he
considers to be necessary, that the information submitted pursuant to
the regulations in this chapter, or the batch covered by such request,
does not comply with the requirements set forth in paragraph (a) of this
section for the issuance of a certificate, the Commissioner shall refuse
to certify such batch and shall give notice thereof to the person who
requested certification, stating his reasons for refusal.
(c) All statements, samples, and other information and materials
submitted in connection with a request for certification shall be
considered to be part of such request.
(d) Compliance of a drug with the standards of identity, strength,
quality, and purity prescribed by regulations in this chapter shall be
determined by the tests and methods of assay prescribed for such drug by
regulations issued under this chapter.
(e) The regulations in this chapter, prescribing tests and methods of
assay for antibiotic and antibiotic-containing drugs, shall not be
construed as preventing the Commissioner from using any other test or
method of assay in his investigations to determine whether or not:
(1) A request for certification contains any untrue statement of a
material fact; or
(2) A certification has been obtained through fraud, or through
misrepresentation or concealment of a material fact.
(f) Except as specifically provided by the regulations in this
chapter, no provision of any regulation shall be construed as exempting
any certifiable antibiotic drug from any applicable provision of the act
or any regulation thereunder.
21 CFR 431.11 Conditions on the effectiveness of certificates.
(a) A certificate shall not become effective:
(1) If it is obtained through fraud or through misrepresentation or
concealment of a material fact;
(2) With respect to any package unless it complies with the packaging
requirements, if any, prescribed by the regulations in this chapter
which were in effect on the date of the certificate;
(3) With respect to any package unless its label and labeling bear
all words, statements, and other information required by the regulations
in this chapter; or
(4) With respect to any package of a certifiable antibiotic drug
subject to the regulations in this chapter, when it is included in a
packaged combination with another drug, unless such other drug complies
with the requirements of the regulations in this chapter.
(b) A certificate shall cease to be effective:
(1) With respect to any immediate container after the expiration
date, if any, prescribed by the regulations in this chapter;
(2) With respect to any immediate container when it or its seal (if
the regulations in this chapter require it to be sealed) is broken, or
when its label or labeling is altered, multilated, destroyed,
obliterated, or removed in whole or in part, or ceases to conform to any
labeling requirement prescribed by the regulations in this chapter,
except that:
(i) If the drug in such container is repacked or used as an
ingredient in the manufacture of another drug, and certification of the
batch thus made is requested, such certificate shall continue to be
effective for a reasonable time to permit certification or destruction
of such batch;
(ii) If the drug is in a container packaged for dispensing and is
used in compounding a prescription issued by a practitioner licensed by
law to administer such drug, such certificate shall continue to be
effective for a reasonable time to permit the delivery of the drug
compounded on such prescription; or
(iii) If its label or labeling is removed in whole or in part for the
purpose of relabeling and supplemental certification of the relabeled
drug is requested, as provided by 433.12 of this chapter.
(3) With respect to any immediate container of penicillin when it is
included in the packaged combination penicillin with aluminum hydroxide
gel or penicillin with a vasoconstrictor, or to any immediate container
of bacitracin when it is included in the packaged combination bacitracin
with a vasoconstrictor, except that when certification of the batch so
included is requested, such certificate shall continue to be effective
for a reasonable time to permit certification of such batch which is
part of such combination;
(4) With respect to any package when the drug therein fails to meet
the standards of identity, strength, quality, and purity which were in
effect on the date of the certificate; except that those minor changes
which occur before the expiration date and which are normal and
unavoidable in good storage and distribution practice shall be
disregarded.
(5) With respect to any package of a certifiable antibiotic drug
subject to the regulations in this chapter, included in a packaged
combination with another drug, when such other drug fails to meet the
requirements of the regulations in this chapter; or
(6) With respect to any immediate container, if such regulations
require its labeling to bear a caution against dispensing otherwise than
on prescription, at the beginning of the act of dispensing or offering
to dispense it otherwise than:
(i) By a practitioner licensed by law to administer such drug; or
(ii) On his prescription issued in his professional practice.
21 CFR 431.12 Certification of antibiotic drugs after shipment in bulk
containers.
(a) The Food and Drug Administration has received inquiries from
certain interested manufacturers concerning their shipment of certified
antibiotics, packaged in bulk containers, to hospitals and pharmacies
for repacking or for use in the manufacture of another drug on the order
or prescription of a physician. The regulations promulgated under
section 507 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 357)
do not prohibit the shipment of certified bulk containers of antibiotics
to such persons. However, under the provisions of 431.11(b)(2)(i),
certification should be requested of each repacked batch and of each
batch of another drug manufactured from such bulk drug, unless the
repackaged drug or other drug has been made exempt from the
certification requirements by regulation. The fact that the drug is to
be repacked or manufactured on the order or prescription of a physician
does not exempt it from the certification requirements of the act.
Under the provisions of 431.11(b)(2)(ii), it is only when the drug used
to compound a prescription is in a container packaged for dispensing
that certification of the drug so compounded is not required.
(b) In the light of these provisions, unless the manufacturer and
shipper of bulk containers of antibiotics has, with the consignee, an
effective permit issued under 433.16 of this chapter, if the drug is to
be repacked, or under 433.13 of this chapter if it is to be used in the
manufacture of another drug, the shipper has the responsibility of
seeing that certification is requested of each repacked batch and of
each batch of another drug manufactured from such drug.
21 CFR 431.17 Request to provide for certification of an antibiotic
drug.
A request under section 507 of the Federal Food, Drug, and Cosmetic
Act to provide for certification of an antibiotic drug is required to
comply with the procedures and meet the requirements applicable to the
submission to the Food and Drug Administration and review by the agency
of applications and abbreviated applications, and amendments and
supplements to them, under part 314 of this chapter.
(50 FR 7516, Feb. 22, 1985)
21 CFR 431.20 Disposition of outdated drugs.
When certification becomes invalid because the expiration date is
passed, such articles should not be disposed of for drug use either
through commercial or charitable channels unless the articles have been
assayed to establish potency and recertified.
21 CFR 431.20 Subpart B -- Administrative Procedures
21 CFR 431.50 Forms for certification or exemption of antibiotic drugs.
The following forms which must be supplied in connection with certain
certification or exemption procedures for antibiotic drugs may be
obtained from the Product Surveillance Branch (HFD-333), Food and Drug
Administration, Department of Health and Human Services, 5600 Fishers
Lane, Rockville, MD 20857.
Form
1 Application for exemption for storage.
2 Application for exemption for processing.
3 Application for exemption for labeling.
4 Application for exemption for manufacturing use.
7 Request for check tests and assays or certification of a batch of
---------------- (the blank to be filled in with the name of the
antibiotic drug).
8 Application for exemption for repacking.
9 Request for supplemental certification of a batch of an antibiotic
drug.
(39 FR 18934, May 30, 1974, as amended at 40 FR 28052, July 3, 1975;
41 FR 10886, Mar. 15, 1976; 50 FR 7516, Feb. 22, 1985; 50 FR 8997,
Mar. 6, 1985; 55 FR 11582, Mar. 29, 1990)
21 CFR 431.51 Suspension of certification service.
When the Commissioner finds that a person has:
(a) Obtained or attempted to obtain a certificate through fraud or
through misrepresentation or concealment of a material fact; or
(b) Falsified the records required to be kept by 431.61; or
(c) Failed to keep such records or to make them available, or to
accord full opportunity to take an inventory of stocks on hand, or
otherwise to check the correctness of such records as required by
431.61; or
(d) Failed to establish a system for maintaining the records required
by 314.81 of this chapter or has repeatedly or deliberately failed to
maintain such records or to make required reports in accordance with the
provisions of that section, or has refused to permit access to, or
copying, or verification of such records or reports; or
(e) Failed to conform to the requirements of good manufacturing
practice prescribed by parts 210, 211, 225, 226 and 229 of this chapter;
the Commissioner will immediately suspend service to such person
under the regulations in this chapter. Upon request a hearing will be
granted to such person to show cause why such service should be resumed.
(39 FR 18934, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975;
55 FR 11582, Mar. 29, 1990)
21 CFR 431.52 Hearings.
Any person who contests the suspension of certification service under
431.51 shall have an opportunity for a regulatory hearing before the
Food and Drug Administration pursuant to part 16 of this chapter.
(41 FR 48267, Nov. 2, 1976, as amended at 42 FR 15675, Mar. 22, 1977)
21 CFR 431.53 Fees.
(a) Fees for the services rendered under the regulations in this
chapter shall be such as are necessary to provide, equip, and maintain
an adequate certification service.
(b) The fee for such services with respect to each batch of a drug,
certification of which is provided by the regulations in this chapter,
shall be $114 for each batch submitted, plus the sum of the fees for all
individual tests required for certification of each batch. The minimum
tests for each batch shall be those prescribed in the section relating
specifically to such drug.
(1) The fee schedule for specific tests required for antibiotic drug
certification is as follows:
(2) The fee for a supplemental request submitted pursuant to the
provisions of 433.12 of this chapter shall be $50.
(3) (Reserved)
(4) In the case of persons using the certification services and whose
manufacturing facilities are not located in the United States or the
Commonwealth of Puerto Rico, such persons shall be required to deposit
each year sufficient funds to cover costs encountered when their
facilities are inspected pursuant to the provisions of section 704 of
the act.
(c) When the Commissioner considers it necessary to make
investigations of a new product containing a certifiable antibiotic drug
on which a request has been submitted in accordance with 431.17, the
fee for such service shall be the cost thereof. In such case the
request shall be followed by an advance deposit in such amount as the
Commissioner specifies, and thereafter such additional advance deposits
shall be made as the Commissioner estimates may be necessary to prevent
arrears in the payment of such fee.
(d) A person requiring continuing certification services may maintain
an advance deposit of the estimated cost of such services for a
two-month period. Such deposit shall be debited with fees for services
rendered, but shall not be debited for any fee the amount of which is
not definitely specified in the regulations in this chapter unless the
depositor has previously requested the performance of the services to be
covered by such fee. A monthly statement for each such advance deposit
shall be rendered.
(e) The fees for the services rendered with respect to each batch
certified under the regulations in this chapter shall accompany the
request for certification, or the request for check tests and assays,
unless such fee is covered by an advance deposit maintained in
accordance with paragraph (d) of this section. Also, if the
Commissioner considers that investigations other than examination of
such samples are necessary to determine whether or not such batch
complies with the requirements of 431.10 for the issuance of a
certificate, the fee shall include the cost of such investigations.
(f) The unearned portion of any advance deposit shall be refunded to
the depositor upon his application.
(g) Whenever in the judgment of the Commissioner the ratio between
fees collected (which are based upon experience and the best estimate of
costs and the best estimate of earnings) and the costs of providing the
service during an elapsed period of time, in the light of all
circumstances and contingencies, warrants a refund from the fund
collected during such period, he shall make ratable refunds to those
persons to whom the services were rendered and charged, except for those
services described under 433.12 of this chapter.
(h) All deposits and fees required by the regulations in this
chapter, shall be paid by money order, bank draft, or certified check
drawn to the order of the Food and Drug Administration, collectible at
par at Washington, D.C. All such deposits and fees shall be forwarded to
the Food and Drug Administration, Department of Health and Human
Services, Accounting Branch (HFA-120), 5600 Fishers Lane, Rockville, MD
20857, whereupon after making appropriate records thereof they will be
transmitted to the Chief Disbursing Officer, Division of Disbursement,
Treasurer of the United States, for deposit to the special account
''Salaries and Expenses, Certification, Inspection, and Other Services,
Food and Drug Administration.''
(39 FR 18934, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975;
40 FR 28052, July 3, 1975; 41 FR 2384, Jan. 16, 1976; 41 FR 18291,
May 3, 1976; 44 FR 67113, Nov. 23, 1979; 45 FR 16471, Mar. 14, 1980;
46 FR 16677, Mar. 13, 1981; 46 FR 60578, Dec. 11, 1981; 46 FR 61071,
Dec. 15, 1981; 50 FR 19918, May 13, 1985; 55 FR 11582, Mar. 29, 1990)
21 CFR 431.53 Subpart C -- Records and Reports
21 CFR 431.61 Records of distribution.
(a) The person who requested certification shall keep complete
records showing each shipment and other delivery (including exports) of
each certified batch or part thereof by such person or by any person
subject to his control. Such records shall show the date and quantity
of each such shipment or delivery and the name and post-office address
of the person to whom such shipment or delivery was made, and shall be
kept for not less than 3 years after such date.
(b) Upon the request of any officer or employee of the Food and Drug
Administration, or of any other officer or employee of the United States
acting on behalf of the Secretary, the person to whom a certificate is
issued shall at all reasonable hours make such records available to any
such officer or employee and shall accord to him full opportunity to
make inventory of stocks of such batch on hand and otherwise to check
the correctness of such records.
21 CFR 431.62 Records retention.
At the option of the person having control of records required to be
kept by any regulation in this part 431, photostatic or other permanent
reproductions may be substituted for such records after the first 2
years of the holding period.
21 CFR 431.62 Subpart D -- Confidentiality of Information
21 CFR 431.70 Confidentiality of data and information in an
investigational new drug notice for an antibiotic drug.
(a) The existence of an IND notice for an antibiotic drug will not be
disclosed by the Food and Drug Administration unless it has previously
been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and
information in an IND file for an antibiotic drug shall be handled in
accordance with the provisions established in 314.430 of this chapter.
(c) Notwithstanding the provisions of 314.430 of this chapter, the
Food and Drug Administration shall disclose upon request to an
individual on whom an investigational antibiotic has been used a copy of
any adverse reaction report relating to such use.
(39 FR 44655, Dec. 24, 1974, as amended at 50 FR 7517, Feb. 22, 1985)
21 CFR 431.70 PART 432 -- PACKAGING AND LABELING OF ANTIBIOTIC DRUGS
Sec.
432.1 Packaging requirements.
432.5 Labeling requirements.
432.9 Labeling of antibiotic drugs intended for export.
432.20 Declaration of potency.
Authority: Secs. 201, 301, 502, 503, 507, 701, 801 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 352, 353, 357, 371,
381).
Cross Reference: For other regulations in this chapter concerning
antibiotic drugs exempted from certain labeling requirements, see also
201.150 of this chapter.
21 CFR 432.1 Packaging requirements.
Each antibiotic drug subject to certification under section 507 or
512(n) of the act shall be packaged in immediate containers which shall
be of such composition as not to cause any change in the strength,
quality, or purity of the contents beyond any limits therefor in
applicable standards, except that minor changes so caused that are
normal and unavoidable in good packaging, storage, and distribution
practice shall be disregarded. The immediate containers shall be tight
containers as defined by the U.S.P., except that if the antibiotic drug
is dispensed as an ointment or cream, the immediate containers shall be
well-closed containers as defined by the U.S.P. If the antibiotic drug
is packaged for dispensing, it may be packaged in combination with a
container of a suitable and harmless diluent approved by the
Commissioner.
(a) If it is a sterile preparation, the containers shall be sterile
at the time of filling and closing and shall be so sealed that the
contents cannot be used without destroying the seal.
(b) If it is intended for parenteral use and the container is glass,
it shall be transparent and colorless or light-resistant as defined by
the U.S.P. The containers are closed either by fusion or by application
of suitable closures, in such manner as to prevent contamination or loss
of content. Multiple-dose containers are closed by a substance through
which a hypodermic needle may be introduced and withdrawn without
removing the closure or destroying its effectiveness. Each container
shall be filled with a quantity of a volume in excess of that
designated, which excess shall be sufficient to permit the withdrawal
and administration of the labeled quantity or volume, whether
administered in single or multiple doses.
(c) If it is dispensed as a tablet, capsule, troche, pellet, or
suppository, it may be enclosed in a foil or plastic film and such
enclosure is a tight container as defined by the U.S.P., except for the
provision that it shall be capable of tight reclosure. The immediate
container may contain a dessicant separated from the drug by a plug of
cotton or other like material.
(d) If it is dispensed as an ointment or cream, it shall be in
collapsible tubes that shall in no case be larger than the 2-ounce size,
except:
(1) If it is labeled for institutional use, it may be packaged in
immediate containers larger than the 2-ounce size and it may be packaged
in immediate containers of glass or plastic; or
(2) If it is an ointment represented for ophthalmic use, it shall be
in collapsible tubes which shall not be larger than the 1/8-ounce size.
(e) If it is intended for ophthalmic use, the closure shall be one
through which a hypodermic needle cannot be introduced.
(39 FR 18938, May 30, 1974, as amended at 42 FR 44225, Sept. 2, 1977;
44 FR 10377, Feb. 20, 1979)
21 CFR 432.5 Labeling requirements.
(a) If an antibiotic drug is packaged for dispensing:
(1) It shall be labeled in accordance with the requirements
prescribed by 201.100 of this chapter, issued under section 502(f) of
the act, unless the regulations pertaining to such drug specifically
exempt it from such requirements.
(2) Its labeling shall bear any additional information required for
the drug by specific regulations.
(3) Each package shall bear on its outside wrapper or container and
the immediate container an expiration date prescribed for the drug by
specific regulations; except that in lieu of the expiration date
prescribed by specific regulations, a date may be used that is 12, 18,
24, 30, 36, 42, 48, 54, or 60 months after the month during which the
batch was certified if the person who requests certification has
submitted to the Commissioner results of tests and assays showing that
such drug as prepared by him is stable for such period of time. If the
specific regulation does not stipulate an expiration period, it shall be
as prescribed by this section. If the manufacturer or repacker of the
drug has been exempted from the certification requirements, such date
shall be the number of months after the month during which the batch was
last assayed and released by the manufacturer or repacker. If an
expiration date is used that is longer than the minimum date provided
for the drug by specific regulations, it may be used only if the
manufacturer has submitted information to the Commissioner adequate to
prove that the drug is stable for such time.
(b) If it is packaged solely for manufacturing use or for repacking,
each package shall bear on its outside wrapper or container and the
immediate container, the following:
(1) The number of units or micrograms of activity per milligram or
per gram, and the number of grams or kilograms in the immediate
container.
(2) The batch mark.
(3) The statement ''Caution: Federal law prohibits dispensing
without prescription.''
(4) The statement ''For manufacturing use,'' ''For repacking,'' or
''For manufacturing use or repacking,'' and, if it is not sterile, the
statement ''nonsterile.''
(5) The required expiration date.
(c) The expiration date prescribed for a drug by the regulations in
this chapter may be omitted from the label of the immediate container if
such container contains a single dose and it is packaged in an
individual wrapper or container that bears the date prescribed.
(39 FR 18938, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 432.9 Labeling of antibiotic drugs intended for export.
(a) Antibiotic drugs subject to certification under section 507 of
the act and intended for export will be certified notwithstanding
failure to meet the labeling requirements of the applicable sections if
the labeling used for such drugs meets the following conditions:
(1) It has been approved before use by the Government authorities of
the country to which the drugs are intended for export; and
(2) Such labeling represents that such drugs are for use only in
those conditions for which they are certified for domestic distribution.
(b) The legend ''Caution: Federal law prohibits dispensing without
prescription'' might be inappropriate on antibiotic drugs exported from
the United States, since their sale may or may not be so restricted
under the laws of the country of destination. The Food and Drug
Administration would not object to a slight modification of the wording
to read, ''Caution: Federal (U.S.A.) law prohibits dispensing without
prescription,'' by a manufacturer who wishes to market a drug under the
same label both in domestic and foreign commerce.
(39 FR 18938, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 432.20 Declaration of potency.
Wherever the potency of an antibiotic drug included in the
regulations in this chapter is expressed in terms of weight, such
potency shall be equivalent to that contained in the same weight of the
master standard of the drug.
(39 FR 18938, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 432.20 PART 433 -- EXEMPTIONS FROM ANTIBIOTIC CERTIFICATION AND LABELING REQUIREMENTS
21 CFR 432.20 Subpart A -- General Provisions
Sec.
433.1 Exemption of antibiotic drugs for human use from batch
certification requirements.
433.2 Conditions on the effectiveness of exemptions of antibiotic
drugs for human use from batch certification requirements.
433.3 Assay requirements for antibiotic drugs exempted from
certification.
21 CFR 432.20 Subpart B -- Exemptions for Which an Application or
Notice Is Required
433.12 Exemption for labeling.
433.13 Exemption for manufacturing use.
433.14 Exemption for storage.
433.15 Exemption for processing.
433.16 Exemption for repacking.
433.17 Exemption for investigational use.
21 CFR 432.20 Subpart C -- Specific Use Exemptions
433.20 Antibiotic drugs for isolation and differentiation of
microorganisms in clinical use.
433.21 Antibiotics for diagnostic use.
433.22 Biologic drugs that contain antibiotics as a preservative.
433.23 Microbiological culture media containing antibiotics.
433.24 Exemption of antibiotic drugs for use in teaching, law
enforcement, research and analysis.
433.25 (Reserved)
433.26 Neomycin sulfate ointment intended for hypersensitivity
testing.
21 CFR 432.20 Subpart D -- Records and Reports
433.30 Records retention.
Authority: Secs. 502, 505, 507 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 352, 355, 357).
Source: 39 FR 18939, May 30, 1974, unless otherwise noted.
21 CFR 432.20 Subpart A -- General Provisions
21 CFR 433.1 Exemption of antibiotic drugs for human use from batch
certification requirements.
(a) Antibiotic drugs for human use are exempt from the batch
certification requirements of part 431 of this chapter if the conditions
of paragraph (b) of this section are met; or, in the case of
over-the-counter antibiotic drugs subject to an over-the-counter drug
monograph in this chapter, if the conditions of paragraph (c) of this
section are met.
(b) The conditions are as follows:
(1) The antibiotic drug is approved for marketing under an
appropriate antibiotic application or abbreviated antibiotic application
or is the subject of review under the Drug Efficacy Study Implementation
Program.
(2) The antibiotic drug is packaged and labeled for dispensing in
accordance with the applicable regulation (monograph) in this chapter
except where other labeling has been approved in an applicable
antibiotic application or abbreviated antibiotic application.
(3) The bulk antibiotic drug used in preparing the antibiotic drug
product meets the standards of identity, strength, quality, and purity
specified in the applicable regulation (monograph) in this chapter
except where other standards have been approved in an applicable
antibiotic application or abbreviated antibiotic application.
(4) The antibiotic drug product meets the standards of identity,
strength, quality, and purity specified in the applicable regulation
(monograph) in this chapter except where other standards have been
approved in an applicable antibiotic application or abbreviated
antibiotic application.
(c) The over-the-counter antibiotic drug product for human use is
required to meet the general conditions established in 330.1 of this
chapter, and the conditions specified in an applicable over-the-counter
drug monograph in this chapter.
(d) In accordance with the provisions of section 507(e) of the act,
an antibiotic-containing drug for human use exempt from the requirements
for batch certification under paragraph (b) of this section is subject
following its approval to section 505 of the act and applicable
regulations for new drugs, generally parts 310 through 314 of this
chapter. For each antibiotic drug subject to an exemption under
paragraph (b) of this section:
(1) An approved antibiotic application is regarded to be an approved
application under 314.50 of this chapter.
(2) An approved abbreviated antibiotic application is regarded to be
an approved abbreviated application under 314.55 of this chapter.
(e) Nothing in this section prevents a manufacturer from applying for
batch certification of an antibiotic drug for human use subject to an
exemption under this section as provided in section 507(c) of this act.
(f) All exemptions from batch certification requirements for
antibiotic drugs for human use under this section are subject to the
conditions of effectiveness under 433.2.
(Approved by the Office of Management and Budget under control number
0910-0001)
(51 FR 25524, July 15, 1986; 51 FR 30478, Aug. 27, 1986)
21 CFR 433.2 Conditions on the effectiveness of exemptions of
antibiotic drugs for human use from batch certification requirements.
(a) If at any time an exemption from batch certification requirements
for an antibiotic drug for human use has been granted, the Commissioner
finds on the basis of new information before the agency with respect to
such exempted drug, evaluated together with the evidence available to
the agency when such exemption was granted, that certification of each
batch is necessary to ensure its safety and efficacy of use, the
Commissioner shall act immediately to revoke all exemptions from batch
certification requirements granted for such drug.
(b) If the Commissioner finds that the person granted an exemption
from batch certification requirements for an antibiotic drug for human
use has failed either to comply with the requirements of section 505 of
the act and the regulations promulgated thereunder or to meet the
general conditions established in 330.1 of this chapter and the
conditions specified in an applicable over-the-counter drug monograph in
this chapter; or if the Commissioner finds that the requirements of
433.1 have not been met; or if the Commissioner finds that the petition
for exemption from batch certification contains any false statements of
fact, the Commissioner may revoke the exemption from batch certification
requirements immediately and require batch certification of the drug
until such person shows adequate cause why the exemption from batch
certification requirements should be reinstated.
(c) If the Commissioner repeals or suspends an exemption from batch
certification requirements for an antibiotic drug for human use, a
notice to that effect and the reasons therefor will be published in the
Federal Register.
(d) Any person who contests the revocation or suspension or denial of
reinstatement of an exemption from batch certification requirements for
an antibiotic drug for human use shall have an opportunity for a
regulatory hearing before the Food and Drug Administration under part 16
of this chapter.
(47 FR 39159, Sept. 7, 1982, as amended at 51 FR 25524, July 15,
1986)
21 CFR 433.3 Assay requirements for antibiotic drugs exempted from
certification.
(a) Certain antibiotic drugs are exempted by regulations in this
chapter from the certification requirements of sections 507 and 512 of
the act if such drugs comply with standards prescribed by such
regulations and on condition that the label of each package bears an
expiration date which is determined from the date during which the batch
was last assayed and released by the manufacturer.
(b) It is the position of the Food and Drug Administration that if
each batch of such exempted drugs is not tested by the manufacturer or
his agent to determine whether it complies with the standards of
identity, strength, quality, and purity prescribed for it, the batch is
not exempt from certification and it may be deemed to be misbranded
under section 502(l) of the act or be adulterated under section
501(a)(5) of the act when in interstate commerce.
21 CFR 433.3 Subpart B -- Exemptions for Which an Application or Notice Is Required
21 CFR 433.12 Exemption for labeling.
(a) Except as provided by paragraphs (c) and (d) of this section, a
shipment or other delivery of a certifiable antibiotic drug which is to
be labeled at an establishment located elsewhere than at the place of
manufacture shall be exempt, during the time of introduction into and
movement in interstate commerce and the time of holding in such
establishment, from the requirement of section 502(l) of the act or the
certification requirements of section 512(n) of the act if the labeling
of each shipping container bears the batch mark of the drug, the number
of units per package and the expiration date, and if the person who
introduced such shipment or delivery into interstate commerce holds a
permit (Antibiotic Form 3) from the Commissioner authorizing shipment
for labeling in such establishment.
(b)(1) An application for such a permit shall be in a form specified
by the Commissioner and shall give the name and location of the
establishment in which such labeling is to be done.
(2) In case the applicant is the operator of such establishment, the
application shall include a written agreement signed by him that he will
request certification of each batch from which any shipment or delivery
is made to such establishment unless it is exempt under section 801(d)
of the act or 433.17; that he will not remove any of such antibiotic
drug from such establishment unless it complies with section 502(l) of
the act or the certification requirements of section 512(n) of the act
or is so exempt, or if certification is refused, unless it is returned
within a reasonable time to permit reprocessing and certification,
destruction, or such exemption at the establishment where it was
manufactured; that he will keep complete records showing the date,
quantity, and batch mark of each such shipment and delivery and the
disposition thereof; that he will make such records available to any
officer or employee of the Food and Drug Administration at any
reasonable hour within 3 years after the date of such disposition; and
that he will accord full opportunity to such officer or employee to make
inventories of stocks on hand and otherwise check the correctness of
such records.
(3) In case the applicant is not the operator of such establishment
such application shall include or be accompanied by:
(i) A written agreement signed by the applicant that he will request
certification of each batch from which any shipment or delivery is made
to such establishment unless it is exempt under section 801(d) of the
act or 433.17; that he will keep complete records showing the date,
quantity, and batch mark of each such shipment and delivery; and that
he will make such records available to any officer or employee of the
Food and Drug Administration at any reasonable hour within 3 years after
the date of such shipment or delivery; and
(ii) A written agreement signed by the operator of such establishment
that he will submit a request, supplemental to that of the applicant,
for the certification of each batch or portion thereof comprised in any
such shipment or delivery received by him unless it is exempt under
section 801(d) of the act or 433.17; that he will specify in his
request the number of packages of each size in such shipment or
delivery, the date of delivery, the batch mark thereof, and the batch
mark he will use therefor; that the batch marks to be used (if
different from those of the applicant) will be only those of which the
key is specified in this agreement; that the expiration date used for
the batch will be only that assigned to the manufacturer by
certification; that the labeling to be used for such packages will be
only that of which specimens are attached to this agreement (including
specimens of all brochures and other printed matter, except readily
available medical publications, referred to in such labeling); that
when any change is made in such key or labeling he will promptly submit
to the Commissioner a full statement of such change or, in the case of
changed labeling, specimens showing all such changes; that he will not
remove any of such antibiotic drug from such establishment unless it
complies with section 502(l) of the act or is exempt under section
801(d) of the act or 433.17 or, if certification is refused, unless it
is returned within a reasonable time to permit reprocessing and
certification, destruction, or such exemption at the establishment where
it was manufactured; that he will keep complete records of the
disposition of each such shipment and delivery; that he will make such
records available to any officer or employee of the Food and Drug
Administration at any reasonable hour within 3 years after the date of
such disposition; and that he will accord full opportunity to such
officer or employee to make inventories of stocks on hand and otherwise
check the correctness of such records.
(4) When the Commissioner finds that such application contains any
untrue statement of a material fact or that any provision of any such
agreement has been violated he may revoke such permit.
(5) Any person who contests the denial or revocation of a permit
shall have an opportunity for a regulatory hearing before the Food and
Drug Administration pursuant to part 16 of this chapter.
(c) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is the operator of such establishment,
shall become void at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof, before or after
labeling, from such establishment unless such batch complies with
section 502(l) of the act or the certification requirements of section
512(n) of the act or is exempt under section 801(d) of the act or
433.17 or, if certification is refused, unless such shipment or delivery
is returned within a reasonable time to permit reprocessing and
certification, destruction, or such exemption at the establishment where
it was manufactured.
(d) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who inintroduced such shipment or
delivery into interstate commerce is not the operator of such
establishment, shall expire at the beginning of the act of removing or
offering to remove such shipment or delivery of any part thereof, before
or after labeling from such establishment unless such batch complies
with section 502(l) of the act or the certification requirements of
section 512(n) of the act or is exempt under section 801(d) of the act
or 433.17 or, if certification is refused, unless such shipment or
delivery, within a reasonable time, is destroyed or returned to permit
reprocessing and certification, destruction, or such exemption at the
establishment where it was manufactured.
(39 FR 18939, May 30, 1974, as amended at 41 FR 48267, Nov. 2, 1976;
42 FR 15675, Mar. 22, 1977)
21 CFR 433.13 Exemption for manufacturing use.
(a) Except as provided by paragraphs (c) and (d) of this section, a
shipment or other delivery of any certifiable antibiotic drug subject to
the regulations in this chapter that is packed in containers of not less
than 10,000,000 units of penicillin or 10 grams each of one of the other
antibiotic drugs shall be exempt, during the time of introduction into
and movement in interstate commerce and the time of holding in the
establishment where it is so used, from the requirements of section
502(l) of the act or the certification requirements of section 512(n) of
the act, if it conforms to the standards prescribed therefor by the
section of the regulations in this chapter which is specifically
applicable to such other antibiotic drug, if the label of each container
bears the batch mark of the drug, the number of units or grams per
package, and the date on which the latest assay of the drug was
completed, and if the person who introduced each shipment or delivery
into interstate commerce holds a permit from the Commissioner
authorizing shipment for manufacturing use in such establishment.
(b) An application for such a permit shall be in a form specified by
the Commissioner, shall give the name and location of the establishment
in which such drug is to be used and shall be accompanied by;
(1) A written agreement signed by the applicant that he will keep
complete records showing the date, quantity, and batch mark of each
shipment and other delivery of any such drug to such establishment, and
that he will make such records available to any officer or employee of
the Food and Drug Administration at any reasonable hour within 3 years
after the date of such shipment or delivery;
(2) A written statement signed by the operator of such establishment
showing that he has adequate facilities for the manufacture of such
other drug; such statement shall contain an agreement that he will keep
complete records showing the date of receipt by him and the quantity and
batch mark of each such shipment and delivery and the disposition
thereof and showing the quantity and batch mark of each batch of such
other drug manufactured by him and the disposition thereof; that he
will make such records available to any officer or employee of the Food
and Drug Administration at any reasonable hour within 3 years after the
date of such disposition, and that he will accord full opportunity to
such officer or employee to make inventories of stocks on hand and
otherwise check the correctness of such records; and
(3) A written agreement signed by the person who will own the drug
after its manufacture is completed that he will request certification of
each batch thereof unless it is exempt under section 801 (d) of the act
or 433.12, 433.14, 433.16, or 433.17, and that he will not remove
any of such drug from such establishment unless it complies with section
502(l) of the act or the certification requirements of section 512(n) of
the act or is so exempt or is returned to him for labeling.
When the Commissioner finds that such application contains any untrue
statement of a material fact or that any provision of any such agreement
has been violated, he may revoke such permit. Any person who contests
the denial or revocation of a permit shall have an opportunity for a
regulatory hearing before the Food and Drug Administration pursuant to
part 16 of this chapter.
(c) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is the operator of such establishment,
shall become void at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof from such
establishment, prior to its use in the manufacture of another drug,
unless it is exempt under section 801(d) of the act.
(d) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is not the operator of such
establishment, shall expire at the beginning of the act of removing or
offering to remove such shipment or delivery or any part thereof from
such establishment, prior to its use in the manufacture of another drug,
unless it is exempt under section 801(d) of the act.
(39 FR 18939, May 30, 1974, as amended at 41 FR 48267, Nov. 2, 1976;
42 FR 15675, Mar. 22, 1977)
21 CFR 433.14 Exemption for storage.
(a) Except as provided by paragraphs (c) and (d) of this section, a
shipment or other delivery of a drug which is to be stored at a
warehouse located elsewhere than at the place of manufacture shall be
exempt, during the time of introduction into and movement in interstate
commerce and the time of holding in such warehouse, from the
requirements of section 502(l) of the act or the certification
requirements of section 512(n) of the act if the labeling of each
shipping container bears the batch mark of the drug, and if the person
who introduced such shipment or delivery into interstate commerce holds
a permit from the Commissioner authorizing shipment for storage in such
warehouse.
(b) An application for such a permit shall be in a form specified by
the Commissioner, and shall give the name and location of the warehouse
in which such drug is to be stored. Such application shall be
accompanied by:
(1) A written agreement signed by the applicant that he will request
certification of each batch thereof unless it is exempt under section
801(d) of the act or 433.12, 433.13, or 433.16, that he will not
remove any of such drug from such warehouse unless it complies with
section 502(l) of the act or the certification requirements of section
512(n) of the act or is so exempt or, if certification is refused unless
it is returned within a reasonable time to permit reprocessing and
certification, destruction, or such exemption at the establishment where
it was manufactured; that he will keep complete records showing the
date, quantity, and batch mark of each shipment and other delivery of
any such drug to such warehouse, and that he will make such records
available to any officer or employee of the Food and Drug Administration
at any reasonable hour within 3 years after the date of such shipment or
delivery; and
(2) A written statement signed by the operator of such warehouse
showing that he has adequate facilities for such storage; such
statement shall contain an agreement that he will hold each shipment or
other delivery of such drug intact, under such conditions as will not
cause failure of the drug to comply with the requirements for
certification, that he will keep complete records showing the date of
receipt by him and the quantity and batch mark of each such shipment and
delivery and the disposition thereof, that he will make such records
available to any officer or employee of the Food and Drug Administration
at any reasonable hour within 3 years after the date of such
disposition, and that he will accord full opportunity to such officer or
employee to make inventories of stocks on hand and otherwise check the
correctness of such records.
If the applicant keeps complete records showing the date, quantity,
and batch mark of each shipment and other delivery of any such drug from
such warehouse and the name and post-office address of the person to
whom such shipment or delivery was made, the agreement to keep records
of such disposals, to make such records available, and to afford
opportunity for checking their correctness may be included in the
applicant's agreement and omitted from that of the operator. When the
Commissioner finds that such application contains any untrue statement
of a material fact or that any provision of any such agreement has been
violated he may revoke such permit. Any person who contests the denial
or revocation of a permit shall have an opportunity for a regulatory
hearing before the Food and Drug Administration pursuant to part 16 of
this chapter.
(c) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is the operator of such warehouse,
shall become void at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof from such warehouse
unless such batch complies with section 502(l) of the act or the
certification requirements of section 512(n) of the act or is exempt
under section 801(d) of the act or 433.12, 433.13, or 433.16, or, if
certification is refused, unless such shipment or delivery is returned
within a reasonable time to permit reprocessing and certification,
destruction, or such exemption at the establishment where it was
manufactured.
(d) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is not the operator of such warehouse,
shall expire at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof from such warehouse
unless such batch complies with section 502(l) of the act or the
certification requirements of section 512(n) of the act or is exempt
under section 801(d) of the act or 433.12, 433.13, or 433.16, or, if
certification is refused, unless such shipment or delivery within a
reasonable time, is destroyed, or returned to permit reprocessing and
certification, destruction, or such exemption at the establishment where
it was manufactured.
(39 FR 18939, May 30, 1974, as amended at 41 FR 48267, Nov. 2, 1976;
42 FR 15675, Mar. 22, 1977)
21 CFR 433.15 Exemption for processing.
(a) Except as provided by paragraphs (c) and (d) of this section, a
shipment or other delivery of any certifiable antibiotic drug subject to
the regulations in this chapter in concentrated aqueous solution which
is to be processed at an establishment located elsewhere than at the
place of manufacture shall be exempt during the time of introduction
into and movement in interstate commerce and the time of holding in such
establishment from the requirements of section 502(l) of the act or the
certification requirements of section 512(n) of the act, if the person
who introduced such shipment or delivery into interstate commerce holds
a permit from the Commissioner authorizing shipment for processing in
such establishment, and each package of such solution bears the batch
mark of the drug.
(b) An application for such a permit shall be in a form specified by
the Commissioner and shall give the name and location of the
establishment in which such processing is to be done. Such application
shall be accompanied by:
(1) A written agreement signed by the applicant that he will keep
complete records showing the date, quantity, potency, and batch mark of
each shipment and other delivery of any such solution to such
establishment, and that he will make such records available to any
officer or employee of the Food and Drug Administration at any
reasonable hour within 3 years after the date of such shipment or
delivery;
(2) A written agreement signed by the operator of such establishment
showing that he has adequate facilities for such processing; such
statement shall contain an agreement that he will keep complete records
showing the date of receipt by him and the quantity and batch mark of
each such shipment and delivery and the disposition thereof, that he
will make such records available to any officer or employee of the Food
and Drug Administration at any reasonable hour within 3 years after the
date of such disposition, and that he will accord full opportunity to
such officer or employee to make inventories of stocks on hand and
otherwise check the correctness of such records; and
(3) A written agreement signed by the person who will own the drug
after the processing is completed that he will request certification of
each batch thereof unless it is exempt under section 801(d) of the act
or 433.12, 433.13, 433.14, 433.16, or 433.17, and that he will not
remove any of such drug from such establishment unless it complies with
section 502(l) of the act or the certification requirements of section
512(n) of the act or is so exempt.
When the Commissioner finds that such application contains any untrue
statement of a material fact or that any provision of any such agreement
has been violated he may revoke such permit. Any person who contests
the denial or revocation of a permit shall have an opportunity for a
regulatory hearing before the Food and Drug Administration pursuant to
part 16 of this chapter.
(c) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is the operator of such establishment,
shall become void at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof, before or after
processing, from such establishment unless the batch made from such
shipment or delivery complies with section 502(l) of the certification
requirements of section 512(n) of the act or is exempt under section
801(d) of the act or 433.12, 433.13, 433.14, 433.16, or 433.17, or,
if certification is refused, unless such shipment or delivery is
reprocessed and certified or destroyed within a reasonable time.
(d) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is not the operator of such
establishment, shall expire at the beginning of the act of removing or
offering to remove such shipment or delivery or any part thereof, before
or after processing, from such establishment unless the batch made from
such shipment or delivery complies with section 502(l) of the act or is
exempt under section 801(d) of the act or the certification requirements
of section 512(n) of the act or 433.12, 433.13, 433.14, 433.16, or
433.17, or, if certification has been refused, unless such shipment or
delivery is reprocessed and certified or destroyed within a reasonable
time.
(39 FR 18939, May 30, 1974, as amended at 41 FR 48267, Nov. 2, 1976;
42 FR 15675, Mar. 22, 1977)
21 CFR 433.16 Exemption for repacking.
(a) Except as provided by paragraphs (c) and (d) of this section, a
shipment or other delivery of a drug which is to be repacked at an
establishment located elsewhere than at the place of manufacture shall
be exempt, during the time of introduction into and movement in
interstate commerce and the time of holding such establishment from the
requirements of section 502(l) of the act or the certification
requirements of section 512(n) of the act if the labeling of each
container bears the batch mark of the drug and the number of units per
package, and if the person who introduces such shipment or delivery into
interstate commerce holds a permit from the Commissioner authorizing
shipment for repacking in such establishment.
(b) An application for such a permit shall be in a form specified by
the Commissioner, and shall give the name and location of the
establishment in which such repacking is to be done. Such application
shall be accompanied by:
(1) A written agreement signed by the applicant that he will keep
complete records showing the date, quantity, and batch mark of each
shipment and other delivery of any such drug to such establishment, and
that he will make such records available to any officer or employee of
the Food and Drug Administration at any reasonable hour within 3 years
after the date of each shipment or delivery;
(2) A written statement signed by the operator of such establishment
showing that he has adequate facilities for such repacking; such
statement shall contain an agreement that he will keep complete records
showing the date of receipt by him and the quantity and batch mark of
each such shipment and delivery and the disposition thereof, that he
will make such records available to any officer or employee of the Food
and Drug Administration at any reasonable hour within 3 years after the
date of such disposition, and that he will accord full opportunity to
such officer or employee to make inventories of stocks on hand and
otherwise check the correctness of such records; and
(3) A written agreement signed by the person who will own the drug
after the repacking is completed that he will request certification of
each batch thereof unless it is exempt under section 801(d) of the act
or 433.12, 433.13, 433.14, or 433.17, and that he will not remove
any of such drug from such establishment unless it complies with section
502(l) of the act or the certification requirements of section 512(n) of
the act or is so exempt or is returned to him for labeling or, if
certification is refused, unless it is returned within a reasonable time
to permit reprocessing and certification, destruction, or such exemption
at the establishment where it was manufactured.
When the Commissioner finds that such application contains any untrue
statement of a material fact or that any provision of any such agreement
has been violated he may revoke such permit. Any person who contests
the denial or revocation of a permit shall have an opportunity for a
regulatory hearing before the Food and Drug Administration pursuant to
part 16 of this chapter.
(c) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is the operator of such establishment,
shall become void at the beginning of the act of removing or offering to
remove such shipment or delivery or any part thereof, before or after
repacking, from such establishment unless such batch complies with
section 502(l) of the act or the certification requirements of section
512(n) of the act or is exempt under section 801(d) of the act or
433.12, 433.13, 433.14, or 433.17, or is returned to such person for
labeling or, if certification is refused, unless such shipment or
delivery is returned within a reasonable time to permit reprocessing and
certification, destruction, or such exemption at the establishment where
it was manufactured.
(d) An exemption of a shipment or other delivery under paragraph (a)
of this section, in case the person who introduced such shipment or
delivery into interstate commerce is not the operator of such
establishment, shall expire at the beginning of the act of removing or
offering to remove such shipment or delivery or any part thereof, before
or after repacking, from such establishment unless such batch complies
with section 502(l) of the act or the certification requirements of
section 512(n) of the act or is exempt under section 801(d) of the act
or 433.12, 433.13, 433.14, or 433.17, or is returned to such person
for labeling or, if certification is refused, unless such shipment or
delivery within a reasonable time, is destroyed or returned to permit
reprocessing and certification, destruction, or such exemption at the
establishment where it was manufactured.
(39 FR 18939, May 30, 1974, as amended at 41 FR 48268, Nov. 2, 1976;
42 FR 15675, Mar. 22, 1977)
21 CFR 433.17 Exemption for investigational use.
A shipment or other delivery of an antibiotic drug shall be exempt
from section 502(l) of the act or the certification requirements of
section 512(n) of the act if all the procedures outlined in part 312 or
511.1 of this chapter are complied with. For the purposes of this
section, the references in part 312 or 511.1 of this chapter to ''new
drug'' and ''approved new animal drug application'' shall be deemed to
read ''antibiotic drug'' and ''approval for certification or exemption
from certification'' respectively.
(39 FR 18939, May 30, 1974, as amended at 40 FR 13497, May 27, 1975;
55 FR 11582, Mar. 29, 1990)
21 CFR 433.17 Subpart C -- Specific Use Exemptions
21 CFR 433.20 Antibiotic drugs for isolation and differentiation of
microorganisms in clinical use.
Antibiotic drugs subject to section 507 of the act shall be exempt
from section 502(l) if such drugs are:
(a) Paper discs impregnated with antibiotics in the amounts listed in
the following table:
(b) Packaged in a container bearing on its label or labeling the
following:
(1) On the outside wrapper or container and the immediate container:
(i) The batch mark.
(ii) The potency of each disc in the batch.
(iii) The expiration date as prescribed under 432.5(a)(3) of this
chapter.
(iv) The statement: Not for Susceptibility Testing.
(2) On the labeling within or attached to the package: Adequate
directions for use.
21 CFR 433.21 Antibiotics for diagnostic use.
Antibiotics packaged for the withdrawal of individually weighed
portions and intended for use solely in laboratory procedures in
connection with the diagnosis or treatment of disease and conspicuously
so labeled shall be exempt from the certification requirements of
section 502(l) and 507 of the act and the certification requirements of
section 512(n) of the act if they comply with all the following
conditions:
(a) The potency, moisture content, and identity comply with the
standards prescribed for the antibiotic by the specific regulations
issued in this chapter.
(b) It is packaged in immediate containers that are tight containers
as defined by the U.S.P. Each such container shall contain not more than
1 gram.
(c) Each package bears on the label or labeling of its outside
wrapper or container and the immediate container the following:
(1) The statements ''For the withdrawal of individual portions of
antibiotic. Each portion must be weighed before use. Diagnostic
reagent. For professional use only.''
(2) The number of milligrams or grams contained in each immediate
container and the potency per milligram.
(3) The batch mark.
(4) The statement ''Expiration date -------- '', the blank being
filled in with the date that does not exceed the expiration date
authorized for the antibiotic by this chapter.
(d) The circular or other labeling within or attached to the package
bears directions adequate for the use of such drug.
Cross References: For tests and methods of assay and certification
of antibiotics susceptibility discs for laboratory diagnosis of disease,
see 460.1 and 460.6 of this chapter.
21 CFR 433.22 Biologic drugs that contain antibiotics as a
preservative.
Biological drugs that contain any certifiable antibiotic drug subject
to the regulations in this chapter, and the purpose of the antibiotic is
for use only as a preservative and the biological drug is conspicuously
so labeled, shall be exempt from the requirements of sections 502(l) and
507 of the act and the certification requirements of section 512(n) of
the act, if such drugs are licensed under the Public Health Service Act
of July 1, 1944 (58 Stat. 682; 42 U.S.C. 201 et seq.) or under the
Virus-Serum-Toxin Act of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et
seq.).
21 CFR 433.23 Microbiological culture media containing antibiotics.
Microbiological culture media that contain any certifiable antibiotic
drug subject to the regulations in this chapter shall be exempt from the
requirements of sections 502(l) and 507 of the act and the certification
requirements of section 512(n) of the act if:
(a) They are intended for use in tissue culture and the antibiotic
drug is added solely for use as an aid in the prevention of microbial
contamination; or
(b) They are intended for use in the isolation of selected organisms
from mixed cultures and the antibiotic drug is added solely for use as
an aid in such isolation; and
(c) The certifiable antibiotic drug used in such culture media
complies with the applicable standards of identity, strength, quality,
and purity prescribed therefor.
21 CFR 433.24 Exemption of antibiotic drugs for use in teaching, law
enforcement, research, and analysis.
Antibiotic drugs subject to section 507 or 512(n) of the act shall be
exempt from the requirements of section 502(l) and from the
certification requirements of section 512(n) of the act if shipped or
sold to, or in the possession of, persons regularly and lawfully engaged
in instruction in pharmacy, chemistry, or medicine not involving
clinical use; or in law enforcement; or in research not involving
clinical use; or in chemical analysis or physical testing, provided
they are to be used only for such instruction, law enforcement,
research, analysis, or testing, and provided further that their labels
bear the statement ''Not for drug use.''
433.25 (Reserved)
21 CFR 433.26 Neomycin sulfate ointment intended for hypersensitivity
testing.
Neomycin sulfate ointment subject to sections 502(l) and 507 of the
act and packaged for use as an allergen for skin patch testing of
hypersensitivity shall be exempt from the certification requirements of
section 502(l) and 507 of the act if it complies with all the following
conditions:
(a) It contains neomycin sulfate equivalent to 200 milligrams of
neomycin per gram in petrolatum.
(b) The neomycin sulfate used in preparing the neomycin sulfate
ointment conforms to the standards prescribed by 444.42(a)(1) of this
chapter except 444.42(a)(1)(ii).
(c) The shipment of neomycin sulfate is made as a result of a
specific request made to the manufacturer or distributor by a
practitioner licensed by law to administer such drug, and the use of
neomycin sulfate ointment for patch testing is not promoted by the
manufacturer or distributor.
(d) Each package shall bear on its outside wrapper or container and
on the immediate container, in addition to other labeling information
required by the act and regulations, the following statements in lieu of
adequate directions for use:
(1) The statement, ''Caution: Federal law prohibits dispensing
without prescription''.
(2) The statement, ''For use only in patch testing''.
(3) The potency of the ointment.
(4) The expiration date as prescribed by 432.5(a)(3) of this
chapter.
(e) The quantity shipped is limited to an amount reasonable for the
purpose of patch testing in the normal course of the practice of
medicine and is used solely for such patch testing.
(f) The manufacturer or distributor maintains records of all
shipments for this purpose for a period of 2 years after shipment and
will make them available to the Food and Drug Administration upon
request.
(43 FR 11151, Mar. 17, 1978)
21 CFR 433.26 Subpart D -- Records and Reports
21 CFR 433.30 Records retention.
At the option of the person having control of records required to be
kept by any regulation in this Part 433, photostatic or other permannnt
reproductions may be substituted for such records after the first 2
years of the holding period.
21 CFR 433.30 PART 436 -- TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-CONTAINING DRUGS
21 CFR 433.30 Pt. 436
21 CFR 433.30 Subpart A -- Definitions; Interpretations; Requirements
Sec.
436.1 Sterility requirements of items packaged with sterile
antibiotic drugs.
436.2 Alternative assay methods.
21 CFR 433.30 Subpart B -- Sterility Test Methods
436.20 Sterility test methods and procedures.
21 CFR 433.30 Subpart C -- Biological Test Methods
436.31 Equipment and diluents for use in biological testing.
436.32 Pyrogen test.
436.35 Depressor substances test.
21 CFR 433.30 Subpart D -- Microbiological Assay Methods
436.100 Laboratory equipment.
436.101 Solutions.
436.102 Culture media.
436.103 Test organisms.
436.104 Penicillin activity.
436.105 Microbiological agar diffusion assay.
436.106 Microbiological turbidimetric assay.
21 CFR 433.30 Subpart E -- General Chemical Tests for Antibiotics
436.200 Loss on drying.
436.201 Moisture determination.
436.202 pH.
436.203 Crystallinity.
436.204 Iodometric assay.
436.205 Hydroxylamine colorimetric assay.
436.206 Test for metal particles in ophthalmic ointments.
436.207 Residue on ignition.
436.208 Heavy metals determination.
436.209 Melting range or temperature.
436.210 Specific rotation.
436.211 Identity tests by infrared spectrophotometry.
436.212 Disintegration test.
436.213 Nonaqueous titrations.
436.214 Heat stability.
436.215 Dissolution test.
436.216 High-performance liquid chromatographic assay.
436.217 Film-coat rupture test.
21 CFR 433.30 Subpart F -- Chemical Tests for Specific Antibiotics
436.300 Polarimetric assay of carbenicillin indanyl sodium.
436.301 Thin layer chromatography identity test for carbenicillin
indanyl.
436.302 Clindamycin vapor phase chromatography.
436.303 Clindamycin content of clindamycin palmitate hydrochloride by
vapor phase chromatography.
436.304 Clindamycin phosphate vapor phase chromatography.
436.305 Thin layer chromatographic identity test for hetacillin.
436.306 Lincomycin gas liquid chromatography.
436.307 Spectinomycin vapor phase chromatography.
436.308 Paper chromatography identity test for tetracyclines.
436.309 Anhydrotetracyclines and 4-epian-hydrotetracycline.
436.310 Thin layer chromatography identitywtest for mitomycin.
436.311 Thin layer chromatography identity test for amoxicillin.
436.312 Atomic absorption method for determining the zinc content of
zinc bacitracin.
436.316 Determination of penicillin G content.
436.317 Solubility characteristic test for griseofulvin
(ultramicrosize) tablets.
436.318 Continuous flow thin layer chromatography identity test.
436.319 Thin layer chromatography identity test for bacitracin and
bacitracin zinc.
436.320 Ferric chloride colorimetric assay.
436.321 Griseofulvin gas liquid chromatography.
436.322 High-pressure liquid chromatographic assay for anthracycline
antibiotics.
436.323 Continuous flow thin layer chromatography identity test for
cefamandole nafate.
436.324 Polarographic analysis of cefamandole.
436.325 High pressure liquid chromatography assay for vidarabine.
436.326 Thin layer chromatographic identity test for cefoxitin
sodium.
436.327 Thin layer chromatographic identity test for cyclacillin.
436.328 High pressure liquid chromatographic assay for sulfisoxazole
acetyl content.
436.329 High-pressure liquid chromatographic assay for meclocycline.
436.330 Thin layer chromatographic identity test for bacampicillin.
436.331 High-pressure liquid chromatographic assay for dactinomycin.
436.332 High-pressure liquid chromatographic assay for moxalactam.
436.333 Thin layer chromatographic identity test for moxalactam.
436.334 High-pressure liquid chromatographic assay for piperacillin.
436.335 High-pressure liquid chromatographic assay for
chloramphenicol palmitate.
436.336 Thin layer chromatographic identity test for azlocillin
436.337 High-pressure liquid chromatographic assay for cephradine.
436.338 High-pressure liquid chromatographic assay for cefoperazone.
436.339 High-pressure liquid chromatographic assay for bleomycin
fractions.
436.340 High-pressure liquid chromatographic assay for tetracycline
hydrochloride content and 4-epitetracycline hydrochloride content.
436.341 High-pressure liquid chromatographic assay for plicamycin.
436.342 High-pressure liquid chromatographic assay for cefazolin.
436.343 High-pressure liquid chromatographic assay for cefuroxime.
436.344 Thin layer chromatographic identity test for cefuroxime.
436.345 High-pressure liquid chromatographic assay for ceftizoxime.
436.346 High-pressure liquid chromatographic assay for cyclosporine.
436.347 High-pressure liquid chromatographic assay for cefoxitin.
436.348 High-pressure liquid chromatographic assay for ceforanide.
436.349 High-pressure liquid chromatographic assay for L-lysine in
ceforanide for injection.
436.350 High-performance liquid chromatographic assay for cefonicid.
436.351 High-performance liquid chromatographic assay for amoxicillin
and clavulanic acid.
436.352 High-performance liquid chromatographic assay for determining
clavam-2-carboxylate content in clavulanate potassium.
436.353 High-performance liquid chromatographic assay for
amdinocillin.
436.354 High-performance liquid chromatographic assay for
ceftriaxone.
436.355 High-performance liquid chromatographic assay for
ticarcillin-clavulanic acid.
436.356 High-performance liquid chromatographic assay for
ceftazidime.
436.357 Atomic absorption test for sodium carbonate content.
436.358 High-performance liquid chromatographic assay for pyridine.
436.360 Gel permeation chromatograhpic assay for high molecular
weight polymer.
436.361 High-performance liquid chromatographic assay for aztreonam.
436.362 Thin-layer chromatographic test for free erythromycin content
in erythromycin estolate bulk.
436.363 High-performance liquid chromatographic assay for
cefmenoxime.
436.364 Atomic absorption test for sodium carbonate content of
cefmenoxime hydrochloride for injection.
436.365 Thin layer chromatographic identity test for rifampin.
436.366 High-performance liquid chromatography assay for determining
chromatographic purity of vancomycin.
436.367 Thin-layer chromatographic identity test for cephalexin
hydrochloride.
21 CFR 433.30 Subpart G -- Chemical Tests for Nonantibiotic Active
Ingredients
436.400 Thin layer chromatographic identity test for
iodochlorhydroxyquin.
21 CFR 433.30 Subpart H -- Tests for Specific Antibiotic Dosage Forms
436.500 Penicillin in oil and wax.
436.503 Procaine penicillin and buffered crystalline penicillin for
aqueous injection.
436.504 Penicillin-bacitracin ointment.
436.505 Penicillin-streptomycin-bacitracin ointment;
penicillin-dihydrostreptomycin-bacitracin ointment;
penicillin-streptomycin-bacitracin methylene disalicylate ointment;
penicillin-dihydrostreptomycin-bacitracin methylene disalicylate
ointment.
436.506 Benzathine penicillin G and buffered crystalline penicillin
for aqueous injection.
436.507 Benzathine-procaine-buffered crystalline penicillins for
aqueous injection.
436.508 Penicillin - bacitracin - neomycin ointment;
penicillin-bacitracin-neomycin in oil.
436.509 Procaine penicillin-streptomycin-polymyxin in oil; procaine
penicillin-dihydrostreptomycin-polymyxin in oil; procaine
penicillin-streptomycin-polymyxin ointment; procaine
penicillin-dihydrostreptomycin-polymyxin ointment.
436.510 Penicillin - streptomycin - erythromycin ointment;
penicillin-dihydro-streptomycin - erythromycin ointment.
436.511 Penicillin-streptomycin-bacitracin methylene
disalicylate-neomycin ointment;
penicillin-dihydrostreptomycin-bacitracin methylene
disalicylate-neomycin ointment.
436.512 Procaine penicillin G-novobiocin-neomycin-dihydrostreptomycin
in oil.
436.513 Chlortetracycline troches; tetracycline hydrochloride
troches.
436.514 Chlortetracycline hydrochloride powder topical; tetracycline
hydrochloride powder topical.
436.515 Capsules tetracycline and oleandomycin phosphate; capsules
tetracycline and troleandomycin; capsules tetracycline hydrochloride
and oleandomycin phosphate; capsules tetracycline hydrochloride and
troleandomycin.
436.516 Tetracycline-neomycin complex powder topical; tetracycline
hydrochloride-neomycin sulfate powder topical.
436.517 Bacitracin-neomycin tablets; zinc bacitracin-neomycin
tablets; bacitracin methylene disalicylate-neomycin tablets.
436.542 Acid resistance/dissolution test for enteric-coated
erythromycin pellets.
436.543 Acid resistance test for pellet-filled doxycycline hyclate
capsules.
436.544 Dissolution test for pellet-filled doxycycline hyclate
capsules.
436.545 Acid resistance test for erythromycin particles in tablets.
Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 357).
Source: 39 FR 18944, May 30, 1974, unless otherwise noted.
21 CFR 433.30 Subpart A -- Definitions; Interpretations; Requirements
21 CFR 436.1 Sterility requirements of items packaged with sterile
antibiotic drugs.
(a) Diluents packaged in combination with sterile antibiotic drugs.
If a sterile antibiotic drug is packaged in combination with an
immediate container of a diluent, the immediate container of diluent
shall be sterile when tested by the method prescribed in 436.20(e)(1).
(b) Dispensers packaged in combination with sterile antibiotic drugs.
If a sterile antibiotic drug is packaged in combination with a
dispenser, such dispenser shall be sterile when tested by the method
prescribed in 436.20(e)(1).
(39 FR 18944, May 30, 1974, as amended at 41 FR 46852, Oct. 26, 1976)
21 CFR 436.2 Alternative assay methods.
Alternative assay methods (including automated procedures) employing
the same basic chemistry or microbiology as the official methods
described in this part and in the individual monographs of this chapter
may be used, provided the results obtained are of equivalent accuracy.
However, only the results obtained from the official methods designated
in the individual monographs are conclusive.
21 CFR 436.2 Subpart B -- Sterility Test Methods
21 CFR 436.20 Sterility test methods and procedures.
(a) Laboratory facilities. The test must be performed using aseptic
techniques in an area as free from contamination as is possible to
achieve. Testing should not be conducted under direct exposure to
ultraviolet light or in areas under aerosol treatment. Environmental
tests to assess the suitability of testing conditions should be made
frequently enough to assure the validity of test results.
(b) Equipment and reagents -- (1) Bacterial membrane filter. The
filter has a nominal porosity of 0.45 micron 0.02 micron, a diameter of
approximately 47 millimeters, and a flowrate of 55 milliliters to 75
milliliters of distilled water passing each square centimeter of filter
area per minute with a differential pressure of 70 centimeters of
mercury at 25 C.
(2) Penicillinase solutions. When the amount of penicillinase to be
used is specified in terms of Levy units, use a penicillinase solution
standardized in terms of Levy units. One Levy unit of penicillinase
inactivates 59.3 units of penicillin G in 1 hour at 25 C. and at a pH
of 7.0 in a phosphate buffered solution of a pure alkali salt of
penicillin G when the substrate is in sufficient concentration to
maintain a zero order reaction.
(c) Culture media. Use ingredients that conform to the standards
prescribed by the U.S.P. or N.F. In lieu of preparing the media from the
individual ingredients, they may be made from dehydrated mixtures which,
when reconstituted with distilled water, have the same or equivalent
composition as such media and have growth-promoting buffering, and
oxygen tension-controlling properties equal to or better than such
media. The pH of each medium should be adjusted with 2N hydrochloric
acid or sodium hydroxide before sterilization, so that after
sterilization and the addition of the penicillinase, if necessary, the
pH will fall within the specified range. Dispense 90 10 milliliter
quantities of the liquid media into individual test tubes (38
millimeters x 200 millimeters). Close the tubes with suitable closures,
and sterilize in an autoclave at 121 C. for 20 minutes. The autoclave
temperature should be reached within 10 minutes. After sterilization,
cool the medium at once to approximately 25 C. and store at 20 C. to
30 C. The sterility of each lot of tubes of liquid medium may be
confirmed by incubating an adequate number of tubes as described in the
test procedures in paragraph (e) of this section.
(1) Medium A. Use U.S.P. fluid thioglycolate medium I.
(2) Medium B. Use U.S.P. fluid thioglycolate medium I, with
sufficient sterile penicillinase added to inactivate the penicillin
activity in the sample under test. The penicillinase must be added to
individual tubes of sterile medium A, using aseptic technique. Prior to
use, or at the time of the test, a representative number of the tubes
containing added penicillinase are incubated at 30 -32 C. for 24
hours to 48 hours, and are examined for sterility. If the sample
contains penicillin as the only antibiotic, the ability of the
penicillinase to inactivate all the penicillin in the sample under test
is checked as follows: Add to one test tube of medium B the proper
amount of penicillin from one of the individual containers under test.
Then add 1.0 milliliter of a 1:1.000 dilution of an 18-24 hour culture
of Staphylococcus aureus (American Type Culture Collection 6538-P)1004
in medium A. Typical microbial growth must be observable after 24 hours
incubation at 30 -32 C. If the sample contains a mixture of penicillin
plus some other antibiotic or antibacterial agent the ability of the
penicillinase to inactivate all the penicillin in the sample is not
tested directly on the sample under test, but is determined separately,
using an amount of penicillin alone equivalent to the amount of
penicillin in the sample or by any other suitable method for
standardizing the penicillin-inactivating power of the penicillinase
preparation.
(3) Medium C. To each liter of medium A add 5.0 milliliters of
polysorbate 80 before sterilization. To each tube of sterilized medium
add sufficient sterile penicillinase, and proceed as directed for medium
B.
(4) Medium D. To each liter of medium A add 5.0 milliliters of
polysorbate 80 and sufficient 2N sodium hydroxide so that the pH will be
7.9 0.1 after sterilization. Then add sufficient sterile penicillinase
to each tube and proceed as directed for medium B.
(5) Medium E. Use U.S.P. XVIII soybean-casein digest medium.
(6) Medium F. To each liter of medium E add 5.0 milliliters of
polysorbate 80 before sterilization. To each tube of sterilized medium
add sufficient sterile penicillinase to solubilize the penicillin in the
sample to be tested.
(7) Medium G. Prepare as follows:
Peptic digest of animal tissue 6.0 gm.
Pancreatic digest of casein 4.0 gm.
Yeast extract 3.0 gm.
Beef extract 1.5 gm.
Dextrose 1.0 gm.
Agar 15.0 gm.
Distilled water, q.s 1,000.0 ml.
pH 6.6 0.1
Suspend the powder in a liter of distilled water. Allow to stand for
5 minutes, then mix thoroughly. Boil for 1 or 2 minutes or until
solution is complete. Dispense in suitable flasks and sterilize at 121
C. for 15 minutes. Aseptically pour approximately 25-milliliter
quantities into sterile Petri dish bottoms measuring 20 millimeters x
100 millimeters. Cover plates with sterile porcelain tops, glazed on
the outside. Allow plates to stand at room temperature for 48 hours
prior to use as a control on the sterility of the plates.
(8) Medium H. Prepare, sterilize, and dispense as described for
medium G, except as follows:
Dextrose 40.0 gm.
Peptic digest of animal tissue 10.0 gm.
Agar 15.0 gm.
Distilled water q.s 1,000.0 ml.
pH 5.6 0.1 after sterilization
(9) Medium I. To each liter of Medium A add 1 milliliter of
p-tert-octylphenoxy polyethoxyethanol.
(10) Medium J. To each liter of Medium E add 1 milliliter of
p-tert-octylphenoxy polyethoxyethanol.
(11) Medium K. (Rinse medium). Prepare as follows:
Peptic digest of animal tissue 5.0 gm.
Beef extract 3.0 gm.
p-tert-octylphenoxy polyethoxyethanol 10.0 ml.
Distilled water, q.s 1,000.0 ml.
pH 6.9 0.2 after sterilization
(12) Medium L. To each liter of Medium A add 1 milliliter of
p-tert-octylphenoxy polyethoxyethanol and approximately 10,000 Levy
units of penicillinase.
(13) Medium M. To each liter of Medium E add 1 milliliter of
p-tert-octylphenoxy polyethoxyethanol and approximately 10,000 Levy
units of penicillinase.
(14) Medium N:
Pancreatic digest of casein 15.0 gm.
Peptic digest of soybean meal 5.0 gm.
Sodium chloride 5.0 gm.
Agar 15.0 gm.
Water 1,000.0 ml.
pH 7.3 0.2 after sterilization
(d) Diluting fluids -- (1) Diluting fluid A. Dissolve 1 gram of
U.S.P. peptic digest of animal tissue or equivalent in sufficient
distilled water to make 1,000 milliliters. Dispense in flasks and
sterilize as described in paragraph (c) of this section. Final pH=7.1
0.1.
(2) Diluting fluid B. To each liter of diluting fluid A add 5.0
milliliters of polysorbate 80 before sterilization.
(3) Diluting fluid C. To each liter of diluting fluid A add 0.5 gram
of sodium thioglycollate, and adjust with NaOH so that after
sterilization the final pH will be pH 6.6 0.6. Dispense in flasks and
sterilize as described in paragraph (c) of this section.
(4) Diluting fluid D. To each liter of diluting fluid A add 1
milliliter of p-tert-octylphenoxy polyethoxyethanol. Dispense in flasks
and sterilize as described in paragraph (c) of this section. Final
pH=7.1 0.1.
(5) Diluting fluid E. Use isopropyl myristate that is sterile and
that has a water-extract pH of 5.5 or greater. Determine the
water-extract pH of a portion of the isopropyl myristate as follows:
Place 100 milliliters of the isopropyl myristate sample and 10
milliliters of distilled water into a centrifuge bottle of approximately
250 milliliters capacity and seal the bottle tightly. Place the
centrifuge bottle on a shaker so that its longest dimension is oriented
in the direction of shaker movement and shake at 250 cycles per minute
for 1 hour. Centrifuge the bottle at 1,800 revolutions per minute for
20 minutes. With a suitable vacuum system, remove and discard the upper
layer; then pipet 5 milliliters of the lower water layer into a beaker
and determine the pH using a standardized pH meter. If the
water-extract pH is less than 5.5, pass the isopropyl myristate through
a glass column packed with basic aluminum oxide, activity grade No. 1.
Determine the water-extract pH of a portion of the isopropyl myristate
that has been passed through the aluminum oxide column. Sterilize
isopropyl myristate by filtration through a 0.22-micron membrane filter
and aseptically dispense 100-milliliter portions into sterile
250-milliliter flasks.
(6) Diluting fluid F. To each liter of diluting fluid A add 20 grams
of disodium edetate, and adjust with NaOH so that after sterilization
the final pH will be 7.1 0.1. Dispense in flasks and sterilize as
described in paragraph (c) of this section.
(7) Diluting fluid G. To each liter of sterile diluting fluid A add
10 grams of sterile L-lysine.
(8) Diluting fluid H. To each liter of diluting fluid A add 10 grams
of sodium bicarbonate before sterilization.
(9) Diluting fluid I. To each liter of diluting fluid A add 23.4
grams of sterile L-arginine base.
(10) Diluting fluid J. Sterilize 2.0 grams of anhydrous sodium
carbonate by dry-heating at 180 C for 2 hours. Dissolve in 100
milliliters of diluting fluid A just prior to use.
(e) Conduct of test -- (1) Bacterial membrane filter method -- (i)
Sample preparation -- (a) Antibiotic drug. From each of 20 immediate
containers, aseptically transfer approximately 300 milligrams of solids
if it is not a liquid drug, or 1 milliliter by volume if it is a liquid
drug, or the entire contents if the container contains less than these
amounts; except that if it is a liquid drug containing penicillin in a
concentration greater than 300,000 units per milliliter, use the volume
that contains 300,000 units, into a sterile 500-milliliter Erlenmeyer
flask containing approximately 200 milliliters of diluting fluid A. (If
it is a composite sample packaged in one immediate container in
accordance with the requirements of 431.5(b) of this chapter, transfer
the entire contents, or approximately 6 grams, into the Erlenmeyer
flask.) Stopper the flask and swirl to dissolve the drug. As soon as
the sample has completely dissolved, proceed as directed in paragraph
(e)(1)(ii) of this section. If the pooled portions from 20 containers
will not dissolve completely in 200 milliliters of diluting fluid or
will not filter rapidly, 400 milliliters of diluting fluid may be used
or two separate tests may be performed using a pool of 10 containers for
each test.
(b) Diluent packaged in combination with a sterile drug. Using the
entire contents from each of 20 immediate containers, proceed as
directed in paragraph (e)(1)(ii) of this section.
(c) Sterile dispensers packaged in combination with a sterile drug.
Prepare 20 clean, empty containers of approximately the same size as
those in which the sterile antibiotic drug is packaged. To each
container add diluting fluid A in a volume approximately the same as
that of the sterile drug when it is prepared for dispensing. Cap the
containers, sterilize by autoclaving at 121 C. for 20 minutes, and
then allow to cool to room temperature. Aseptically open each dispenser
package and remove each dispenser in turn. Use each aseptically to
remove 1 milliliter of the fluid from a separate sterile container
prepared as described above. Aseptically transfer the fluid to a
500-milliliter Erlenmeyer flask containing approximately 200 milliliters
of diluting fluid A. Stopper the flask and proceed as directed in
paragraph (e)(1)(ii) of this section.
(ii) Test procedure. Aseptically filter the solution through a
bacteriological membrane filter. All air entering the filtering system
is filtered through air filters capable of removing microorganisms.
Filter three 100-milliliter quantities of diluting fluid A through the
membrane. For the penicillin and cephalosporin classes of antibiotics,
add sufficient penicillinase to diluting fluid A to inactivate the
residual antibiotic activity on the membrane after filtration. By means
of a sterile circular blade, paper punch, or any other suitable sterile
device, cut a circular portion (approximately 17.5 millimeters in
diameter) from the center of the filtering area. Transfer the cut
center area to a sterile 38 by 200 millimeter (outside dimensions) test
tube containing 90 10 milliliters of sterile medium A. Incubate the
tube for 7 days at 30 -32 C. Using sterile forceps, transfer the
remaining outer portion of the membrane into a second similar tube
containing 90 10 milliliters of medium E. Incubate the second tube for
7 days at 22 -25 C.
(2) Direct method. From each of 20 immediate containers, transfer
approximately 300 milligrams of solids if it is not a liquid drug, or 1
milliliter by volume if it is a liquid drug, or the entire contents if
it contains less than these amounts, except if it is a liquid drug
containing penicillin in a concentration greater than 300,000 units per
milliliter use that volume that contains 300,000 units, into individual
sterile test tubes (38 millimeters 200 millimeters) containing 90 10
milliliters of medium A. Incubate all tubes at 30 C. to 32 C. for 7
days. Gently agitate the tubes every 1 to 3 days or until complete
solubilization occurs. At intervals, examine all tubes for visible
growth. If growth is observed in any tube, confirm by microscopic
examination. From each of the same 20 immediate containers, transfer a
second portion (equivalent to that portion initially transferred to the
tubes containing medium A) to individual sterile test tubes (38
millimeters 200 millimeters) containing 90 10 milliliters of medium E,
except when each container does not have sufficient material to provide
for the two similar-size portions, obtain the second portion from 20
additional immediate containers. Incubate all tubes at 22 C. to 25
C. for 7 days. Gently agitate the tubes every 1 to 3 days or until
complete solubilization occurs. At intervals, examine all tubes for
visible growth. If growth is observed in any tube, confirm by
microscopic examination.
(3) Bacterial membrane filter method for ophthalmic ointments -- (i)
Ointments that do not contain penicillin. From each of 10 immediate
containers aseptically transfer 0.1 gram of the product into a sterile
250-milliliter flask containing 100 milliliters of diluting fluid E
which has previously been heated to a temperature of 47 C. Repeat the
process, using 10 additional containers. Swirl both of the flasks to
dissolve the ointment. Immediately aseptically filter each solution
through a separate bacteriological membrane filter previously moistened
with approximately 0.2 milliliter of medium K. Filter all air entering
the system through air filters capable of removing microorganisms.
Remove any residual antibiotic from the membranes by rinsing each filter
five times with 100 milliliters of medium K. The membranes should be
covered with fluid throughout each step of the filtration procedure
until the end of the last filtering step. By means of a sterile
circular blade, paper punch, or other suitable sterile device, cut a
circular portion (approximately 17.5 millimeters in diameter) from the
center of the filtering area of each membrane. Transfer the center
portion of the filtering area of each filter to a sterile test tube 38
millimeters 200 millimeters (outside dimensions) containing 90
milliliters 10 milliliters of sterile medium I. Incubate the tube for 7
days at 30 C. to 32 C. Using sterile forceps transfer the outer
portion of each filter to a similar test tube containing 90 milliliters
10 milliliters of sterile medium J. Incubate this tube for 7 days at 22
C. to 25 C.
(ii) Ointments containing penicillin. Proceed as directed in
paragraph (e)(3)(i) of this section, except in lieu of sterile medium I
use sterile medium L for the center portion of the filtering area of
each filter and in lieu of sterile medium J use sterile medium M for the
remaining outer portion of each filter.
(f) Evaluation of results -- (1) Bacterial membrane-filter method.
The batch, or the part of the batch represented by a particular filling
operation meets the requirements of the test if no sample tube shows
growth. If growth is observed in any sample tube, run a second test in
the appropriate medium, except perform it in duplicate, using 40
immediate containers. If in the original test, growth is observed in
only one of the two media, test both portions of the cut filter membrane
by placing each into a separate tube of the same medium. The batch
meets the requirements if no tube on the second test shows growth. If
growth is observed in any of the control tubes as well as in the sample
tubes in either the original or the second test such test is invalid and
must be performed again. In any event, further tests may be justified
if there is sufficient reason to believe that the results obtained in
the first and second tests may not be valid. In such instances, the
batch is satisfactory if on the final test no tube shows growth.
(2) Direct method. The batch, or the part of the batch represented
by a particular filling operation, meets the requirements of the test if
no tube shows growth after incubation. If growth is observed in any
sample tube, run a second test in the appropriate medium using 40
immediate containers. The batch is satisfactory if, on the second test,
no tube shows growth. If growth is observed in any of the control tubes
(except inoculated tubes, if the sample is penicillin) as well as in the
sample tubes in either the original or the second test, such test is
invalid and must be performed again. In any event, further tests may be
justified if there is sufficient reason to believe that the results
obtained on the first and second tests may not be valid. In such
instances the batch is satisfactory if in the final test no tube shows
growth.
(39 FR 18944, May 30, 1974, as amended at 41 FR 46852, Oct. 26, 1976;
42 FR 27228, May 27, 1977; 43 FR 43457, Sept. 26, 1978; 49 FR 25846,
June 25, 1984; 49 FR 40006, Oct. 12, 1984; 50 FR 48397, Nov. 25,
1985; 52 FR 4611, Feb. 13, 1987; 53 FR 13401, Apr. 25, 1988)
0041Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
21 CFR 436.20 Subpart C -- Biological Test Methods
21 CFR 436.31 Equipment and diluents for use in biological testing.
(a) Equipment -- (1) Temperature-measuring devices. Use an accurate
clinical thermometer or any other temperature-measuring device of equal
sensitivity that has been tested to determine the time necessary to
reach the maximum reading.
(2) Pyrogen-free glassware. Render all glassware free from pyrogens
by heating at 250 C. for not less than 30 minutes or by any other
suitable method.
(3) Pyrogen-free syringes and needles. Render all syringes and
needles free from pyrogens by heating at 250 C. for not less than 30
minutes or by any other suitable method.
(4) Pyrogen-free sodium chloride. Heat sodium chloride for not less
than 2 hours at 200 C.
(5) Pyrogen-free sodium carbonate. Heat anhydrous sodium carbonate
for not less than 4 hours at 170 C.
(b) Diluents. (1) Diluent 1 (pyrogen-free water): Prepare
pyrogen-free water by collecting freshly distilled water and sterilizing
it in an autoclave at 121 C. for not less than 20 minutes.
Pyrogen-free water meets the requirements for the absence of pyrogens as
described in 436.32(a)(3) when 10 milliliters per kilogram are
administered as described in 436.32(a)(2). In testing water for the
absence of pyrogens, the aliquot to be tested is made isotonic by the
addition of pyrogen-free sodium chloride.
(2) Diluent 2 (pyrogen-free saline solution): Prepare an isotonic
solution of sodium chloride by dissolving 9.0 grams of pyrogen-free
sodium chloride (prepared as described in 436.31(a)(4)) in
pyrogen-free, distilled water (diluent 1) to make 1,000 milliliters.
Sterilize in an autoclave at 121 C. for not less than 20 minutes.
Pyrogen-free saline solution meets the requirements for the absence of
pyrogens as described in 436.32(a)(3) when 10 milliliters per kilogram
are administered as described in 436.32(a)(2).
(3) Diluent 3 (sterile distilled water): Prepare freshly distilled
water. Sterilize in an autoclave at 121 C. for 20 minutes.
(4) Diluent 4 (sterile saline solution): Dissolve 9.0 grams of
sodium chloride in distilled water to make 1,000 milliliters. Sterilize
in an autoclave at 121 C. for 20 minutes.
(5) Diluent 5 (10 percent gum acacia): Dissolve 10 grams of gum
acacia in approximately 50 milliliters of distilled water. Allow to
stand overnight at room temperature and dilute to 100 milliliters with
distilled water. Filter through cotton. Store under refrigeration.
(6) Diluent 6 (0.5 percent gum acacia in distilled water).
(7) Diluent 7 (1.0N hydrochloric acid).
(8) Diluent 8 (0.1N hydrochloric acid).
(9) Diluent 9 (0.05N sodium hydroxide).
(10) Diluent 10 (1 percent U.S.P. methylcellulose (4,000 centipoises)
solution): Dissolve 1 gram of U.S.P. methylcellulose (4,000
centipoises) in 100 milliliters of distilled water. Allow to stand
overnight at room temperature or until solution is complete. Store
under refrigeration.
(11) Diluent 11 (0.12N sodium hydroxide).
(12) Diluent 12 (0.5 percent methylcellulose (4,000 centipoises) in
distilled water). Proceed as directed in paragraph (b)(10) of this
section, except use 0.5 gram of methylcellulose (4,000 centipoises).
(13) Diluent 13 (pyrogen-free sodium carbonate solution). Dissolve
25.6 grams of anhydrous pyrogen-free sodium carbonate (prepared as
described in paragraph (a)(5) of this section) in 1,000 milliliters
pyrogen-free, distilled water (diluent 1). Pyrogen-free, sodium
carbonate solution meets the requirements for the absence of pyrogens as
described in 436.32(a)(3) when 1.0 milliliter per kilogram is
administered as described in 436.32(a)(2).
(14) Diluent 14 (0.07M sterile sodium carbonate solution). Dissolve
7.3 grams of sodium carbonate in distilled water to make 1,000
milliliters. Sterilize in an autoclave at 121 C. for 20 minutes.
(15) Diluent 15 (pyrogen-free sodium carbonate solution): Dissolve
9.9 grams of anhydrous pyrogen-free sodium carbonate (prepared as
directed in paragraph (a)(5) of this section) in 1,000 milliliters of
pyrogen-free, distilled water (diluent 1). Pyrogen-free sodium
carbonate solution meets the requirements for the absence of pyrogens as
described in 436.32(a)(3) when 1.0 milliliter per kilogram is
administered as described in 436.32(a)(2).
(16) Diluent 16 (0.13M sterile pyrogen-free sodium carbonate
solution). Dissolve 14.0 grams of anhydrous pyrogen-free sodium
carbonate (prepared as described in paragraph (a)(5) of this section) in
1,000 milliliters pyrogen-free, distilled water. Sterilize in an
autoclave at 121 C for 20 minutes.
(39 FR 18944, May 30, 1974, as amended at 40 FR 51625, Nov. 6, 1975;
50 FR 48397, Nov. 25, 1985; 53 FR 13401, Apr. 25, 1988)
21 CFR 436.32 Pyrogen test.
(a) Method 1 -- (1) Test animal. Use healthy, mature rabbits
weighing not less than 1,800 grams each that have maintained their
weight on an antibiotic-free diet for at least 1 week under the
environmental conditions specified in this section. House the animals
individually in an area of uniform temperature ( 3 C.) and free from
disturbances likely to excite them. Do not use animals for pyrogen
tests more frequently than once every 48 hours or prior to 2 weeks
following their having been given a test sample that was adjudged
pyrogenic. Before using an animal that has not been used for a test
during the previous 2 weeks, condition it 1 to 3 days prior to pyrogen
testing by conducting a sham test as directed in paragraph (a)(2) of
this section, omitting the injection.
(2) Procedure. Using equipment and diluents described in 436.31, as
necessary, perform the test in an area where the animals are housed or
under similar environmental conditions. On the day of the test:
Withhold all food from the animals being used until after completion of
the test, except that access to water may be allowed; and determine the
''control temperature'' of each animal by inserting the
temperature-measuring device into the rectum of the test animal to a
depth of not less than 7.5 centimeters and allowing sufficient time to
reach a maximum temperature, as previously determined, before taking the
reading. In any one test use only those animals whose control
temperatures do not deviate by more than 1 C. from each other and do
not use any animal with a temperature exceeding 39.8 C. The control
temperature recorded for each rabbit constitutes the temperature from
which any subsequent rise following the injection of the material is
calculated. If the product is packaged for dispensing and is in a
combination package with a container of diluent, dilute the product as
directed in the labeling. Warm the product to be tested to
approximately 37 C. Dilute the sample with sterile, pyrogen-free
saline (prepared as described in 436.31(b)(2)) to the appropriate
concentration specified in the individual section for each antibiotic to
be tested. Inject a test dose of 1 milliliter of the diluted sample per
kilogram of rabbit weight into an ear vein of each of three rabbits
within 30 minutes subsequent to the control temperature reading. Record
the temperature at 1, 2, and 3 hours subsequent to the injection.
(3) Evaluation. If no rabbit shows an individual rise in temperature
of 0.6 C. or more above its respective control temperature, and if the
sum of the three temperature rises does not exceed 1.4 C., the sample
meets the requirements for the absence of pyrogens. If one or two
rabbits show a temperature rise of 0.6 C. or more, or if the sum of the
temperature rises exceeds 1.4 C., repeat the test using five other
rabbits. If not more than three of the eight rabbits show individual
rises in temperature of 0.6 C. or more, and if the sum of the eight
temperature rises does not exceed 3.7 C., the sample meets the
requirements for the absence of pyrogens.
(b) Method 2. Proceed as directed in paragraph (a) of this section,
except dilute the sample with pyrogen-free water (diluent 1).
(c) Method 3. Proceed as directed in paragraph (a) of this section,
except dilute the sample with pyrogen-free water (diluent 1) and inject
a test dose of 2.0 milliliters of the diluted sample per kilogram of
rabbit weight.
(d) Method 4. Proceed as directed in paragraph (a) of this section,
except inject a test dose of 0.5 milliliter of the diluted sample per
kilogram of rabbit weight.
(e) Method 5. Proceed as directed in paragraph (a) of this section,
except dilute the sample with pyrogen-free water (diluent 1) and inject
a test dose of 0.5 milliliter of the diluted sample per kilogram of
rabbit weight.
(f) Method 6. Proceed as directed in paragraph (a) of this section,
except dilute sample with 0.05N sodium hydroxide (diluent 9).
(g) Method 7. Proceed as directed in paragraph (a) of this section,
except dilute sample with sodium carbonate solution (diluent 13).
(h) Method 8. Proceed as directed in paragraph (a) of this section,
except inject a test dose of 2.0 milliliters of the diluted sample per
kilogram of rabbit weight.
(i) Method 9. Proceed as directed in paragraph (a) of this section,
except dilute sample with pyrogen-free sodium carbonate solution
(diluent 15).
(j) Method 10. Proceed as directed in paragraph (a) of this section,
except dilute the sample with sodium carbonate solution (diluent 16).
(39 FR 18944, May 30, 1974, as amended at 40 FR 51625, Nov. 6, 1975;
45 FR 22921, Apr. 4, 1980; 50 FR 48397, Nov. 25, 1985; 53 FR 13401,
Apr. 25, 1988)
21 CFR 436.35 Depressor substances test.
Proceed as directed in the USP XX depressor substances test. Prepare
the sample test solution as follows: For each antibiotic listed in the
table below, select the appropriate diluent and test dose (concentration
and volume). If the product is packaged for dispensing and is in a
combination package with a container of diluent, dilute the product as
directed in the labeling.
(46 FR 60568, Dec. 11, 1981, as amended at 46 FR 61071, Dec. 15,
1981; 49 FR 5096, Feb. 10, 1984)
21 CFR 436.35 Subpart D -- Microbiological Assay Methods
21 CFR 436.100 Laboratory equipment.
Equipment should be selected which is adequate for its intended use
and should be thoroughly cleansed after each use to remove any
antibiotic residues. The equipment should be kept covered when not in
use. Clean glassware intended for holding and transferring the test
organisms should be sterilized in a hot air oven at 200-220 C. for 2
hours. Volumetric flasks, pipettes, or accurately calibrated diluting
devices should be used when diluting standard and sample solutions.
(a) Microbiological agar diffusion assay -- (1) Cylinders. Use
stainless steel cylinders with an outside diameter of 8 millimeters (
0.1 millimeter), an inside diameter of 6 millimeters ( 0.1 millimeter),
and a length of 10 millimeters ( 0.1 millimeter).
(2) Plates. Plastic or glass Petri dishes may be used, having
dimensions of 20 by 100 millimeters. Covers should be of suitable
material.
(b) Microbiological turbidimetric assay -- (1) Tubes. Tubes which
give satisfactory results and have uniform length and diameter should be
used. If reusable tubes are employed, care must be taken to remove not
only all antibiotic residues from the previous test but also all traces
of cleaning solution.
(2) Colorimeter. Use a suitable photoelectric colorimeter at a
wavelength of 530 millimicrons. Set the instrument at zero absorbance
with clear, uninoculated broth prepared as described in the applicable
method for the antibiotic being assayed.
(39 FR 18944, May 30, 1974, as amended at 41 FR 34743, Aug. 17, 1976)
21 CFR 436.101 Solutions.
(a) Antibiotic assay solutions are prepared as follows (solution
numbers 1, 2, 3, 4, and 6 correspond to those used in ''Assay Methods of
Antibiotics,'' D. C. Grove and W. A. Randall, Medical Encyclopedia,
Inc., New York, N.Y. (1955), p. 222), which is incorporated by
reference. Copies are available from the Medical Encyclopedia Inc., 30
East 60th St., New York, NY 11220, or available for inspection at the
Office of the Federal Register, 1100 L St. NW., Washington, DC 20408.
(1) Solution 1 (1 percent potassium phosphate buffer, pH 6.0).
Dibasic potassium phosphate: 2.0 gm.
Monobasic potassium phosphate: 8.0 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 5.95 to 6.05 after sterilization.
(2) Solution 2 (citrate buffer solution pH 6.3).
Citric acid: 13.2 gm.
Sodium hydroxide: 7.06 gm.
Sodium citrate: 97.0 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 10 percent citric acid solution or 10N sodium hydroxide
to yield pH 6.2 to 6.4 after sterilization.
(3) Solution 3 (0.1M potassium phosphate buffer, pH 8.0).
Dibasic potassium phosphate: 16.73 gm.
Monobasic potassium phosphate: 0.523 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 7.9 to 8.1 after sterilization.
(4) Solution 4(0.1M potassium phosphate buffer, pH 4.5).
Monobasic potassium phosphate: 13.6 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 4.45 to 4.55 after sterilization.
(5) (Reserved)
(6) Solution 6 (10 percent potassium phosphate buffer, pH 6.0).
Dibasic potassium phosphate: 20.0 gm.
Monobasic potassium phosphate: 80.0 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 5.95 to 6.05 after sterilization.
(7) -- (9) (Reserved)
(10) Solution 10 (0.2M potassium phosphate buffer, pH 10.5).
Dibasic potassium phosphate: 35.0 gm.
10 N potassium hydroxide: 2.0 ml.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 10.4 to 10.6 after sterilization.
(11) Solution 11 (10 percent potassium phosphate buffer, pH 2.5).
Monobasic potassium phosphate: 100.0 gm.
Concentrated hydrochloric acid: 0.2 ml. (approximately).
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 2.0 to 2.8 after sterilization.
(12) Solution 12 (10 percent potassium phosphate buffer, pH 7.0).
Monobasic potassium phosphate: 100.0 gm.
Distilled water, q.s: 1,000.0 ml.
Adjust with 18N phosphoric acid or 10N potassium hydroxide to yield a
pH 6.95 to 7.05 after sterilization.
(13) Solution 13 (0.01N methanolic hydrochloric acid).
1.0N hydrochloric acid: 10.0 ml.
Methyl alcohol, q.s: 1,000.0 ml.
(14) Solution 14 (2 percent sodium bicarbonate solution).
Sodium bicarbonate: 20.0 gm.
Distilled water, q.s: 1,000.0 ml.
Prepare daily.
(15) Solution 15 (80 percent isopropyl alcohol solution).
Isopropyl alcohol: 800.0 ml.
Distilled water, q.s: 1,000.0 ml.
(16) Solution 16 (0.1 M potassium phosphate buffer, pH 7.0).
Dibasic potassium phosphate: 13.6 gm.
Monobasic potassium phosphate: 4.0 gm.
Distilled water, q.s.: 1,000.0 ml.
Adjust with 18 N phosphoric acid or 10 N potassium hydroxide to yield
a pH 6.8 to 7.2 after sterilization.
(17) Solution 17 (5 percent methyl alcohol in 1 percent potassium
phosphate buffer, pH 6.0).
Methyl alcohol: 50.0 ml.
1 percent potassium phosphate buffer, pH 6.0, q.s.: 1,000.0 ml.
(18) Solution 18 (0.054M sodium phosphate buffer, pH 6.9).
Sodium dihydrogen phosphate monohydrate: 3.97 gm.
Disodium hydrogen phosphate anhydrous: 3.55 gm.
Distilled water, q.s.: 1,000.0 mL.
(39 FR 18944, May 30, 1974, as amended at 40 FR 52004, Nov. 7, 1975;
45 FR 75194, Nov. 14, 1980; 47 FR 9396, Mar. 5, 1982)
21 CFR 436.102 Culture media.
(a) Ingredients. Use ingredients that conform to the standards, if
any, prescribed by the U.S.P. or N.F. In lieu of preparing the media
from the individual ingredients specified, they may be made from
dehydrated mixtures that, when reconstituted with distilled water, have
the same composition as such media. Minor modifications of the
individual ingredients specified in this section are permissible if the
resulting media possess growth-promoting properties at least equal to
the media described.
(b) Description of media. Medium numbers 1, 2, 3, 4, 5, 8, 9, 10,
11, and 13 correspond to those used in ''Assay Methods of Antibiotics,''
D. C. Grove and W. A. Randall, Medical Encyclopedia, Inc., New York,
N.Y. (1955) p. 220, which is incorporated by reference. Copies are
available from Medical Encyclopedia Inc., 30 East 60th St., New York,
NY, or available for inspection at the Office of the Federal Register,
1100 L St. NW., Washington, DC 20408. Medium numbers 18 through 21
correspond to those used in ''Outline of Details for Official
Microbiological Assays of Antibiotics,'' A. Kirshbaum and B. Arret,
''Journal of Pharmaceutical Sciences,'' vol. 56, No. 4, April 1967, p.
512, which is incorporated by reference. Copies are available from the
American Pharmaceutical Association, 2215 Constitution Ave. NW.,
Washington, DC 20037, or available for inspection at the Office of the
Federal Register (see address in this paragraph).
(1) Medium 1.
Peptone: 6.0 gm.
Pancreatic digest of casein: 4.0 gm.
Yeast extract: 3.0 gm.
Beef extract: 1.5 gm.
Dextrose: 1.0 gm.
Agar: 15.0 gm.
Distilled water, q.s: 1,000.0 ml.
pH 6.5 to 6.6 after sterilization.
(2) Medium 2.
Peptone: 6.0 gm.
Yeast extract: 3.0 gm.
Beef extract: 1.5 gm.
Agar: 15.0 gm.
Distilled water, q.s: 1,000.0 ml.
pH 6.5 to 6.6 after sterilization.
(3) Medium 3.
Peptone: 5.0 gm.
Yeast extract: 1.5 gm.
Beef extract: 1.5 gm.
Sodium chloride: 3.5 gm.
Dextrose: 1.0 gm.
Dipotassium phosphate: 3.68 gm.
Potassium dihydrogen phosphate: 1.32 gm.
Distilled water, q.s: 1,000.0 ml.
pH 6.95 to 7.05 after sterilization.
(4) Medium 4.
Peptone: 6.0 gm.
Yeast extract: 3.0 gm.
Beef extract: 1.5 gm.
Dextrose: 1.0 gm.
Agar: 15.0 gm.
Distilled water, q.s: 1,000.0 ml.
pH 6.5 to 6.6 after sterilization.
(5) Medium 5. Medium 5 is the same as medium 2, except adjust the
final pH to 7.8 to 8.0 after sterilization.
(6) -- (7) (Reserved)
(8) Medium 8. Medium 8 is the same as medium 2, except adjust the
final pH to 5.8 to 6.0 after sterilization.
(9) Medium 9.
Pancreatic digest of casein: 17.0 gm.
Papaic digest of soybean: 3.0 gm.
Sodium chloride: 5.0 gm.
Dipotassium phosphate: 2.5 gm.
Dextrose: 2.5 gm.
Agar: 20.0 gm.
Distilled water, q.s: 1,000.0 ml.
pH 7.2 to 7.3 after sterilization.
(10) Medium 10. Medium 10 is the same as medium 9, except:
Agar: 12.0 gm.
Polysorbate 80 (add polysorbate 80 after boiling the medium to
dissolve the agar): 10.0 ml.
pH 7.2 to 7.3 after sterilization.
(11) Medium 11. Medium 11 is the same as medium 1, except adjust the
final pH to 7.8 to 8.0 after sterilization.
(12) (Reserved)
(13) Medium 13.
Peptone: 10.0 gm.
Dextrose: 20.0 gm.
Distilled water, q.s: 1,000.0 ml.
pH 5.6 to 5.7 after sterilization.
(14) -- (18) (Reserved)
(19) Medium 19.
Peptone: 9.4 gm.
Yeast extract: 4.7 gm.
Beef extract: 2.4 gm.
Sodium chloride: 10.0 gm.
Dextrose: 10.0 gm.
Agar: 23.5 gm.
Distilled water, q.s: 1,000.0 ml.
pH 6.0 to 6.2 after sterilization.
(20) -- (31) (Reserved)
(32) Medium 32. Prepare as medium 1, except add 300 milligrams of
hydrated manganese sulfate (MnSO4 H2O) to each liter of medium.
(33) Medium 33. Use medium 1, sterilized and cooled to 50 C.
Aseptically add sufficient sterile sodium novobiocin solution to give a
final concentration of 10 micrograms of novobiocin activity per
milliliter of medium. Sterile sodium novobiocin solution is prepared by
filtering a solution containing 2.5 milligrams of novobiocin per
milliliter of distilled water through a membrane filter of 0.22-micron
porosity.
(34) Medium 34.
Glycerol: 10.0 gm.
Peptone: 10.0 gm.
Beef extract: 10.0 gm.
Sodium chloride: 3.0 gm.
Distilled water, q.s.: 1,000.0 ml.
pH 7.0 after sterilization.
(35) Medium 35. Same as medium 34, except add 17.0 grams of agar to
each liter of medium.
(36) Medium 36.
(37) Medium 37.
Pancreatic digest of casein: 17.0 gm.
Soybean peptone: 3.0 gm.
Dextrose: 2.5 gm.
Sodium chloride: 5.0 gm.
Dipotassium phosphate: 2.5 gm.
Distilled water, q.s.: 1,000.0 ml.
pH 7.3 after sterilization.
(38) Medium 38.
Peptone: 15.0 gm.
Papaic digest of soybean meal: 5.0 gm.
Sodium chloride: 4.0 gm.
Sodium sulfite: 0.2 gm.
L-cystine: 0.7 gm.
Dextrose: 5.5 gm.
Agar: 15.0 gm.
Distilled water, q.s.: 1,000.0 ml.
pH 7.0 after sterilization.
(39 FR 18944, May 30, 1974, as amended at 40 FR 52004, Nov. 7, 1975;
42 FR 14092, Mar. 15, 1977; 47 FR 9396, Mar. 5, 1982; 47 FR 22514, May
25, 1982)
21 CFR 436.103 Test organisms.
(a) Preparation of test organism suspensions. For each test organism
listed in the following table, select the media (as listed by medium
number in 436.102(b)), incubation period of the Roux bottle, suggested
dilution factor, and suggested storage period for the particular test
organism and proceed by the appropriate method described in paragraph
(b) of this section. Test organism letters A through K, M, and N
correspond to those used in ''Outline of Details for Official
Microbiological Assays of Antibiotics,'' A. Kirshbaum and B. Arret,
''Journal of Pharmaceutical Sciences,'' Vol. 56, No. 4, p. 512 (April
1967), which is incorporated by reference. Copies are available from
the American Pharmaceutical Association, 2215 Constitution Ave. NW.,
Washington, DC 20037, or available for inspection at the Office of the
Federal Register, 1100 L St. NW., Washington, DC 20408.
(b) Methods for preparation of test organism suspensions -- (1)
Method 1 -- (i) Preparation of suspension. Maintain organisms on agar
slants containing 10 milliliters of the appropriate medium. Incubate
the slants at 32 C.-35 C. for 24 hours. Using 3 milliliters of
sterile U.S.P. saline T.S., wash the growth from the agar slant onto a
large agar surface, such as a Roux bottle, containing 250 milliliters of
the appropriate medium. Spread the suspension of organisms over the
entire surface of the Roux bottle with the aid of sterile glass beads.
Incubate the Roux bottle at 32 C.-35 C. Wash the resulting growth from
the agar surface with 50 milliliters of sterile U.S.P. saline T.S.
(ii) Standardization of suspension. Determine the dilution factor
that will give a 25-percent light transmission at a wavelength of 580
millimicrons using a suitable photoelectric colorimeter and a
13-millimeter diameter test tube as an absorption cell. It may be
necessary to adjust the suspension. Determine the amount of suspension
to be added to each 100 milliliters of agar or nutrient broth by the use
of test plates or test broth. Store the test organism suspension under
refrigeration.
(2) Method 2. Proceed as directed in paragraph (b)(1) of this
section, except in lieu of paragraph (b)(1)(ii) thereof, heat-shock and
standardize the suspension as follows: Centrifuge and decant the
supernatant liquid. Resuspend the sediment with 50 to 70 milliliters of
sterile U.S.P. saline T.S. and heat the suspension for 30 minutes at 70
C. Use test plates to assure the viability of the spores and to
determine the amount of spore suspension to be added to each 100
milliliters of agar. Maintain the spore suspension under refrigeration.
(3) Method 3. Proceed as directed in paragraph (b)(1) of this
section, except in lieu of paragraph (b)(1)(ii) thereof, heat-shock and
standardize the suspension as follows: Heat the suspension for 30
minutes at 70 C. Wash the spore suspension three times with 25 to 50
milliliters of sterile distilled water. Resuspend the organisms in 50
to 70 milliliters of sterile distilled water and heat-shock again for 30
minutes at 70 C. Use test plates to assure the viability of the spores
and to determine the amount of spore suspension to be added to each 100
milliliters of agar. Maintain the spore suspension under refrigeration.
(4) (Reserved)
(5) Method 5. Maintain the test organisms in 100-milliliter
quantities of nutrient broth -- Medium 3 as described in 436.102(b)(3).
For the test prepare a fresh subculture by transferring a loopful of the
stock culture to 100 milliliters of the same nutrient broth and incubate
for 16 to 18 hours at 37 C. Store this broth culture under
refrigeration.
(6) Method 6. Maintain the test organisms on agar slants containing
10 milliliters of the medium specified in paragraph (a) of this section.
Incubate the slants at 32 C.-35 C. for 24 hours. Inoculate 100
milliliters of nutrient broth -- Medium 13 as described in
436.102(b)(13). Incubate for 16 to 18 hours at 37 C. Proceed as
directed in paragraph (b)(1)(ii) of this section.
(7) Method 7. Proceed as directed in paragraph (b)(1) of this
section, except incubate the slants at 30 C. for 24 hours and incubate
the Roux bottle at 30 C. for 48 hours.
(8) Method 8. Maintain organisms on agar slants containing 10
milliliters of the appropriate medium and transfer to a fresh slant
about once a week. Incubate the slants at 37 C for 48 hours. Using 3
milliliters of sterile U.S.P. saline T.S., wash the growth from the agar
slant into a 500-milliliter Erlenmeyer flask containing 100 milliliters
of medium 34, as described in 436.102(b) (34), and 50 grams of glass
beads. Agitate the culture by rotation at a speed of 130 cycles per
minute and a radius of 3.5 centimeters at 27 C for 5 days. Determine
the amount of suspension to be added to each 100 milliliters of agar by
the use of test plates. Store the test organism suspension under
refrigeration.
(9) Method 9. Proceed as directed in paragraph (b)(1) of this
section, except incubate the slant and Roux bottle at 37 C and wash the
resulting growth from the agar surface with 50 milliliters of Medium 37
as described in 436.102(b)(37).
(39 FR 18944, May 30, 1974, as amended at 40 FR 52004, Nov. 7, 1975;
42 FR 14092, Mar. 15, 1977; 42 FR 18058, Apr. 5, 1977; 44 FR 10378,
Feb. 20, 1979; 47 FR 22514, May 25, 1982; 47 FR 27552, June 25, 1982)
21 CFR 436.104 Penicillin activity.
Use penicillin-free equipment and glassware.
(a) Preparation of inoculated plates. Proceed as directed in
436.105(a), using 10 milliliters of medium 1 for the base layer. For
the seed layer, use 4 milliliters of medium 4, inoculated with the
amount of test organism C which gave the clearest, sharpest zones of
inhibition measuring 17 to 21 millimeters in diameter when standardized
as described in 436.103(b)(1)(ii). Use the plates the same day they are
prepared.
(b) Preparation of working standard stock solutions and standard
response lines solutions. Proceed as directed for penicillin G in
436.105(b), except dilute the working standard stock solution to a final
concentration of 100 units of penicillin G per milliliter and use the
following final concentrations for the standard response line: 0.005,
0.0125, 0.025, 0.050, 0.100, and 0.200 unit of penicillin G per
milliliter. The 0.050 unit of penicillin G-per-milliliter solution is
the reference concentration of the assay.
(c) Sample preparation. Dissolve 1.0 gram of the sample in
sufficient distilled water to make 18 milliliters. Filter if not clear.
Transfer 9.0 milliliters to a separatory funnel, and add 20 milliliters
of amyl acetate. Add 1 milliliter of 10 percent potassium phosphate
buffer, pH 2.5 (solution 11 as described in 436.101), shake, allow to
separate, and draw off the aqueous layer into a second separatory
funnel. Check the pH of the aqueous solution with pH paper, and
readjust with concentrated hydrochloric acid if the pH is three or
above. Extract again with 20 milliliters or amyl acetate, discard the
aqueous phase, and combine the amyl acetate extracts. Wash the extracts
with 10 milliliters of 1 percent potassium phosphate buffer, pH 2.5, and
discard the buffer wash. Extract the penicillin from the amyl acetate
with a 10-milliliter aliquot of 1 percent potassium phosphate buffer, pH
6.0 (solution 1 as described in 436.101). This is the assay solution.
(d) Procedure for assay. For the standard response line, use a total
of 15 plates (three plates for each response line solution, except the
reference concentration solution, which is included on each plate). On
each set of three plates, fill three alternate cylinders with the
reference concentration solution and the other three cylinders with the
concentration of the response line under test. Thus, there will be 45
reference concentration zones of inhibition and nine zones of inhibition
for each of the other concentrations of the response line. Treat a
portion of the sample solution (2 to 5 milliliters) with 0.1 milliliter
of penicillinase solution and incubate at 37 C. for 1 hour. For each
sample tested, use three plates. On each plate fill two cylinders with
the 0.050 unit of penicillin G per milliliter standard, two cylinders
with the untreated sample, and two cylinders with the
penicillinase-treated sample. Incubate all plates, including those of
the standard response line, overnight at 30 C. A zone of inhibition
with the untreated sample and no zone with the penicillinase-treated
sample are a positive test for penicillin. If a positive test is
obtained, measure the diameters of the zones of inhibition using an
appropriate measuring device such as a millimeter rule, calipers, or an
optical projector.
(e) Estimation of penicillin G activity. To prepare the standard
response line, average the diameters of the standard reference
concentration and average the diameters of the standard response line
concentration tested for each set of three plates. Average also all 45
diameters of the reference concentration. The average of the 45
diameters of the reference concentration is the correction point of the
response line. Correct the average diameter obtained for each
concentration to the figure it would be if the average reference
concentration diameter for that set of three plates were the same as the
correction point. Thus, if in correcting the 0.025 penicillin G
concentration, the average of the 45 readings of the 0.050 unit of
penicillin G-per-milliliter concentration is 18.5 millimeters and the
average of the 0.050 unit of pencillin G-per milliliter concentration of
this set of three plates is 18.3 millimeters, the correction is +0.2
millimeters. If the average reading of the 0.025 unit of pencillin
G-per-milliliter concentration of these same three plates is 15.5
millimeters, the corrected value is 15.7 millimeters. Plot these
corrected values, including the average of the 0.050 unit of penicillin
G-per-milliliter concentration, on semilogarithmic graph paper using the
pencillin concentration in units per milliliter on the logarithmic scale
and the diameter of the zone of inhibition on the arithmetic scale.
Draw the line of best fit through these points. To estimate the sample
potency, average the zone diameters of the standard and the zone
diameters of the sample on the three plates used. If the average zone
diameter of the sample is lower than that of the standard, subtract the
difference between them from the reference concentration diameter of the
standard response line. From the response line, read the concentrations
corresponding to these corrected values of zone diameters. Multiply the
concentration by the dilution factor to obtain the units of penicillin G
per sample size tested.
(39 FR 18944, May 30, 1974, as amended at 41 FR 34743, Apr. 17, 1976)
21 CFR 436.105 Microbiological agar diffusion assay.
Using the sample solution prepared as described in the section for
the particular antibiotic to be tested, proceed as described in
paragraphs (a), (b), (c), and (d) of this section.
(a) Preparation of inoculated plates. For each antibiotic listed in
the table in this paragraph, select the media (as listed by medium
number in 436.102(b)), the amount of media to be used in the base and
seed layers, the test organism (as listed in 436.103(a)), and the
suggested inoculum and prepare the inoculated plates as follows:
Prepare the base layer by adding the appropriate amount of melted agar
to each Petri dish (nominal dimensions 20 by 100 millimeters).
Distribute the agar evenly in each dish on a flat, level surface,
placing a cover on each plate in turn; if a nonporous cover is used,
leave it slightly ajar to prevent accumulation of condensed moisture
from the hot agar base layer. After the agar hardens, seat the
nonporous cover on each plate. To prepare the seed layer, add the
suggested inoculum of the test organism suspension to a sufficient
amount of agar, which has been melted and cooled to 48 C-50 C. Swirl
the flask to obtain a homogeneous suspension, and add the appropriate
amount of the inoculated media to each of the plates containing the
uninoculated base agar. Spread evenly over the agar surface, cover, and
allow to harden on a flat, level surface. After the agar has hardened,
place 6 cylinders described in 436.100(a)(1) on the inoculated agar
surface so that they are at approximately 60 intervals on a 2.8 --
centimeter radius.
(b) Preparation of working standard stock solutions and standard
response line solutions. For each antibiotic listed in the table in
this paragraph, select the working standard drying conditions,
solvent(s), concentrations, and storage time for the standard solutions
and proceed as follows: If necessary, dry the working standard as
described in 436.200; dissolve and dilute an accurately weighed
portion to the proper concentration to prepare the working standard
stock solution. Store the working standard stock solution under
refrigeration and do not use longer than the recommended storage time.
Further dilute an aliquot of the working standard stock solution to the
proper concentrations to prepare the standard response line solutions.
The reference concentration of the assay is the mid concentration of the
response line.
(c) Procedure for assay. For the standard response line, use a total
of 12 plates -- three plates for each response line solution, except the
reference concentration solution which is included on each plate. On
each set of three plates, fill three alternate cylinders with the
reference concentration solution and the other three cylinders with the
concentration of the response line under test. Thus, there will be 36
reference concentration zones of inhibition and nine zones of inhibition
for each of the four other concentrations of the response line. For
each sample tested use three plates. Fill three alternate cylinders on
each plate with the standard reference concentration solution and the
other three cylinders with the sample reference concentration solution.
After all the plates have incubated for 16 to 18 hours at the
appropriate incubation temperature for each antibiotic listed in the
table in paragraph (b) of this section, measure the diameters of the
zones of inhibition using an appropriate measuring device such as a
millimeter rule, calipers, or an optical projector.
(d) Estimation of potency. To prepare the standard response line,
average the diameters of the standard reference concentration and
average the diameters of the standard response line concentration tested
for each set of three plates. Average also all 36 diameters of the
reference concentration for all four sets of plates. The average of the
36 diameters of the reference concentration is the correction point of
the response line. Correct the average diameter obtained for each
concentration to the figure it would be if the average reference
concentration diameter for that set of three plates were the same as the
correction point. Thus, if in correcting the highest concentration of
the response line, the average of the 36 diameters of the reference
concentration is 16.5 millimeters and the average of the reference
concentration of the set of three plates (the set containing the highest
concentration of the response line) is 16.3 millimeters, the correction
is +0.2 millimeter. If the average reading of the highest concentration
of the response line of these same three plates is 16.9 millimeters, the
corrected diameter is then 17.1 millimeters. Plot these corrected
diameters, including the average of the 36 diameters of the reference
concentration on 2-cycle semilog paper, using the concentration of the
antibotic in micrograms or units per milliliter as the ordinate (the
logarithmic scale), and the diameter of the zone of inhibition as the
abscissa. The response line is drawn either through these points by
inspection or through points plotted for highest and lowest zone
diameters obtained by means of the following equation:
where:
L=Calculated zone diameter for the lowest concentration of the
standard response line;
H=Calculated zone diameter for the highest concentration of the
standard response line;
c=Average zone diameter of 36 readings of the reference point
standard solution;
a, b, d, e=Corrected average values for the other standard solutions,
lowest to highest concentration, respectively.
To estimate the potency of the sample, average the zone diameters of
the standard and the zone diameters of the sample on the three plates
used. If the average zone diameter of the sample is larger than that of
the standard, add the difference between them to the reference
concentration diameter of the standard response line. If the average
zone diameter of the sample is lower than that of the standard, subtract
the difference between them from the reference concentration diameter of
the standard response line. From the response line, read the
concentrations corresponding to these corrected values of zone
diameters. Multiply the concentration by the appropriate dilution
factor to obtain the antibiotic content of the sample.
(39 FR 18944, May 30, 1974)
Editorial Note: For Federal Register citations affecting 436.105,
see the List of CFR Sections Affected appearing in the Finding Aids
section of this volume.
21 CFR 436.106 Microbiological turbidimetric assay.
Using the sample solution prepared as described in the section for
the particular antibiotic to be tested, proceed as described in
paragraphs (a), (b), and (c) of this section.
(a) Preparation of working standard stock solutions and standard
response line solutions. For each antibiotic listed in the table in
this paragraph, select the working standard, drying conditions,
solvent(s), concentrations, and storage time for the standard solutions
and proceed as follows: If necessary, dry the working standard as
described in 436.200; dissolve and dilute an accurately weighed
portion to the proper concentration for the working standard stock
solution. Store the working standard stock solution under refrigeration
and do not use longer than the recommended storage time. Prepare the
proper concentrations for the standard response line solutions by
further diluting an aliquot of the working standard stock solution. The
reference concentration of the assay is the mid concentration of the
standard response line.
(b) Procedure for assay. For each antibiotic listed in the table in
this paragraph, select the test organism (as listed in 436.103(a)),
nutrient broth (as listed by medium number in 436.102(b)), and
suggested inoculum and proceed as follows: Place 1.0 milliliter (or 0.1
milliliter in the case of gramicidin and tyrothricin) of each
concentration of the standard response line (prepare as described in
paragraph (a) of this section) and of the sample solution in each set of
three replicate tubes (as described in 436.100(b)(1)). Fifteen tubes
are used for the five-point standard response line and three for each
sample. To each tube add 9 milliliters of the inoculated broth and
place immediately in a water bath at the appropriate temperature for 2
to 4 hours. The exact length of the incubation period should be
determined by observation of growth in the reference concentration tube
of the standard. Remove the tubes from the water bath and add 0.5
milliliter of a 12-percent formaldehyde solution to each tube.
Determine the absorbance value of each tube in a suitable photoelectric
colorimeter, at a wavelength of 530 millimicrons. Set the instrument at
zero absorbance with an uninoculated blank composed of the same amounts
of nutrient broth and formaldehyde used in the assay.
Note: The amount of working standard and sample solutions may be
reduced as long as all other solutions used are reduced proportionately.
where:
L=Calculated absorbance value for the lowest concentration of the
standard response line.
H=Calculated absorbance value for the highest concentration of the
standard response line.
a, b, c, d, e=Average absorbance values for each concentration of the
standard response line, lowest to the highest, respectively.
(c) Estimation of potency. To prepare the standard response line,
plot the average absorbance values for each concentration of the
standard response line on one-cycle semilogarithmic graph paper with the
absorbance values on the arithmetric scale and concentrations on the
logarithmic scale. The response line is drawn either through these
points by inspection or through points plotted for highest and lowest
absorbance values obtained by means of the following equations.
To estimate the potency of the sample, average the absorbance values
for the sample and determine the antibiotic concentration from the
standard response line. Multiply the concentration by the appropriate
dilution factor to obtain the antibiotic content of the sample.
(39 FR 18944, May 30, 1974, as amended at 40 FR 57797, Dec. 12, 1975;
41 FR 49483, Nov. 9, 1976; 44 FR 22057, Apr. 13, 1979; 46 FR 3835,
3839, Jan. 16, 1981; 46 FR 16682, Mar. 13, 1981; 46 FR 33512, June 30,
1981; 46 FR 61072, Dec. 15, 1981; 47 FR 22515, May 25, 1982; 47 FR
23708, June 1, 1982; 48 FR 3960, Jan. 28, 1983; 53 FR 32607, Aug. 26,
1988)
21 CFR 436.106 Subpart E -- General Chemical Tests for Antibiotics
21 CFR 436.200 Loss on drying.
Use the method specified in the individual section for each
antibiotic.
(a) Method 1. In an atmosphere of about 10 percent relative
humidity, grind the sample, if necessary, to obtain a fine powder. When
tablets, troches, or capsules are to be tested, use four tablets,
troches, or capsules in preparing the sample. Transfer about 100
milligrams of the sample to a tared weighing bottle equipped with a
ground-glass stopper. Weigh the bottle and place it in a vacuum oven,
tilting the stopper on its side so that there is no closure during the
drying period. Dry at a temperature of 60 C. and a pressure of 5
millimeters of mercury or less for 3 hours. At the end of the drying
period, fill the vacuum oven with air dried by passing it through a
drying agent such as sulfuric acid or silica gel. Replace the stopper
and place the weighing bottle in a desiccator over a desiccating agent,
such as phosphorous pentoxide or silica gel, allow to cool to room
temperature, and reweigh. Calculate the percent of loss.
(b) Method 2. Proceed as directed in paragraph (a) of this section,
except use a tared weighing bottle or weighing tube equipped with a
capillary-tube stopper, the capillary having an inside diameter of
0.20-0.25 millimeter, and place it in a vacuum oven without removing the
stopper.
(c) Method 3. Proceed as directed in paragraph (a) of this section,
except dry the sample at a temperature of 110 C. and a pressure of 5
millimeters of mercury or less for 3 hours.
(d) Method 4. Proceed as directed in paragraph (a) of this section,
except dry the sample at a temperature of 40 C. and a pressure of 5
millimeters of mercury or less for 2 hours.
(e) Method 5. Proceed as directed in paragraph (a) of this section,
except dry the sample at a temperature of 100 C. and a pressure of 5
millimeters of mercury or less for 4 hours.
(f) Method 6. Proceed as directed in paragraph (a) of this section,
except dry the sample at a temperature of 40 C. and a pressure of 5
millimeters of mercury or less for 3 hours.
(g) Method 7. Proceed as directed in paragraph (a) of this section,
except dry the sample at a temperature of 25 C. and a pressure of 5
millimeters of mercury or less for 4 hours.
(h) Method 8. Proceed as directed in paragraph (a) of this section,
except transfer approximately 300 milligrams of the sample to a tared
weighing bottle equipped with a ground-glass stopper; dry the sample at
a temperature of 25 C and a pressure of 5 millimeters of mercury or
less for 4 hours, and then dry the sample at a temperature of 100 C and
a pressure of 5 millimeters of mercury or less for 3 additional hours.
(i) Method 9. Use a suitable thermogravimetric apparatus prepared
for vacuum operation. Rapidly and thoroughly grind a portion of the
sample and promptly transfer 5 to 10 milligrams to the sample pan.
Place the system under vacuum and allow it to come to equilibrium before
heating. Obtain an accurate sample weight and continuously record the
weight loss as the sample is heated at a rate of 20 per minute from
room temperature to about 200 C. The weight loss plateau, or
inflection, at about 150 C is taken as the total volatile weight loss.
Calculate the percent weight loss on drying.
(39 FR 18944, May 30, 1974, as amended at 50 FR 48397, Nov. 25, 1985;
51 FR 11572, Apr. 4, 1986)
21 CFR 436.201 Moisture determination.
(a) Equipment -- (1) Apparatus. Use a closed system consisting of
all glass automatic burettes, platinum electrodes, and a magnetic
stirrer connected to a suitable electrometric apparatus. This apparatus
embodies a simple electrical circuit which serves to pass 5 to 10
microamperes of direct current between a pair of platinum electrodes
immersed in the solution to be titrated. At the endpoint of the
titration a slight excess of the reagent increases the flow of current
to between 50 and 150 microamperes for 30 seconds or longer, depending
upon the solution being titrated.
(2) Titrating vessel. Use a suitable titrating vessel which has been
previously dried at 105 C. and cooled in a desiccator.
(b) Reagents -- (1) Karl Fischer reagent. Dissolve 125 grams of
iodine in 170 milliliters of pyridine, add 670 milliliters of methanol
and cool. To 100 milliliters of pyridine kept in an ice bath, add
sulfur dioxide until the volume reaches 200 milliliters. Slowly add
this solution to the cooled iodine-methanol-pyridine mixture and shake
well. (A commercially prepared Karl Fischer reagent, pyridine
containing or pyridine-free, may be used.) Preserve the reagent in
glass-stoppered bottles protected from light and from moisture in the
air.
(2) Methanol solution. Add sufficient water (usually 2 milligrams
per milliliter) to methanol so that each milliliter of the resulting
methanol solution is equivalent to about 0.5 milliliter of Karl Fischer
reagent.
(3) Solvents -- (i) Solvent A. Methanol:chloroform:carbon
tetrachloride (1:2:2 by volume).
(ii) Solvent B. Chloroform:carbon tetrachloride (1:1 by volume).
(iii) Solvent C. Anhydrous methanol.
(c) Standardization of reagents -- (1) Water equivalence of Karl
Fischer reagent. Standardize the Karl Fischer reagent no longer than 1
hour before use by one of the following methods.
(i) Accurately weigh 25-35 milligrams of water into a dry titration
vessel and add 20 milliliters of solvent A. Start the stirrer and
titrate to the endpoint by adding measured quantities of Karl Fischer
reagent. Calculate the water equivalence of the Karl Fischer reagent as
follows:
where:
e=Water equivalence of the Karl Fischer reagent in terms of
milligrams of water per milliliter;
W=Milligrams of water; VT=Milliliters of Karl Fischer reagent
used; VA=Milliliters of Karl Fischer reagent equivalent to the 20
milliliters of solvent A, determined as directed in paragraph (c)(3) of
this section.
(ii) Accurately weigh about 25-35 milligrams of water into a dry
titration vessel, add an excess of Karl Fischer reagent, start the
stirrer, and titrate to the endpoint with methanol solution. Calculate
the water equivalence of the Karl Fischer reagent as follows:
where:
e=Water equivalence of the Karl Fischer reagent in terms of
milligrams of water per milliliter;
W=Milligrams of water; VT=Milliliters of Karl Fischer reagent
used; Vm=Milliliters of methanol solution used; f=Milliliters of
Karl Fischer reagent equivalent to each
milliliter of methanol solution determined as directed in paragraph
(c)(2) of this section.
(2) Karl Fischer reagent equivalence of methanol solution. Titrate a
known volume of Karl Fischer reagent with methanol solution until the
endpoint is reached. Calculate the milliliters of Karl Fischer reagent
equivalent to each milliliter of methanol solution as follows:
where:
f=Milliliters of Karl Fischer reagent equivalent to each
milliliter of methanol solution;
VT=Milliliters of Karl Fischer reagent used; Vm=Milliliters of
methanol solution used.
(3) Karl Fischer reagent equivalence of solvents. (i) Solvent A:
Use 20 milliliters of solvent A as the sample. Start the stirrer and
titrate to the endpoint by adding measured quantities of Karl Fischer
reagent.
(ii) Solvent B: Use 10 milliliters of solvent B as the sample. Add
an excess of Karl Fischer reagent to the sample and start the stirrer.
Titrate to the endpoint with methanol solution.
(iii) Solvent C. Use 20 milliliters of solvent C as the sample.
Start the stirrer and titrate to the endpoint by adding measured
quantities of Karl Fischer reagent.
(iv) Calculate the Karl Fischer reagent equivalence of the solvents
as follows:
VA=VC=VT,
VB=(VT^Vm) X f
where:
VA,VB, and VC=Milliliters of Karl Fischer reagent equivalent to
the aliquots used of solvents A, B, and C, respectively;
VT=Milliliters of Karl Fischer reagent used; Vm=Milliliters of
methanol solution used; f=Milliliters of Karl Fischer reagent
equivalent to each
milliliter of methanol solution determined as directed in paragraph
(c)(2) of this section.
(d) Sample preparation -- (1) Powders. In the case of tablets, grind
4 tablets to a fine powder. In the case of capsules containing
enteric-coated pellets, grind the pellets to a fine power. If the
maximum moisture limit is greater than 1 percent, accurately weigh about
300 milligrams of the sample into a dry titrating vessel. If the
maximum moisture limit is less than 1 percent, accurately weigh 1 to 2
grams of the sample. Proceed as directed in paragraph (e)(1) or (2) of
this section.
(2) Ointments and oils. (i) Transfer about 1 to 2 grams, accurately
weighed, into a dry titrating vessel. Proceed as directed in paragraph
(e)(1) of this section; or
(ii) Transfer about 1 to 2 grams, accurately weighed, into a dry
titrating vessel. Add 10 milliliters of solvent B and proceed as
directed in paragraph (e)(2) of this section.
(3) Aerosols with propellant. Place the immediate container to be
tested in a suitable freezing unit having a temperature of not higher
than 0 C. for at least 2 hours. Remove the container from the
freezing unit, puncture it, mix the entire contents by swirling.
Proceed as directed in paragraph (e)(3) of this section, using an
accurately measured 10-milliliter aliquot from the container as the
sample and allowing the solution to warm to at least 10 C. before
determining the endpoint.
(4) Hygroscopic powders. Weigh the immediate container. Using a
suitable dry hypodermic needle and syringe, inject 3 milliliters of
anhydrous methanol into the container and shake to dissolve the
contents. Using the same syringe, remove the withdrawable contents and
transfer into the titration vessel. Rinse the syringe and needle by
drawing in an additional 3 milliliters of anhydrous methanol. Add the
rinsings to the titration vessel. Titrate the solution immediately,
proceeding as directed in paragraph (e)(3) of this section. Determine
the Karl Fischer equivalent (in milliliters), if any, of the anhydrous
methanol by titrating a blank of the same total volume used in preparing
the sample and rinsing the syringe and needle. Dry the immediate
container and its closure for three hours at 100 C., cool to room
temperature in a desiccator, and weigh. Determine the weight of sample
tested by subtracting the weight obtained from the original weight of
the immediate container.
(5) Solutions. Proceed as directed in paragraph (e)(3) of this
section, using about 1 to 2 grams of the sample, accurately weighted.
(e) Titration procedures and calculations -- (1) Procedure 1. Add 20
milliliters of solvent A to the sample. Start the stirrer and titrate
to the endpoint by adding measured quantities of Karl Fischer reagent.
Determine the percent moisture in the sample as follows:
Percent moisture=
where:
e=Water equivalence of the Karl Fischer reagent determined as
directed in paragraph (c)(1) of this section;
VT=Milliliters of Karl Fischer reagent used; VA=Milliliters of
Karl Fischer reagent equivalent to the 20
milliliters of solvent A, determined as directed in paragarph (c)(3) of
this section;
Ws=Weight of the sample in milligrams.
(2) Procedure 2. Add an excess of Karl Fischer reagent to the
sample, start the stirrer, and titrate to the endpoint with methanol
solution. Calculate the percent moisture in the sample as follows:
(i) For powders:
Percent moisture=
(ii) For oils and ointments:
Percent moisture=
where:
VT=Milliliters of Karl Fischer reagent used;
Vm=Milliliters of methanol solution used;
f=Milliliters of Karl Fischer reagent equivalent to each milliliter
of methanol solution determined as directed in paragraph (c)(2) of this
section.
VB=Milliliters of Karl Fischer reagent equivalent to the 10
milliliters of solvent B determined as directed in paragraph (c)(3) of
this section;
e=Water equivalence of the Karl Fischer reagent determined as
directed in paragraph (c)(1) of this section;
Ws=Weight of the sample in milligrams.
(3) Procedure 3. Add about 20 milliliters of solvent A to a dry
titrating vessel and proceed as directed in titration procedure 1 or 2.
Disregard the volume of reagents used to determine the endpoint.
Promptly introduce an accurately weighed or measured quantity of sample
into the titrating vessel and titrate to the endpoint using either
titration procedure 1 or 2 without additional solvents. Calculate the
percent moisture in the sample as follows:
(i) If titration procedure 1 is used:
Percent moisture in weighed samples=
Percent moisture in aerosols=
Percent moisture in hygroscopic powders=
(ii) If titration procedure 2 is used:
Percent moisture in weighed samples=
Percent moisture in aerosols=
Percent moisture in hygroscopic powders=
where:
VT=Milliliters of Karl Fischer reagent used;
Vm=Milliliters of methanol solution used;
f=Milliliters of Karl Fischer reagent equivalent to each milliliter
of methanol solution determined as directed in paragraph (c)(2) of this
section;
Vb=Karl Fischer equivalent (in milliliters) of the methanol used as a
sample solvent;
e=Water equivalence of the Karl Fischer reagent determined as
directed in paragraph (c)(1) of this section.
(39 FR 18944, May 30, 1974, as amended at 48 FR 51292, Nov. 8, 1983;
50 FR 41679, Oct. 15, 1985; 51 FR 22071, June 18, 1986; 51 FR 27532,
Aug. 1, 1986)
21 CFR 436.202 pH.
(a) Apparatus. A suitable potentiometer fitted with two electrodes,
one being constructed of glass and sensitive to hydrogen ion activity
and the other being a calomel or a silver/silver chloride reference
electrode. A combination electrode with glass electrode and reference
electrode contained in the same system may be used.
(b) Standardization. Select two standard buffer solutions such that
the expected pH value of the sample is within their pH range and is also
within 2 pH unit of one of the standard buffer solutions. Standardize
the pH meter with the two buffer solutions. Make any necessary
adjustment of the meter if the observed pH value of either standard
solution differs by more than 0.05 pH units of its known value.
(c) Sample preparation. If necessary, dilute the sample with carbon
dioxide-free distilled water to the concentration specified in the
individual section for each antibiotic.
(d) Test procedure. Determine the pH of the sample at 25 2 C.
Rinse the electrode(s) between determinations first with distilled water
and then with a portion of the next sample to be tested. Store
electrode(s) with tips immersed in water.
(39 FR 18944, May 30, 1974, as amended at 42 FR 29857, June 10, 1977;
42 FR 31449, June 21, 1977)
21 CFR 436.203 Crystallinity.
Use the method specified in the individual section for each
antibiotic.
(a) Method 1. To prepare the sample for examination, mount a few
particles in mineral oil on a clean glass slide. Examine the sample by
means of a polarizing microscope. The particles reveal the phenomena of
birefringence and extinction positions on revolving the microscope
stage.
(b) Method 2. Proceed as directed in paragraph (a) of this section,
except to prepare the sample for examination, mount a few particles in
mineral oil, add 1 drop of ethyl alcohol, and allow to react for about
30 seconds.
21 CFR 436.204 Iodometric assay.
(a) Reagents. (1) 0.01N Sodium thiosulfate (2.482 grams Na2S2O35H2O
and 125 milligrams Na2CO3 per liter).
(2) 1.0N Sodium hydroxide.
(3) 1.2N Hydrochloric acid.
(4) 0.01N Iodine solution (prepared from 0.1N iodine U.S.P.).
(5) Starch iodide paste, T.S. (U.S.P.).
(b) Preparation of sample and working standard solutions -- (1)
Workingstandard solutions. From the following table, select the initial
solvent, diluent, and final concentration as listed for each antibiotic
working standard. Dissolve and dilute an accurately weighed portion to
the specified final concentration and proceed as directed in paragraphs
(c) and (d) of this section.
(2) Bulk antibiotic solutions. From the following table, select the
initial solvent, diluent, and final concentration as listed for each
antibiotic. Dissolve an accurately weighed aliquot (approximately 30 to
60 milligrams) of the sample, dilute to the appropriate final
concentration, and proceed as directed in paragraphs (c) and (d) of this
section.
(3) Finished product solutions. Prepare the sample for assay as
directed in the individual section for each antibiotic product to be
tested by diluting to the concentration prescribed in the table in
paragraph (b)(2) of this section and proceed as described in paragraphs
(c) and (d) of this section.
(c) Inactivated sample and standard solutions. (1) Transfer 2.0
milliliters each of the sample and the appropriate working standard
solutions to glass-stoppered Erlenmeyer flasks.
(2) Add 2.0 milliliters of 1N sodium hydroxide, except if the sample
has been diluted in 1N sodium hydroxide, and allow to stand at room
temperature for 15 minutes.
(3) Add 2.0 milliliters of 1.2N hydrochloric acid.
(4) Add 10.0 milliliters of 0.01N iodine solution, stopper, allow to
stand at room temperature for 15 minutes, and proceed as directed in
paragraph (e) of this section.
(d) Blank determination. Transfer 2.0 milliliters each of the sample
and the appropriate working standard solutions to glass-stoppered
Erlenmeyer flasks. Add 10.0 milliliters of 0.01N iodine solution and
immediately proceed as directed in paragraph (e) of this section.
(e) Titration procedure. Titrate the excess iodine using 0.01N
sodium thiosulfate. Toward the end of the titration, add 1 drop of the
starch iodide paste. Continue the titration by the addition of 0.01- to
0.02-milliliter portions of 0.01N sodium thiosulfate, shaking vigorously
after each addition. The endpoint is reached when the blue color of the
starch-iodine complex is discharged. Calculate the antibiotic content
as described in paragraph (f) of this section.
(f) Calculations -- (1) F factor determination. Using the
appropriate working standard for the particular antibiotic to be tested,
assay the standard as directed in this section. Calculate the F factor
(the units of micrograms of activity equivalent of each milliliter of
0.01N sodium thiosulfate consumed) by means of the following formula:
where:
Ws=Actual weight in milligrams of standard in the 2.0 milliliters
titrated;
P=Potency of the working standard in units or micrograms per
milligram;
Vs=Milliliters of sodium thiosulfate used in the working standard
blank determination minus the milliliters of sodium thiosulfate used in
the titration of the inactivated working standard solution (the
difference is the equivalent of the number of milliliters of 0.01N
iodine absorbed by the inactivated standard).
(2) Bulk antibiotic. Calculate the potency of the sample in units or
micrograms per milligram by means of the following formula:
Units or micrograms of antibiotic per milligram=
where:
Vu=Milliliters of sodium thiosulfate used in the sample blank
determination minus the milliliters of sodium thiosulfate used in the
titration of the inactivated sample solution (the difference is the
equivalent of the number of milliliters of 0.01N iodine absorbed by the
inactivated sample);
Wu=Actual weight in miligrams of sample in the 2.0 milliliters
titrated.
(3) Finished products. Calculate the potency of the sample in units
or milligrams by means of the appropriate one of the following formulas:
Units of antibiotic per dose or item=
Milligrams of antibiotic per dose or item=
where:
d=Dilution factor for the sample;
n=Number of doses or items in the sample assayed.
(39 FR 18944, May 30, 1974, as amended at 39 FR 34032, Sept. 23,
1974; 42 FR 59856, Nov. 22, 1977; 44 FR 10378, Feb. 20, 1979; 46 FR
2980, Jan. 13, 1981; 46 FR 25602, May 8, 1981; 46 FR 46312, Sept. 18,
1981; 46 FR 58298, Dec. 1, 1981; 46 FR 61072, Dec. 15, 1981; 49 FR
6091, Feb. 17, 1984)
21 CFR 436.205 Hydroxylamine colorimetric assay.
(a) Reagents -- (1) Hydroxylamine hydrochloride solution. Dissolve
350 grams of hydroxylamine hydrochloride in sufficient distilled water
to make 1 liter.
(2) Buffer. Dissolve 173 grams of sodium hydroxide and 20.6 grams of
sodium acetate in sufficient distilled water to make 1 liter.
(3) Neutral hydroxylamine. Mix 1 volume each of hydroxylamine
hydrochloride solution described in paragraph (a)(1) of this section and
the buffer described in paragraph (a)(2) of this section. Check the pH
and if necessary adjust to pH 7.0 0.1 by adding an additional amount of
one of the components. To 1 volume of this neutralized solution add 8
volumes of distilled water and 2 volumes of 95 percent ethanol. This
solution should be used for 1 day only.
(4) Ferric ammonium sulfate. Dissolve 272 grams of ferric ammonium
sulfate in a mixture of 26 milliliters of concentrated sulfuric acid and
sufficient distilled water to make 1 liter. This reagent may be used
for 1 week when stored in a brown bottle at room temperature.
(b) Preparation of working standard solutions. From the following
table, select the diluent and final concentration as listed for each
antibiotic working standard. Dissolve and dilute an accurately weighed
portion to the specified final concentration and proceed as directed in
paragraph (d) of this section.
(c) Preparation of sample solutions. From the following table,
select the diluent and final concentration as listed for each
antibiotic. Dissolve an accurately weighed portion of the sample,
dilute to the appropriate final concentration, and proceed as directed
in paragraph (d) of this section; if the product is packaged for
dispensing, dilute an aliquot of the stock solution (prepared as
described in the individual monograph) to the appropriate concentration
and then proceed as directed in paragraph (d) of this section.
(d) Procedure. Using a volume of from 1 to 2 milliliters of standard
or sample solution, add an equal volume of water and mix. Add the
following reagents in the specified volumetric proportions with respect
to the sample or standard solutions: Add 1.25 volumes of neutral
hydroxylamine reagent and allow to react for 5 minutes. Add 1.25
volumes of ferric ammonium sulfate reagent, mix, and after 3 minutes
determine the absorbance of the resulting solution at the wavelength of
480 millimicrons, using a suitable spectrophotometer and a reagent blank
prepared by treating a volume of water in the same manner as the
standard or sample solution. The time elapsed after the addition of the
ferric ammonium sulfate reagent and the reading of the absorbance must
be precisely the same (within 10 seconds) for each solution. Calculate
the potency of the sample in units or micrograms per milligram as
follows:
Units or micrograms per milligram of sample=
A1=Absorbance of sample solution.
A2=Absorbance of standard solution.
(39 FR 18944, May 30, 1974, as amended at 39 FR 34032, Sept. 23,
1974; 39 FR 44012, Dec. 20, 1974; 42 FR 59856, Nov. 22, 1977; 44 FR
10378, Feb. 20, 1979; 45 FR 16474, Mar. 14, 1980; 46 FR 2981, Jan.
13, 1981; 46 FR 25602, May 8, 1981; 46 FR 61072, Dec. 15, 1981; 49 FR
34350, Aug. 30, 1984)
21 CFR 436.206 Test for metal particles in ophthalmic ointments.
(a) Procedure. Extrude the contents of each of 10 tubes as
completely as practicable into separate, clear, glass Petri dishes (60
millimeters in diameter), cover the dishes, and heat to 80 C. to 85
C. for at least 2 hours or until the ointment has melted completely and
evenly in the dishes. A higher temperature of 100 C. 2 C. may be
used if necessary to allow adequate settling of metal particles. Allow
the ointment to cool to room temperature without agitation. Invert each
Petri dish on the stage of a suitable microscope adjusted to furnish 30
times magnification and equipped with an eye-piece micrometer disc which
has been calibrated at the magnification being used. In addition to the
usual source of light, direct an illuminator from above the ointment at
a 45 angle. Examine the entire bottom of the Petri dish for metal
particles. By varying the intensity of the illuminator from above, such
metal particles are recognized by their characteristic reflection of
light. Count the total number of metal particles exceeding 50 microns
in any single dimension.
(b) Evaluation. The batch is acceptable if (1) a total of not more
than 50 such particles is found in 10 tubes; and (2) not more than one
tube is found to contain more than eight such particles. If the batch
fails the above test, repeat the test on 20 additional tubes of
ointment. The total number of metal particles exceeding 50 microns in
any single dimension from the 30 tubes tested shall not exceed 150, with
not more than three tubes containing more than eight such particles.
(39 FR 18944, May 30, 1974; 40 FR 11869, Mar. 14, 1975)
21 CFR 436.207 Residue on ignition.
Use the method specified in the individual section for each
antibiotic.
(a) Method 1. Place approximately 1 gram of the sample, accurately
weighed, in a tared porcelain crucible and carefully ignite at a low
temperature until thoroughly charred. The crucible may be loosely
covered with a porcelain lid during the charring. Add 2 milliliters of
nitric acid and 5 drops of sulfuric acid to the contents of the crucible
and cautiously heat until white fumes are evolved, then ignite,
preferably in a muffle furnace, at 500 C. to 600 C. until the carbon
is all burned off. Cool the crucible in a desiccator and weigh. From
the weight of residue obtained, calculate the sulfated ash content.
(b) Method 2. Proceed as directed in paragraph (a) of this section,
except use 2 milliliters of sulfuric acid and do not use the nitric
acid.
21 CFR 436.208 Heavy metals determination.
(a) Reagents -- (1) Ammonia solution. Prepare an aqueous solution
containing not less than 9 grams and not more than 10 grams of ammonia
(NH3) per 100 milliliters.
(2) 6 percent acetic acid. Dilute 60 milliliters of glacial acetic
acid with sufficient water to give a solution of 1,000 milliliters.
(3) Hydrogen sulfide solution. Prepare a saturated solution of
hydrogen sulfide by passing hydrogen sulfide into cold water for a
sufficient time. It is suitable if it produces an immediate copious
precipitate when added to an equal volume of 1N ferric chloride.
Prepare a fresh hydrogen sulfide solution each time a heavy metals test
is to be performed.
(4) Lead nitrate stock solution. Dissolve 159.8 milligrams of lead
nitrate with 100 milliliters of 0.15N nitric acid, and dilute with water
to a volume of 1,000 milliliters. Prepare and store this solution in
glass containers free from soluble lead salts.
(5) Standard lead solution. Dilute a 10-milliliter aliquot of the
lead nitrate stock solution to 100 milliliters with water. This
solution must be freshly prepared each time a heavy metals test is
performed. One milliliter of this standard lead solution represents a
lead level of 10 parts per million in a 1.0-gram sample or 20 parts per
million in a 0.5-gram sample.
(b) Preparation of the sample. Use the sulfated ash obtained as
described in 436.207(a). If the heavy metal limit is greater than 30
parts per million, the sulfated ash may be obtained from a 0.5-gram
sample. Add 2 milliliters of hydrochloric acid to the sulfated ash and
slowly evaporate to dryness on a steam bath. Moisten the residue with 1
drop of hydrochloric acid, add 10 milliliters of hot water, and digest
by heating on the steam bath for 2 minutes. After cooling to room
temperature, add ammonia solution dropwise until a pH of 7.2 is reached,
then add 2 milliliters of 6 percent acetic acid. Filter the solution,
if necessary, and wash the crucible and the filter with about 10
milliliters of water. Combine the washings with the filtrate and dilute
to exactly 25 milliliters with water.
(c) Procedure. Prepare a series of five standard lead solutions, in
increments of 10 parts per million, in which the solution of lowest
concentration contains 20 parts of lead per million less than the
maximum limit of heavy metals permitted for the sample. Transfer the
necessary quantities of standard lead solution described in paragraph
(a)(5) of this section directly into metal-free 50-milliliter Nessler
tubes of uniform diameter, add 2 milliliters of 6 percent acetic acid to
each, and adjust each to a final volume of 25 milliliters with water.
Transfer the 25-milliliter solution of the sample described in paragraph
(b) of this section to another Nessler tube. Add 10 milliliters of
hydrogen sulfide solution to each standard and sample solution, mix
well, and allow to stand for 10 minutes. View downward over a white
surface; the color of the solution of the sample should be no darker
than the standard that contains the lead equivalent of the heavy metals
limit of the test.
21 CFR 436.209 Melting range or temperature.
(a) Apparatus. Melting range apparatus consists of a glass container
for a bath of colorless fluid, a suitable stirring device, an accurate
thermometer, and a controlled source of heat. Any apparatus or method
of equal accuracy may be used. The accuracy should be checked
periodically by use of melting point standards, preferably those that
melt near the expected melting range of the product to be tested. The
bath fluid is selected with a view to the temperature required, but
light paraffin is used generally and certain liquid silicones are well
adapted to the higher temperature ranges. The fluid is deep enough to
permit immersion of the thermometer to its specified immersion depth so
that the bulb is still 2 centimeters above the bottom of the bath.
(b) Sample preparation. If necessary, reduce the sample to a fine
powder and store it in a desiccator over sulfuric acid for 24 hours. If
a method for loss on drying is included in the section for the
antibiotic to be tested, a sample dried by that method may be used.
(c) Test procedure. Use a capillary glass tube about 10 centimeters
long and 0.8 to 1.2 millimeters internal diameter with the wall 0.2 to
0.3 millimeter in thickness. Charge the tube with a sufficient amount
of the dry power to form a column 2.5 to 3.5 millimeters high from the
sealed end when packed down as closely as possible by moderate tapping
on a solid surface. Heat the bath until a temperature 10 1 C. below
the expected melting range is reached, then introduce the charged tube,
and heat at a rate of rise of 3 0.5 C. per minute until melting is
completed. The temperature at which the column of the sample is
observed to collapse definitely against the side of the tube at any
point is defined as the beginning of melting, and the temperature at
which the sample becomes liquid throughout is defined as the end of
melting or the melting point.
(39 FR 18944, May 30, 1974, as amended at 41 FR 24883, June 21, 1976)
21 CFR 436.210 Specific rotation.
(a) Test procedure. The appropriate solvent, test concentration, and
polarimeter tube length are specified in the section for each antibiotic
to be tested. Accurately weigh the sample to be tested in a
glass-stoppered volumetric flask, dissolve in the appropriate solvent,
and dilute to the specified test concentration at 25 C. Maintain the
solution at 25 C. and transfer to the appropriate polarimeter tube.
Determine the angular rotation of both solvent and sample solution in a
suitable polarimeter, using a sodium light source or a white light
source with a 589.3-millimicron filter. The zero correction is the
average of the blank readings and is subtracted from the average
observed rotation of the sample solution if the two figures are of the
same sign, or is added if they are opposite in sign, to give the
corrected angular rotation of the sample solution. The determination
must be completed within one-half hour from the time the solution is
prepared.
(b) Calculations. Determine the specific rotation. ( ), by the
following formula:
where:
a=The corrected angular rotation of the sample solution in degrees at
temperature t using a light source of a wavelength of x millimicrons;
l=The length of the polarimeter tube in decimeters;
c=The concentration of the solution expressed as number of grams of
substance in 100 milliliters of solution.
21 CFR 436.211 Identity test by infrared spectrophotometry.
(a) Apparatus -- (1) Spectrophotometer. A suitable spectrophotometer
capable of recording the infrared absorption spectrum in the 2 to 15
micron range.
(2) Hydraulic press. A 30-ton hydraulic press with 12-inch square
platens.
(b) Sample preparation methods. Use the sample preparation method
specified in the individual section for each antibiotic.
(1) Potassium bromide discs. Quantities of materials specified are
for a 13-millimeter die. Appropriate adjustments should be made in the
quantities of materials when dies of other sizes are used. To prepare a
1.0 percent mixture weigh approximately 2 milligrams of the sample and
mix thoroughly with 200 milligrams of dried potassium bromide (infrared
spectrophotometric quality). For a 0.5 percent potassium bromide
mixture, use 1 milligram of sample. For a 0.25 percent potassium
bromide mixture, use 0.5 milligram of sample. A mortar and pestle, a
ball mill, or other suitable mixing device may be used. Transfer the
uniformly milled mixture to the die, evacuate gradually while raising
the pressure to 3,000 pounds per square inch until evacuation is
complete, then raise the pressure to 16,000 pounds per square inch, and
hold that pressure for 2 to 3 minutes. Release the pressure, dismantle
the die, and recover the potassium bromide disc. Mount the disc in a
suitable holder and proceed as directed in paragraph (c) of this
section.
(2) Mineral oil mull. Weigh approximately 20 milligrams of the
sample into an agate mortar and add 2 drops of mineral oil. Triturate
thoroughly with a pestle until a uniform consistency is obtained. Use
two rock salt plates as an absorption cell. Place a small drop of the
mull in the center of one of the plates. Gently put the other plate on
the mull and slowly squeeze the plates together to spread the mull
uniformly. Clamp the two plates firmly together in a metal holder.
Examine the assembled cell by holding it up to the light. It should
appear smooth and free of any air bubbles. Proceed as directed in
paragraph (c) of this section.
(3) 1 percent solution. Prepare a 1 percent solution of the sample
in chloroform and use 1.0 millimeter matched absorption cells. Proceed
as directed in paragraph (c) of this section.
(c) Procedure. Place the sample, prepared as directed in paragraph
(b) of this section, in the spectrophotometer. Determine the infrared
absorbance spectrum between the wavelengths of 2 to 15 microns. To be
suitable the spectrum should have a transmittance of between 20 and 70
percent at most of the wavelengths showing significant absorption.
Compare the spectrum to that of an authentic sample of the same
antibiotic prepared in an identical manner. To pass the infrared
identity test, the absorption spectrum of the sample should compare
qualitatively with that of the authentic sample.
21 CFR 436.212 Disintegration test.
(a) Apparatus -- (1) Basket-rack assembly. The basket-rack assembly
consists of 6 open-ended glass tubes, each 7.75 0.25 centimeters long
and having an inside diameter of approximately 21.5 millimeters and a
wall approximately 2 millimeters thick; the tubes are held in a
vertical position by two plastic plates, each about 9 centimeters in
diameter and 6 millimeters in thickness, with six holes, each about 24
millimeters in diameter, equidistant from the center of the plate and
equally spaced from one another. Attached by screws to the undersurface
of the lower plate is 10-mesh No. 23 (0.025 inch) W. and M. gauge
woven stainless steel wire cloth. The glass tubes and the upper plastic
plate are secured in position at the top by means of a stainless steel
plate, about 9 centimeters in diameter and 1 millimeter in thickness,
having six perforations each about 20 millimeters in diameter, which
coincide with those of the upper plastic plate and the upper open ends
of the glass tubes. A central shaft about 8 centimeters in length, the
upper end of which terminates in an eye through which a string or wire
may be inserted, is attached to the stainless steel plate. The parts of
the apparatus are assembled and rigidly held by means of three bolts
passing through the two plastic plates and the steel plate. The design
of the basket-rack assembly may be varied somewhat provided the
specifications for the glass tubes and the screen mesh size are
maintained.
(2) Disks. Each tube is provided with a slotted and perforated
cylindrical disk 9.5 0.15 millimeters thick and 20.7 0.15 millimeters in
diameter. The disk is made of a suitable, transparent plastic material
having a specific gravity of between 1.18 and 1.20. Five 2-millimeter
holes extend between the ends of the cylinder, one of the holes being
through the cylinder axis and the others parallel with it and equally
spaced on a 6-millimeter radius from it. Equally spaced on the sides of
the cylinder are four notches that form V-shaped planes perpendicular to
the ends of the cylinder. The dimensions of each notch are such that
the openings on the bottom of the cylinder are 1.60 millimeters square
and those on the top are 9.5 millimeters wide and 2.55 millimeters deep.
All surfaces of the disk are smooth.
(3) Raising and lowering device. Use a device for raising and
lowering the basket in the immersion fluid at a constant rate between 28
and 32 cycles per minute through a distance of not less than 5
centimeters and not more than 6 centimeters.
(b) Immersion fluids. During the performance of the tests all
immersion fluids are maintained at a temperature of 37 2 C. by using
a thermostatically controlled water bath.
(1) Distilled water.
(2) Simulated gastric fluid: Dissolve 2.0 grams of sodium chloride
and 7.0 milliliters of hydrochloric acid in about 500 milliliters of
water. Dissolve 3.2 grams of pepsin in this solution and add sufficient
water to make 1,000 milliliters. This solution has a pH of about 1.2.
(3) Simulated intestinal fluid: Dissolve 6.8 grams of monobasic
potassium phosphate in 250 milliliters of water, mix and add 190
milliliters of 0.2N sodium hydroxide and 400 milliliters of water. Add
10.0 grams of pancreatin, mix, and adjust the resulting solution with
0.2N sodium hydroxide to a pH of 7.5 0.1. Dilute to 1,000 milliliters.
(c) Immersion vessel. Use a suitable vessel, such as a 1-liter
beaker.
(d) Operation. Add enough immersion fluid to the immersion vessel so
that when the basket-rack assembly is placed on the raising and lowering
device at the highest point of the upward stroke, the wire mesh remains
at least 2.5 centimeters below the surface of the fluid and descends to
not less than 2.5 centimeters from the bottom of the immersion vessel.
(e) Procedure -- (1) Uncoated or filmcoated tablets. Place one
tablet into each of the six tubes of the basket, add a disk to each
tube, and operate the apparatus, using simulated gastric fluid as the
immersion fluid. At the end of the time limit specified in the
individual section for the particular antibiotic tablet being tested,
lift the basket from the fluid and observe the tablets.
(2) Plain-coated tablets. Place one tablet in each of the six tubes
of the basket, add a disk to each tube, and operate the apparatus, using
simulated gastric fluids as the immersion fluid. After 30 minutes, lift
the basket from the fluid and observe the tablets. If the tablets have
not disintegrated completely, substitute simulated intestinal fluid as
the immersion fluid and continue the test for a total period of time
(including previous immersion in simulated gastric fluid) equal to the
time limit specified in the individual section for the particular
antibiotic tablet being tested. Lift the basket and observe the
tablets.
(3) Enteric-coated tablets. Place one tablet in each of the six
tubes of the basket and operate the apparatus, using simulated gastric
fluid as the immersion fluid. One hour later, lift the basket from the
fluid and observe the tablets. If the tablets show no distinct evidence
of dissolution or disintegration, add a disk to each tube and operate
the apparatus, using simulated intestinal fluid as the immersion fluid,
for a total period of time (including the previous immersion in
simulated gastric fluid) equal to the time limit specified in the
individual section for the particular antibiotic tablet being tested.
Lift the basket and observe the tablets.
(4) Pastilles. Place one pastille into each of the six tubes of the
basket, add a disk to each tube, and operate the apparatus, using
distilled water as the immersion fluid. At the end of the time limit
specified in the individual section for the particular antibiotic
pastille being tested, lift the basket from the fluid and observe the
pastilles.
(5) Capsules. Place one capsule into each of the six tubes of the
basket, add a disk to each tube, and operate the apparatus, using
distilled water as the immersion fluid. At the end of the time limit
specified in the individual section for the capsules being tested, lift
the basket from the fluid and observe the capsules.
(f) Evaluation. Complete disintegration is defined as the state in
which any residue of the tablet, pastille, or capsule (except fragments
of the insoluble coating) remaining on the screen is a soft mass having
no palpably firm core. The tablets, pastilles, or capsules pass the
disintegration test if all of the units tested disintegrate completely
under the conditions and time specified in the individual section for
the antibiotic tablet, pastille, or capsule being tested. If one or two
tablets, pastilles, or capsules fail to disintegrate completely, repeat
the test on 12 additional tablets, pastilles, or capsules. The tablets,
pastilles, or capsules pass the disintegration test if not less than 16
of the total 18 tested disintegrate completely. Enteric coated tablets
fail the disintegration test if they show any distinct evidence of
dissolution or disintegration after 1 hour immersion in simulated
gastric fluid.
(39 FR 18944, May 30, 1974, as amended at 52 FR 4617, Feb. 13, 1987;
55 FR 19873, May 14, 1990)
21 CFR 436.213 Nonaqueous titrations.
(a) Equipment -- (1) Apparatus. Use a closed system consisting of a
suitable titrimeter equipped with a potentiometer, an automatic burette,
a chart recorder, and a glass calomel combinatin electrode (with
saturated methanolic potassium chloride as the electrolyte).
(2) Titration vessel. Use a 100-milliliter tall form beaker without
a spout.
(b) Reagents -- (1) Methyl alcohol, reagent grade, anhydrous.
(2) Dimethylsulfoxide, A.C.S., reagent grade.
(3) Glacial acetic acid, A.C.S., reagent grade.
(4) Lithium methoxide reagent: 0.02N lithium methoxide in methyl
alcohol, standardized against primary grade benzoic acid.
(5) Perchloric acid reagent: 0.02N perchloric acid in glacial acetic
acid, standardized against primary grade potassium acid phthalate.
(c) Preparation of sample solutions. Select the weight of the sample
and the solvent listed for each antibiotic. Transfer the accurately
weighed sample to a titration vessel. Add the appropriate solvent,
cover, and stir magnetically until the sample is dissolved. Proceed as
directed in paragraph (e) of this section, using the procedure or
procedures specified in the individual section for each antibiotic.
(d) Blank determination. Place the same volume of solvent used to
prepare the sample solution into a titration vessel and proceed as
directed in paragraph (e) of this section, using the procedure or
procedures specified in the individual section for each antibiotic.
(e) Titration procedures -- (1) Acid titration. Equilibrate the
electrode by soaking it overnight in the solvent used for preparing the
sample solution. Start the magnetic stirrer and titrate the sample
solution with the lithium methoxide reagent. Record the change in
potential of the solution with the addition of the titrant. Determine
the number of milliliters of reagent consumed at neutralization (the
inflection point of the titration curve). Calculate the antibiotic
content as directed in the individual section.
(2) Base titration. Proceed as directed in paragraph (e)(1) of this
section, except use the perchloric acid reagent as the titrant and
calculate the antibiotic content as directed in the individual section.
(39 FR 18944, May 30, 1974, as amended at 40 FR 22251, Apr. 22, 1975;
40 FR 23725, June 2, 1975; 40 FR 57797, Dec. 12, 1975; 46 FR 2981,
Jan. 13, 1981)
21 CFR 436.214 Heat stability.
Store an accurately weighed portion of the sample of approximately 30
milligrams in an unstoppered 50-milliliter Erlenmeyer flask for 4 days
in an electric oven at 100 C 1 C. At the end of this period, remove
the flask from the oven and allow to cool in a desiccator. Accurately
weigh an unheated portion of the original sample of approximately 30
milligrams. Assay both the heated and unheated samples for potency as
directed in 436.204 or 436.205 of this chapter. Determine the percent
loss from the difference in potency between the unheated original sample
and the heat-treated sample.
(42 FR 59856, Nov. 22, 1977)
21 CFR 436.215 Dissolution test.
(a) Equipment. Use either Apparatus 1 or 2 as described in the
United States Pharmacopeia XXI dissolution test.
(b) Procedure. For each dosage form listed in the table in this
paragraph select the appropriate dissolution medium, rotation rate,
sampling time, and apparatus, and proceed as set forth in either
Apparatus 1 or 2 methodology of the United States Pharmacopeia XXI
dissolution test. Determine the amount of drug substance dissolved by
performing the assay described in paragraph (c) of this section. The
amount of dissolution medium removed for sampling purposes may be
disregarded if the amount removed is not more than 15 milliliters. If
more than 15 milliliters is removed, then correct for the volume
removed.
(c) Antibiotic drug content -- (1) Tetracycline hydrochloride -- (i)
Preparation of working standard solution. Accurately weigh 20 to 30
milligrams of tetracycline hydrochloride working standard into a
suitable-sized volumetric flask. Dissolve and dilute to volume with
water. Further dilute an accurately measured portion with distilled
water to obtain a known concentration of 0.01 to 0.02 milligram of
tetracycline hydrochloride per milliliter.
(ii) Preparation of sample solutions. Dilute an accurately measured
portion of the sample with sufficient distilled water to obtain a
concentration of 0.01 to 0.02 milligram of tetracycline hydrochloride
per milliliter (estimated).
(iii) Procedure. Using a suitable spectrophotometer and water as the
blank, determine the absorbance of each standard and sample solution at
the absorbance peak at approximately 276 nanometers. Determine the
exact position of the absorption peak for the particular instrument
used.
(iv) Calculation. Determine the total amount of tetracycline
hydrochloride dissolved as follows:
Where:
T=Total milligrams of drug dissolved;
Au=Absorbance of sample;
c=Concentration of standard in milligrams;
d=Dilution factor of sample filtrate;
As=Absorbance of standard.
*If more than 15 mL of dissolution medium is removed, correct for the
volume removed.
(2) Oxytetracycline hydrochloride; preparation of working
standard-solution. (i) Accurately weigh 30 milligrams of
oxytetracycline-base working standard into a suitable-sized volumetric
flask. Add 5 milliliters of 0.1N hydrochloric acid and swirl the flask
to dissolve oxytetracycline base. Dilute an accurately measured portion
with distilled water to obtain a known concentration of 0.01 to 0.02
milligram of oxytetracycline per milliliter.
(ii) Proceed as directed in paragraphs (c)(1) (ii), (iii), and (iv)
of this section except measure the absorbance at the absorption peak at
approximately 273 nanometers.
(3) Doxycycline hyclate. Proceed as directed in paragraph (c)(1) of
this section, except use the doxycycline working standard.
(4) Bacampicillin hydrochloride. Use the ampicillin working standard
as the standard of comparison and assay for ampicillin content by either
of the following methods.
(i) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except dilute the working standard to a final concentration of
0.3 milligram of ampicillin per milliliter and use the sample solution
as it is removed from the dissolution vessel without further dilution.
(ii) Hydroxylamine colorimetric assay. Proceed as directed in
442.40(b)(1)(ii) of this chapter, except:
(a) Buffer. In lieu of the buffer described in
442.40(b)(1)(ii)(b)(2) of this chapter, use the buffer prepared as
follows: Dissolve 200 grams of primary standard tris (hydroxymethyl)
aminomethane in sufficient distilled water to make 1 liter. Filter
before use.
(b) Preparation of the working standard solution. Dissolve and
dilute an accurately weighed portion of the ampicillin working standard
with sufficient distilled water to obtain a final concentration of 0.3
milligram of ampicillin per milliliter;
(c) Sample solution. Use the sample solution as it is removed from
the dissolution vessel without further dilution; and
(d) Calculations. Determine the total amount of ampicillin dissolved
as follows:
T=(Au) (c)(d) (900*)/As,
Where:
T=Total milligrams of ampicillin equivalent dissolved;
Au=Absorbance of sample;
c=Concentration of working standard solution in milligrams per
milliliter;
d=Dilution factor of sample filtrate;
As=Absorbance of standard.
*If more than 15 mL of dissolution medium is removed, correct for the
volume removed.
(5) Cephradine dihydrate -- (i) Preparation of working standard
solution. Accurately weigh approximately 40 milligrams of cephradine
working standard into a suitable-sized volumetric flask. Dissolve and
dilute to volume with 0.12N hydrochloric acid. Further dilute with a
buffer solution (prepared by dissolving 27.2 grams of sodium acetate
trihydrate in a mixture of 12 milliliters of glacial acetic acid and
sufficient distilled water to make 2 liters) to obtain a known
concentration of 0.01 to 0.03 milligram of cephradine per milliliter.
(ii) Preparation of sample solution. Filter the sample and dilute an
accurately measured portion of the filtrate with sufficient buffer
solution, described in paragraph (c)(5)(i) of this section, to obtain a
concentration of 0.01 to 0.03 milligram of cephradine per milliliter
(estimated).
(iii) Proceed as directed in paragraphs (c)(1) (iii) and (iv) of this
section, except measure the absorbance at the absorption peak at
approximately 262 nanometers.
(6) Amoxicillin trihydrate. Assay for the amoxicillin content as
described in 440.103d of this chapter, except use the sample as it is
removed from the dissolution vessel.
(7) Vancomycin hydrochloride. Assay for the vancomycin content as
described in 436.105 of this chapter, except use the sample as it is
removed from the dissolution test.
(8) Erythromycin -- (i) Preparation of working standard solution.
Accurately weigh approximately 140 milligrams of erythromycin working
standard into a 250-milliliter volumetric flask and dissolve in 10
milliliters of methyl alcohol. Add water nearly to volume, mix, and
allow the solution to cool. Dilute to volume with water and mix. On
the day of use, dilute an accurately measured aliquot with water to
obtain a known concentration of 0.28 milligram of erythromycin per
milliliter (before adjusting for standard potency).
(ii) Preparation of sample solution. Dilute an accurately measured
portion of the filtered sample with sufficient 0.05M potassium phosphate
buffer, pH 6.8, to obtain a concentration of about 0.28 milligram of
erythromycin per milliliter (estimated).
(iii) Procedure. Transfer 5.0-milliliter aliquots of the working
standard solution and sample solution to 25-milliliter volumetric flasks
and treat as follows: Add 2.0 milliliters of water, allow to stand for
5 minutes with intermittent swirling. Add 15.0 milliliters of 0.25N
sodium hydroxide, dilute to volume with sufficient 0.05M potassium
phosphate buffer, pH 6.8, and mix. Heat to 60 C for 5 minutes and
allow to cool. Using a suitable spectrophotometer and a blank (prepared
as per the procedure above except that 2.0 milliliters of 0.5N sulfuric
acid is substituted for the 2.0 milliliters of water) for each solution,
determine the absorbance of each working standard and sample solution at
the absorbance peak at approximately 236 nanometers. Determine the
exact position of the absorption peak for the particular instrument
used.
(iv) Calculation. Proceed as directed in paragraph (c)(1)(iv) of
this section.
(9) Cefuroxime axetil -- (i) Preparation of working standard
solution. Accurately weigh approximately 60 milligrams of cefuroxime
axetil working standard into a suitable-sized volumetric flask.
Dissolve in 5 milliliters of methanol and dilute to volume with 0.07N
hydrochloric acid. Further dilute with 0.07N hydrochloric acid to
obtain a known concentration equivalent to 0.01 to 0.02 milligram of
cefuroxime activity per milliliter.
(ii) Preparation of sample solution. Filter the sample through a
0.45-micrometer filter and dilute an accurately measured portion of the
filtrate with sufficient 0.07N hydrochloric acid to obtain a
concentration equivalent to 0.01 to 0.02 milligram of cefuroxime
activity per milliliter (estimated).
(iii) Procedure. Using a suitable spectrophotometer and 0.07N
hydrochloric acid as the blank, determine the absorbance of each
standard and sample solution at the absorbance peak at approximately 278
nanometers. Determine the exact position of the absorption peak for the
particular instrument used.
(iv) Calculation. Determine the total amount of cefuroxime activity
dissolved as follows:
where:
T = Total milligrams of cefuroxime activity dissolved;
Au = Absorbance of sample;
c = Cefuroxime activity of working standard solution in milligrams
per milliliter;
d = Dilution factor of sample filtrate; and
As = Absorbance of standard.
(10) Cefixime -- (i) Preparation of working standard solution.
Accurately weigh approximately 25 milligrams of cefixime working
standard into a 500-milliliter volumetic flask. Wet the powder with 0.5
milliliters of methanol, and dilute to volume with 0.05 M potassium
phosphate buffer, pH 7.2 (prepared by dissolving 6.8 grams of monobasic
potassium phosphate in distilled water to a volume of one liter. The pH
is adjusted to 7.2 with 1.0N NaOH). Sonicate to assure dissolution and
mix.
(ii) Preparation of sample solution. Forty-five minutes after the
beginning of the rotation, withdraw and filter a portion of the
solution. For the 400-milligram tablets, pipet 10.0 milliliters of the
filtered sample solution into a 100-milliliter volumetric flask. For
the 200-milligram tablets, pipet 10.0 milliliters of the filtered sample
into a 50-milliliter volumetric flask. Dilute to volume with 0.05 M
postassium phosphate buffer, pH 7.2.
(iii) Procedure. Proceed as directed in paragraphs (c)(1) (iii) and
(iv) of this section, except measure the absorbance of the peak at
approximately 320 nanometers using 0.05 M potassium phosphate buffer, pH
7.2 as the blank.
(11) Cephalexin hydrochloride monohydrate. Assay for cephalexin
activity of the cephalexin hydrochloride monohydrate as directed in
442.28 of this chapter, and use U.S.P. dissolution apparatus 1 (10 mesh
basket). Use the sample as it is removed from the dissolution vessel.
(12) Doxycycline monohydrate. Proceed as directed in paragraph
(c)(1) of this section, except use the doxycycline standard.
(d) Evaluation. Use the dissolution acceptance table and
interpretation in the United States Pharmacopeia XXI.
(44 FR 48188, Aug. 17, 1979)
Editorial Note: For Federal Register citations affecting 430.215,
see the List of CFR Sections Affected appearing in the Finding Aids
section of this volume.
21 CFR 436.216 High-performance liquid chromatographic assay.
(a) Equipment. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, flow rate, and
calculations specified in the monograph for the drug being tested. Use
a detector sensitivity setting that gives a peak height for the working
standard solution that is at least 50 percent of scale with typical
chart speed of not less than 2.5 millimeters per minute. Use the
equipment described in paragraph (a) of this section. Use the reagents,
working standard solution, and sample solution described in the
monograph for the drug being tested. Equilibrate and condition the
column by passage of 10 to 15 void volumes of mobile phase followed by
five replicate injections of the same volume of the working standard
solution. Allow an operating time sufficiently long to obtain
satisfactory separation and elution of the expected components after
each injection. Record the peak responses and calculate the prescribed
system suitability requirements described for the system suitability
test in paragraph (c) of this section.
(c) System suitability test. Select the system suitability
requirements specified in the monograph for the drug being tested.
Then, using the equipment and procedure described in this section, test
the chromatographic system for assay as follows:
(1) Trailing factor or asymmetry factor. Calculate either the
trailing factor (T), from distances measured along the horizontal line
at 5 percent of the peak height above the baseline or the asymmetry
factor (As) measured at a point 10 percent of the peak height from the
baseline; whichever is required in the appropriate monograph, as
follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
where:
a=Horizontal distance from point of ascent to point of maximum peak
height; and
b=Horizontal distance from the point of maximum peak height to point
of descent.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
Wh=Peak width at half-height.
Calculate the absolute efficiency of the column, (reduced plate
height) (hr) if required in the monograph, as follows:
where:
L=Length of column in centimeters;
n=Number of theoretical plates; and
dp=Average diameter of the particles in column packing in
micrometers.
(3) Resolution. Calculate the resolution (R) as follows:
where:
tRj=Retention time of a solute eluting after i (tRj is larger than
tRi);
tRi=Retention time for any solute;
wi=Width of peak at baseline for any solute; and
wj=Width of peak at baseline for any solute eluting after i.
(4) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N of individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, except alternate injections
of the working standard solution with injections of the sample solution.
(5) Capacity factor. Calculate the capacity factor (k), if required
in the monograph as follows:
where:
tr=Retention time of solute; and
tm=Retention time of solvent or unretained substance, calculated as
follows:
where:
D=Column diameter in centimeters;
L=Column length in centimeters;
0.75=Average total column porosity; and
F=Flow rate in milliliters per minute.
(51 FR 11572, Apr. 4, 1986, as amended at 54 FR 47351, Nov. 14, 1989)
21 CFR 436.217 Film-coat rupture test.
(a) Immersion fluid. Dilute 6.0 milliliters of hydrochloric acid to
1,000 milliliters with water. During the performance of the test
maintain the immersion fluid at a temperature of 37 0.5 C by using a
thermostatically controlled water bath.
(b) Immersion vessel. Use a suitable vessel, such as a 1-liter
beaker.
(c) Operation. Add 750 milliliters of immersion fluid to the
immersion vessel.
(d) Procedure. Drop a tablet into the immersion fluid and record the
time for the tablet coat to rupture. Repeat the test with a further 19
tablets, testing not more than 10 tablets with a given volume of
immersion fluid.
(e) Evaluation. The tablets pass the film-coat rupture test if the
mean coat rupture time does not exceed 20 seconds and not more than 2
tablets have a coat rupture time exceeding 40 seconds.
(52 FR 42432, Nov. 5, 1987)
21 CFR 436.217 Subpart F -- Chemical Tests for Specific Antibiotics
21 CFR 436.300 Polarimetric assay of carbenicillin indanyl sodium.
(a) Equipment. Polarimeter capable of measuring optical rotatory
activity at 365 nanometers: Perkin-Elmer Model 141 or equivalent, with
a suitable 1-decimeter polarimeter tube.
(b) Reagents -- (1) 4-methyl-2-pentanone. Meets ACS specifications.
(2) Phosphate-citrate buffer. Dissolve 61.0 grams of anhydrous
disodium phosphate and 11.0 grams of citric acid in 950 milliliters of
distilled water. Adjust the pH to 6.0 with 6N hydrochloric acid.
Dilute to 1,000 milliliters with distilled water.
(c) Preparation of carbenicillin indanyl sodium sample and working
standard solutions. Accurately weigh approximately 125 milligrams of
the carbenicillin indanyl sodium sample or working standard into a
25-milliliter volumetric flask. Dissolve and dilute to volume with
distilled water. Transfer a 5-milliliter aliquot to a 50-milliliter
glass-stoppered centrifuge tube. Add 15 milliliters of the
phosphate-citrate buffer and 20 milliliters of 4-methyl-2-pentanone;
stopper and shake the tube for 10 seconds. Centrifuge at 2,000
revolutions per minute for 10 minutes to separate the phases. Remove
about 15 milliliters of the upper (4-methyl-2-pentanone solvent) phase
and proceed as directed in paragraph (e) of this section.
(d) Preparation of the blank. Place a 5-milliliter aliquot of
distilled water into a 50-milliliter glass-stoppered centrifuge tube,
add 15 milliliters of phosphate-citrate buffer and 20 milliliters of
4-methyl-2-pentanone; stopper and shake the tube for 10 seconds.
Centrifuge at 2,000 revolutions per minute for 10 minutes to separate
the phases. Remove about 15 milliliters of the upper phase and proceed
as directed in paragraph (e) of this section.
(e) Procedure. Fill the polarimeter tube with the blank solution
prepared as described in paragraph (d) of this section. Place the tube
in the polarimeter. Adjust the polarimeter to zero rotation using a
light source with a wavelength of 365 nanometers. Use the same
procedure to determine the optical rotation of both the sample solution
and the working standard solution prepared as directed in paragraph (c)
of this section.
(f) Calculations. Calculate the carbenicillin content (potency) of
the sample on an anhydrous basis as follows:
Micrograms of carbenicillin per milligram of sample=
where: m=moisture content of the sample.
21 CFR 436.301 Thin layer chromatography identity test for
carbenicillin indanyl.
Using the sample solution prepared as described in the section for
the antibiotic drug to be tested, proceed as described in paragraphs
(a), (b), (c), and (d) of this section.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 9 9 3.5 inches lined with Whatman's 3MM
chromatographic paper (0.3 millimeters) or equivalent.
(2) Iodine vapor chamber. A rectangular tank approximately 9 9
3.5 inches, with a suitable cover, containing iodine crystals.
(3) Plates. Use 20 20 centimeters thin layer chromatography plates
coated with silica gel G or equivalent to a thickness of 250 microns.
(b) Reagents -- (1) Extraction solvent. Mix ethyl acetate, acetone,
pyridine, water, and acetic acid in volumetric proportions of
100:200:25:75:1.5 respectively.
(2) Developing solvent. Mix ethyl acetate, acetone, pyridine, water,
and acetic acid in volumetric proportions of 300:400:25:75:2
respectively.
(3) Ferric chloride-potassium ferricyanide reagent. Immediately
before use, mix 100 milliliters of a 1 percent ferric chloride solution
in 1 percent hydrochloric acid with 100 milliliters of a 1 percent
potassium ferricyanide solution and 75 milliliters of methanol.
(c) Preparation of working standard solution. Weigh an amount of the
carbenicillin indanyl working standard equivalent to approximately 10
milligrams of carbenicillin into a 50-milliliter Erlenmeyer flask.
Dissolve the material in sufficient extraction solvent to make a
solution containing 1 milligram carbenicillin per milliliter.
(d) Procedure. Pour developing solvent into the bottom of the
chromatography tank. Cover and seal the tank. Allow it to equilibrate
for 1 hour. Prepare a plate as follows: On a line 2 centimeters from
the base of the silica gel plate, and at intervals of 2 centimeters,
spot 10 microliters of the standard solution and the sample solution.
The plate should be air dried for 30 minutes. Place the plate into the
chromatography tank. Allow the solvent front to travel about 15
centimeters from the starting line and then remove the plate from the
tank. Heat the plate for 30 minutes at 80 C. in a circulating air
oven and then allow the plate to cool to room temperature. Place the
plate in the iodine vapor chamber for about 30 seconds, remove the plate
and spray it with the ferric chloride-potassium ferricyanide reagent.
Carbenicillin indanyl appears as a blue spot on a yellow-green
background at an Rf of about 0.5. The test is satisfactory if the sample
compares qualitatively with the standard.
(39 FR 18944, May 30, 1974, as amended at 41 FR 18509, May 5, 1976)
21 CFR 436.302 Clindamycin vapor phase chromatography.
(a) Equipment. Gas chromatograph equipped with a flame ionization
detector: Barber-Colman 5,000 or equivalent.
(b) Reagents. (1) Pyridine, reagent grade, dried over sodium
sulfate.
(2) Chloroform, reagent grade.
(3) Acetic anhydride, reagent grade, used as acteylating agent.
(4) Internal standard: Prepare a solution containing 3 milligrams of
cholestane per milliliter in pyridine.
(c) Typical conditions. (1) Column: 4 feet 4 millimeters ID,
glass, with 1 percent SE-30 on Diatoport S (60/80 mesh), or equivalent.
(2) Temperatures: Column 200 C.; detector 215 C.; injection port,
ambient temperature.
(3) Carrier gas: Helium approximately 120 milliliters per minute.
(4) Detector: Hydrogen flame -- hydrogen at 120 pounds per square
inch, air at 40 pounds per square inch.
(5) Sensitivity: 1,000; attenuation, 2 for clindamycin, 1 for
internal standard: 2 10^8 amperes.
(d) Preparation of clindamycin sample and working standard solutions.
Accurately weigh approximately 15 milligrams of sample or working
standard into a glass-stoppered conical 15-milliliter centrifuge tube.
Add 1.0 milliliter of chloroform, 1.0 milliliter of internal standard
solution, and 0.6 milliliter of acetic anhydride. Agitate the tubes to
insure dissolution of the sample and complete mixing of the liquids.
Proceed as directed in paragraph (e) of this section.
(e) Procedure. Cover the top of each centrifuge tube with a plastic
cap. Punch a small hole in the top of each cap to allow vapor to
escape. Place the tubes in a 100 C. drying oven for 2.5 hours.
Remove the tubes from the oven and allow to cool. Take the plastic cap
from each tube and replace with the glass stopper. Centrifuge 10-15
minutes at 2,000-2,500 r.p.m. to separate the white solid from the
liquid in the tube. Inject 0.5 microliter of the clear liquid into the
gas chromatograph. Use the conditions and materials listed in
paragraphs (a), (b), and (c) of this section. The conditions should be
adequate to maintain a stable baseline and provide at least 60 percent
deflection of the recorder scale by the clindamycin peak. The
resolution of the peaks should be complete. The elution order is:
Internal standard, clindamycin, and epiclindamycin (if present).
Calculate the clindamycin content as directed in paragraph (f) of this
section.
(f) Calculations. Calculate the clindamycin content of the sample as
follows:
Micrograms of clindamycin per milligram=
where:
Ru=Area of the clindamycin sample peak (at a retention time equal to
that observed for the clindamycin standard)/Area of internal standard
peak;
Rs=Area of the clindamycin standard peak/Area of internal standard
peak;
Ws=Weight of the clindamycin working standard in milligrams;
Wu=Weight of the sample in milligrams;
f=Potency of the clindamycin working standard in micrograms per
milligram.
21 CFR 436.303 Clindamycin content of clindamycin palmitate
hydrochloride by vapor phase chromatography.
(a) Equipment. Gas chromatograph equipped with a flame ionization
detector: Hewlett-Packard 76064 or equivalent.
(b) Reagents. (1) Acetic anhydride, reagent grade.
(2) Pyridine, reagent grade.
(3) Chloroform, reagent grade.
(4) Internal standard: Prepare a solution containing 5 milligrams of
cholesteryl benzoate per milliliter in chloroform.
(c) Typical conditions. (1) Column: 6 feet 2 millimeters ID,
glass, with 1 percent UC-W98 on Chromosorb WHP (80/100 mesh) or
equivalent.
(2) Temperatures: Column 275 C.; detector 290 C.; injection port
280 C.
(3) Carrier gas: Helium approximately 60 milliliters per minute.
(4) Detector: Hydrogen flame ionization -- hydrogen at 12 pounds per
square inch, air at 32 pounds per square inch.
(5) Sensitivity: 1,000; attenuation, 16; 1 10^9 amperes.
(d) Preparation of clindamycin palmitate hydrochloride sample and
working standard solutions. Accurately weigh approximately 15
milligrams of both the sample and the working standard into separate
glass-stoppered, conical 15-milliliter centrifuge tubes. Add 1.0
milliliter of internal standard solution, 1.0 milliliter of pyridine,
and 0.5 milliliter of acetic anhydride to each tube. Agitate the tubes
to insure dissolution and complete mixing of the liquids. Proceed as
directed in paragraph (e) of this section.
(e) Procedure. Cover the top of each centrifuge tube with a plastic
cap. Punch a small hole in the top of each cap to allow vapor to
escape. Place the tubes in a 100 C. drying oven for 2.5 hours.
Remove the tubes from the oven and allow to cool. Take the plastic cap
from each tube and replace with the glass stopper. Centrifuge 10-15
minutes at 2,000-2,500 r.p.m. to separate the white solid from the
liquid in the tube. Inject 1 microliter of the clear liquid into the
gas chromatograph. Use the conditions and materials listed in
paragraphs (a), (b), and (c) of this section. The conditions should be
adequate to maintain a stable baseline and provide at least 40 percent
deflection of the recorder scale by the clindamycin palmitate peak. The
resolution of the peaks should be complete. The internal standard will
be eluted before the clindamycin palmitate. Calculate the clindamycin
content as directed in paragraph (f) of this section.
(f) Calculations. Calculate the clindamycin content of the sample as
follows:
Micrograms of clindamycin per milligram=
where:
Ru=Area of the sample peak (at a retention time equal to that
observed for the clindamycin palmitate hydrochloride standard)/Area of
internal standard peak;
Rs=Area of the clindamycin palmitate hydrochloride standard peak/Area
of internal standard peak;
Ws=Weight of the clindamycin palmitate hydrochloride working standard
in milligrams;
Wu=Weight of the sample in milligrams;
f=Micrograms of clindamycin activity per milligram of clindamycin
palmitate hydrochloride working standard.
4Available from: Hewlett Packard Co., P.O. Box 301, Loveland, CO
80537.
21 CFR 436.304 Clindamycin phosphate vapor phase chromatography.
(a) Equipment. Gas chromatograph equipped with an electronic
integrator and with a flame ionization detector that has a sensitivity
of at least 1 10^10 amperes: Hewlett-Packard 76004009 or equivalent.
(b) Reagents. (1) Trifluoroacetic anhydride.
(2) Intestinal alkaline phosphatase.
(3) pH 9.0 borate buffer: Transfer 3.1 grams of boric acid into a
1-liter volumetric flask containing 500 milliliters of water, mix, and
add 21 milliliters of 1.0N sodium hydroxide and 10 milliliters of 0.1M
magnesium chloride. Dilute to volume with water and mix well.
(4) Internal standard: Prepare a chloroform solution containing
approximately 0.45 milligram hexacosane per milliliter.
(5) Anhydrous sodium carbonate.
(c) Typical conditions. (1) Column: 2 feet 3 millimeters ID,
glass, with 1 percent SE-30 on Diatoport S (80/100 mesh), or equivalent.
(2) Temperatures: Column, 180 C., detector, 215 C., injection
port, ambient temperature.
(3) Carrier gas: Helium approximately 60 milliliters per minute.
(4) Detector: Hydrogen flame -- hydrogen flow at 40 milliliters per
minute. Air flow at 400 milliliters per minute.
(5) Sensitivity: 1 10^9 amperes.
(d) Preparation of clindamycin phosphate sample solution. Accurately
weigh approximately 12 milligrams of the clindamycin phosphate sample
into a 50-milliliter glass-stoppered centrifuge tube. Pipet 25
milliliters of the pH 9.0 borate buffer into the centrifuge tube. Add
10 milliliters chloroform and shake vigorously for 15 minutes.
Centrifuge the resulting mixture and pipet a 20-milliliter aliquot of
the aqueous phase into a 35-milliliter centrifuge tube. Add a weighed
amount of intestinal alkaline phosphatase equivalent to 50 units of
activity5010 and allow the solution to stand until the enzyme has
completely dissolved. Place the tube into a water bath at 37 C. 2 C.
for 2.5 hours. After the 2.5-hour hydrolysis, allow the solution to cool
and proceed as directed in paragraph (f) of this section.
(e) Preparation of the clindamycin hydrochloride standard solution.
Accurately weigh approximately 9 milligrams of the clindamycin
hydrochloride working standard into a 35-milliliter glass-stoppered
centrifuge tube and dissolve in 20 milliliters of pH 9.0 borate buffer.
Proceed as directed in paragraph (f) of this section.
(f) Procedure. Add 10 milliliters of the internal standard solution
to each sample and standard solution. Shake the centrifuge tubes
vigorously for 30 minutes and centrifuge. Remove the aqueous layer and
discard. Shake the tubes again; mix in an ultrasonic mixer for 2
minutes, then centrifuge. No emulsion should be present at this stage.
Remove the remaining aqueous layer by suction and transfer a
3-milliliter aliquot of the chloroform layer to a 1-dram tablet vial
containing approximately 1 gram of anhydrous sodium sulfate. Swirl the
vial to dry the chloroform and transfer a 1-milliliter aliquot to
another 1-dram tablet vial. Using a 0.25-milliliter pipet, add 0.25
milliliter of trifluoracetic anhydride to each of the vials and place
into a water bath at 45 C. 2 C. for 30 minutes. Remove the vials
from the bath, add about 10 granules of anhydrous sodium carbonate to
each vial, and allow to stand for approximately 30 minutes. Centrifuge
the vials for approximately 10 minutes at 5,000 r.p.m. Inject 2
microliters of each of the resulting solutions into the gas
chromatograph. Use the conditions and materials listed in paragraphs
(a), (b), and (c) of this section. The elution order is:
Epiclindamycin (if present), clindamycin B (if present), clindamycin,
and internal standard. Calculate the clindamycin content as directed in
paragraph (g) of this section.
(g) Calculations. Calculate the clindamycin content of the sample as
follows:
Micrograms of clindamycin per milligram=
where:
Ru=Area of the clindamycin sample peak (at a retention time equal to
that observed for the clindamycin standard)/Area of internal standard
peak;
Ru=Area of the clindamycin standard peak/Area of internal standard
peak;
Ws=Weight of the clindamycin working standard in milligrams;
Wu=Weight of the sample in milligrams;
f=Potency of the clindamycin working standard in micrograms per
milligram.
(39 FR 18944, May 30, 1974, as amended at 41 FR 24704, June 18, 1976)
0094See footnote 4 to 436.303(a).
0105Defined such that 50 units hydrolyzes at least 20 micromoles of a
clindamycin phosphate authentic sample under the assay conditions
described in this section.
21 CFR 436.305 Thin layer chromatographic identity test for hetacillin.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 9 9 3.5 inches with a glass solvent trough on the
bottom.
(2) Plates. Use 20 20 centimeter thin layer chromatography plates
coated with Silica Gel G or equivalent to a thickness of 250 microns.
(b) Developing solvent. Mix 650 milliliters acetone with 100
milliliters distilled water, 100 milliliters benzene, and 25 milliliters
acetic acid.
(c) Spray solution. Dissolve 300 milligrams of ninhydrin in 100
milliliters of ethanol.
(d) Preparation of spotting solutions -- (1) Sample solution. Use
the sample solution prepared as described in the section for the
particular product to be tested.
(2) Reference solutions. Prepare a solution containing 10 milligrams
of an authentic hetacillin sample per milliliter in a 4:1 solution of
acetone and 0.1N hydrochloric acid, and a solution of ampicillin
standard at 1 mg/ml in the same solvent.
(e) Procedure. Spot a plate as follows: Apply approximately 10
microliters of the sample solution, 1 l, of the reference hetacillin
solution, and 1 l, of the ampicillin reference solution on a line 1.5
centimeters from the base of the silica gel plate and at intervals of
not less than 2.0 centimeters. Pour developing solvent into the glass
trough in the bottom of the chromatography tank. After all spots are
thoroughly dry, place the silica gel plate directly into the glass
trough of the chromatography tank. Cover and seal the tank. Allow the
solvent front to travel about 11.5 centimeters from the bottom of the
plate, remove the plate from the tank, and allow to air dry. Apply the
spray solution (do not saturate) and place immediately into an oven
maintained at 90 C. Heat 15 minutes.
(f) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
sample and standard should have spots of corresponding Rf values.
(39 FR 18944, May 30, 1974, as amended at 45 FR 16472, Mar. 14, 1980)
21 CFR 436.306 Lincomycin gas liquid chromatography.
(a) Equipment. Gas chromatograph equipped with a flame ionization
detector; Barber-Colman 5000 or equivalent.
(b) Reagents. (1) Pyridine, reagent grade, kept over potassium
hydroxide.
(2) Methanol, reagent grade, anhydrous.
(3) Ethanol, absolute, reagent grade.
(4) Internal standard: Prepare a solution containing 2 milligrams of
tetraphenylcyclopentadienone per milliliter in pyridine.
(5) Silylating reagent: Mix (9+1) of hexamethyldisilazane and
trimethyl chlorosilane.
(c) Typical conditions. (1) Column: 4 feet 3 millimeters ID,
glass, with 3 percent SE-30 on Gas-Chrom Q (100/120 mesh), or
equivalent.
(2) Temperatures: Column 225 C.; detector 280 C., injector 270 C.
(3) Carrier gas: Helium at 15 pounds per square inch.
(4) Detector: Hydrogen flame ionization -- hydrogen at 20 pounds per
square inch, air at 40 pounds per square inch.
(5) Sensitivity: 100; attenuation 2; current 2 10^8 amperes.
(d) Preparation of lincomycin sample and working standard solutions.
Prepare the sample and working standard as follows: Weigh accurately an
aliquot of about 40 milligrams into a 10-milliliter volumetric flask,
add sufficient pyridine to dissolve, and make to mark. Transfer a
1-milliliter aliquot to a glass-stoppered conical centrifuge tube and
proceed as directed in paragraph (e) of this section.
(e) Procedure. Add 0.2 milliliter of the silylating reagent to each
centrifuge tube and allow to stand at least 30 minutes. Then add
exactly 1 milliliter of the internal standard, shake well, and
centrifuge. Inject 5 microliters of the supernatant into the gas
chromatograph. Use the typical conditions and materials listed in
paragraphs (a), (b), and (c) of this section. The conditions should be
adequate to provide at least 60 percent scale deflection with the
lincomycin peak and to maintain a stable base line. The resolution of
the peaks should be complete. The elution order is lincomycin B,
lincomycin, and the internal standard. If necessary, adjust the current
setting for the lincomycin B peak to give a satisfactory response
relative to that of the lincomycin peak. Calculate the lincomycin
content and lincomycin B content as directed in paragraph (f) of this
section.
(f) Calculations.
Lincomycin content of sample in micrograms per milligram=
where:
Ru=Area of the lincomycin sample peak/Area of internal standard peak;
Rs=Area of the lincomycin standard peak/Area of internal standard
peak;
Ws=Weight of the lincomycin working standard in milligrams;
Wu=Weight of the sample in milligrams;
f=Potency of lincomycin working standard in micrograms per milligram.
Percent lincomycin B content=
where:
A=Area of lincomycin peak of the sample;
B=Area of lincomycin B peak of the sample corrected for the
attenuation adjustment.
(39 FR 18944, May 30, 1974, as amended at 46 FR 3839, Jan. 16, 1981)
21 CFR 436.307 Spectinomycin vapor phase chromatography.
(a) Equipment. Gas chromatograph equipped with a flame ionization
detector; Barber-Colman 5,000 or equivalent.
(b) Reagents. (1) Dimethylformamide, reagent grade, kept dry over
anhydrous sodium sulfate.
(2) Internal standard: Prepare a solution containing 2 milligrams of
triphenylantimony per milliliter in dry dimethylformamide.
(3) Silylating reagent: Hexamethyl-disilazane.
(c) Typical conditions. (1) Column: 4 feet by 4 millimeters ID,
glass, with 5 percent SE-52 on Diatoport S (80/100 mesh), or equivalent.
(2) Temperatures: Column 215 C.; detector 270 C.; injection port
265 C.
(3) Carrier gas: Helium 93 milliliters per minute at 15 pounds per
square inch.
(4) Detector: Hydrogen flame -- hydrogen at 20 pounds per square
inch, air at 40 pounds per square inch.
(5) Sensitivity: 1,000; attenuation, 10 for both spectinomycin and
internal standard; 2 10^6 amperes.
(d) Preparation of spectinomycin sample and working standard -- (1)
Working standard and bulk antibiotic solutions. (i) Accurately weigh
approximately 30 milligrams of sample or working standard into separate
glass-stoppered 25-milliliter Erlenmeyer flasks.
(ii) Add 10 milliliters of the internal standard solution and 1.0
milliliter of hexamethyldisilazane to each flask. Agitate the flasks to
insure dissolution of the sample and working standard and complete
mixing of the liquids. Shake the flasks intermittently for 1 hour.
Proceed as directed in paragraph (e) of this section.
(2) Finished product solutions. Prepare the sample for assay as
directed in the individual section for each antibiotic product to be
tested.
(e) Procedure. Inject 2.5 microliters of each solution into the gas
chromatograph. Use the conditions and materials listed in paragraphs
(a), (b), and (c) of this section. The conditions should be adequate to
maintain a stable base line and provide at least 60 percent deflection
of the recorder scale by the spectinomycin peak. The resolution of the
peaks should be complete. The internal standard will be eluted before
spectinomycin. Calculate the spectinomycin content as directed in
paragraph (f) of this section.
(f) Calculations. Calculate the spectinomycin content of the sample
as follows:
Micrograms of spectinomycin per milligrams=
where:
Ru=Area of spectinomycin sample peak (at a retention time equal to
that observed for the spectinomycin standard)/Area of internal standard
peak;
Rs=Area of the spectinomycin standard peak/Area of internal standard
peak;
Ws=Weight of the spectinomycin working standard in milligrams;
Wu=Weight of the sample in milligrams;
f=Potency of the spectinomycin working standard in micrograms per
milligram.
21 CFR 436.308 Paper chromatography identity test for tetracyclines.
(a) Equipment -- (1) Sheet (chromatographic). Whatman No. 1 filter
paper for chromatography, 20 20 centimeters.
(2) Chamber (chromatographic). Cylindrical glass chromatographic
jar, 25 centimeters high by 12 centimeters in diameter, with a
ground-glass lid.
(3) Preparation of solutions -- (i) pH3.5 buffer. Mix 13.93 volumes
of 0.1M citric acid with 6.07 volumes of 0.2M of disodium phosphate.
(ii) Solvent (organic phase). Mix chloroform, nitromethane, and
pyridine in volumetric proportions of 10:20:3, respectively.
(b) Preparation of spotting solutions. Prepare solutions of the
working standard and sample as follows: Accurately weigh a portion of
the working standard and sample and dilute with methanol to obtain a
concentration of 1 milligram per milliliter of antibiotic to be tested.
(c) Procedure. Fill the chamber to a depth of 0.6 centimeter with
freshly prepared solvent. Draw a starting line about 2.5 centimeters
from and parallel to the bottom of the sheet. Wet the sheet thoroughly
with the pH 3.5 buffer and blot it firmly between sheets of absorbent
paper. Starting about 5 centimeters from the edge of the sheet and at
1.5-centimeter intervals, apply to the starting line 2 microliters each
of standard solution, sample solution, and a 1:1 mixture of the standard
and sample solutions. Allow a few minutes for the sheet to dry
partially, and while still damp place it in the chamber with the bottom
edge touching the solvent. When the solvent front has risen about 10
centimeters, remove the sheet from the chamber. Expose the paper to
ammonia vapor. Examine the dried sheet under a strong source of
ultraviolet light and record the position of any fluorescent spots.
Measure the distance the solvent front traveled from the starting line
and the distance that the fluorescent spots are from the starting line.
Calculate the Rf value by dividing the latter by the former.
(39 FR 18944, May 20, 1974, as amended at 44 FR 30333, May 5, 1979;
45 FR 16472, 16474, Mar. 14, 1980)
21 CFR 436.309 Anhydrotetracyclines and 4-epianhydrotetracycline.
Determination of 4-epianhydrotetracycline and anhydrotetracyclines in
tetracycline, tetracycline hydrochloride, tetracycline phosphate, and in
dosage forms thereof is as follows:
(a) Screening procedure for total anhydrotetracyclines content -- (1)
Sample solution preparation -- (i) Bulk packaged for repacking or for
use in the manufacture of another drug. Accurately weigh approximately
50 milligrams of the sample into a 50-milliliter volumetric flask and
add 10 milliliters of 0.1N hydrochloric acid. Shake until sample is
completely dissolved, and then dilute to volume with water.
(ii) Sterile dispensing containers. Proceed as directed in paragraph
(a)(1)(i) of this section.
(iii) Capsules. Transfer a representative quantity of capsule
contents equivalent to 250 milligrams of tetracycline hydrochloride to a
250-milliliter volumetric flask. Add 50 milliliters of 0.1N
hydrochloric acid and shake on a mechanical shaker for 5 minutes.
Dilute to volume with water and filter through a fluted filter paper.
Discard the first 20 milliliters of filtrate and collect the next 20
milliliters.
(iv) Tablets. Grind a representative number of tablets to a fine
powder. Transfer an amount of the powder equivalent to 250 milligrams
of tetracycline hydrochloride to a 250-milliliter volumetric flask. Add
50 milliliters of 0.1N hydrochloric acid and shake on a mechanical
shaker for 5 minutes. Dilute to volume with water and filter through a
fluted filter paper. Discard the first 20 milliliters of filtrate and
collect the next 20 milliliters.
(v) Oral powders and suspensions. Proceed as described in paragraph
(b) of this section.
(2) Test procedure. Using a suitable spectrophotometer, determine
the absorbance of the sample solution prepared as directed in paragraph
(a)(1) of this section at 430 millimicrons using 0.02N hydrochloric acid
as a blank. Then accurately dilute 1.0 milliliter of the sample
solution to 100 milliliters with 0.02N hydrochloric acid and determine
the absorbance of this solution at 356 millimicrons, using 0.02N
hydrochloric acid as a blank.
(3) Calculations.
Percent anhydrotetracyclines=
where:
a430=Absorptivity (1%, 1 cm.) of sample at 430 millimicrons;
For bulk, absorptivity=
For sterile dispensing containers, capsules, and tablets;
absorptivity=Absorb-ance 10; a356=Absorptivity (1%, 1 cm.) of sample at
356 millimicrons;
For bulk, absorptivity=
For sterile dispensing containers, capsules and tablets;
absorptivity=Absorb-ance 1,000; 0.0019 Absorbance ratio (A430/A356)
observed with tetracycline;
195=Absorptivity (1%, 1 cm.) of anhydrotetracycline hydrochloride at
430 millimicrons.
(4) Evaluation. If the total anhydrotetracyclines content determined
by the screening procedure described in paragraph (a) of this section
exceeds 2 percent for bulks and 3 percent for injectables, tablets, and
capsules, perform the determination for anhydrotetracyclines and
4-epianhydrotetracycline described in paragraph (b) of this section. If
the results of the test described in paragraph (a) of this section for
total anhydrotetracyclines content are within the required limits in the
case of bulks, injectables, tablets, and capsules, these results may be
submitted in lieu of the results of the test for
4-epianhydrotetracycline and that test as described in paragraph (b) of
this section need not be performed.
(b) Determination of anhydrotetracyclines content and
4-epianhydrotetra-cycline content -- (1) Apparatus and reagents -- (i)
Chromatographic tubes (15 millimeters ID 170 millimeters long having
an outlet tube 4 millimeters ID 50 millimeters long).
(ii) pH meter standardized at pH 7.0 and at pH 10.0.
(iii) Diatomaceous earth, acid-washed (Celite 545 or equivalent).
(iv) EDTA buffer. Dissolve 0.1 mole ethylenediaminetetraacetic acid
disodium salt in 800 milliliters of water. Adjust to pH 7.8 with
ammonium hydroxide, reagent grade, and dilute to 1 liter with water.
(v) Chloroform, spectrophotometric grade.
(vi) Diluted ammonium hydroxide: Mix 1 volume of ammonium hydroxide,
reagent grade, with 9 volumes of distilled water.
(vii) 0.1N hydrochloric acid.
(viii) 1.0N hydrochloric acid.
(2) Preparation of support phase. Add 5 milliliters of EDTA buffer
to 10 grams of diatomaceous earth and mix until the diatomaceous earth
is uniformly moistened. It will no longer be free-flowing.
(3) Preparation of sample solutions. Prepare the sample solutions as
follows:
(i) Tetracycline, tetracycline phosphate complex, and tetracycline
hydrochloride bulk packaged for repacking or for use in the manufacture
of another drug. Place an amount of sample equivalent to 250 milligrams
of tetracycline hydrochloride into a 50-milliliter beaker and dissolve
in 10 milliliters of 0.1N hydrochloric acid. Immediately adjust the pH
to 7.8 with the diluted ammonium hydroxide, and if necessary, with 1.0N
hydrochloric acid and 0.1N hydrochloric acid. Quantitatively transfer
this solution to a 50-milliliter volumetric flask by rinsing the beaker
with EDTA buffer, fill to volume with EDTA buffer and shake well. Use
this solution without delay to prepare a column as directed in paragraph
(b)(4) of this section.
(ii) Capsules. Proceed as directed in paragraph (b)(3)(i) of this
section, except pool the contents of a representative number of capsules
and use an amount of the pooled capsule contents equivalent to 250
milligrams of tetracycline hydrochloride.
(iii) Tablets. Proceed as directed in paragraph (b)(3)(i) of this
section, except grind tablets to a powder in a small mortar and use an
amount of powder equivalent to 250 milligrams of tetracycline
hydrochloride.
(iv) Oral suspension and pediatric drops. Place 5 milliliters of
oral suspension equivalent to 125 milligrams of tetracycline
hydrochloride or 2 milliliters of pediatric drops equivalent to 200
milligrams of tetracycline hydrochloride into a 50-milliliter beaker and
add sufficient 0.1N hydrochloric acid to make 10 milliliters. Quickly
adjust the pH to 7.8 with the diluted ammonium hydroxide, and if
necessary, with 1N hydrochloric acid and 0.1N hydrochloric acid.
Quantitatively transfer this solution to a 25-milliliter flask by
rinsing the beaker with EDTA buffer, fill to volume with EDTA buffer,
and shake well. Use this solution without delay to prepare a column as
directed in paragraph (b)(4) of this section.
(v) Oral powders. Reconstitute as directed in the labeling and
proceed as directed in paragraph (b)(3)(iv) of this section.
(vi) Sterile dispensing containers. Proceed as directed in paragraph
(b)(3)(i) of this section.
(4) Column preparation. Pack support phase into the chromatographic
tube by increments and firmly tamp down each increment. Do not use any
glass wool in the column outlet. Add enough support phase to the column
to reach a height of 9 to 11 centimeters; then add 1 milliliter of
sample solution to 1 gram of diatomaceous earth in a small beaker, and
mix thoroughly. Pack the sample: diatomaceous earth mixture on top of
the column. Dry wash the beaker with support phase and pack an
additional 1-centimeter layer of support phase on top of the sample
layer.
(5) Column elution and fraction collection. Within 30 minutes after
preparing the column, elute with chloroform. Collect 5 successive
fractions of 5 milliliters, 5 milliliters, 10 milliliters, 10
milliliters, and 5 milliliters. During elution, two clear separate
yellow bands will appear on the column. The first band is
anhydrotetracyclines and will almost always elute in the first
5-milliliter fraction, but occasionally in the first and second
5-milliliter fractions. The second band is 4-epianhydrotetracycline and
will elute in the remaining fractions. Label the fraction or fractions
containing the first yellow band anhydrotetracyclines. Label the
fractions after the first yellow band 4-epianhydrotetracycline.
Determine the absorbance of each fraction at a wavelength of 438
nanometers using a suitable spectrophotometer equipped with a
1.0-centimeter cell and chloroform as the blank. If necessary, make
appropriate dilutions with choloroform to obtain a readable value.
(6) Calculations -- (i) Percent anhydrotetracyclines. Calculate the
percent anhydrotetracyclines as follows:
Number of milligrams of anhydrotetracyclines in each fraction
containing anhy-drotetracyclines=
where:
A=Absorbance of the sample solution at 438 nanometers;
b=Volume of fraction in milliliters;
c=Dilution factor of the fraction (for example, if 2 milliliters of
the fraction are diluted to 10 milliliters for reading, c will be 5).
20.28=Absorptivity (1 milligram per milliliter, 1 centimeter) of
anhydrotetra- cyclines in chloroform at 438 nanometers.
Total weight of anhydrotetracyclines in the sample=Sum of weights of
anhydrotetracyclines in the fractions labeled anhydrotetracyclines
Number of milliliters in the sample solution
Percent anhydrotetracyclines in tetracycline, tetracycline
hydrochloride, tetracycline phosphate complex bulk packaged for
repacking or for use in the manufacture of another drug=
Percent anhydrotetracyclines in dosage forms=
(ii) Percent 4-epianhydrotetracycline. Calculate the percent
4-epianhydrotetracycline as follows:
Number of milligrams of 4-epianhydrotetracycline in each fraction
labeled 4-epianhydrotetracycline=
where:
A=Absorbance of the sample solution at 438 nanometers;
b=Volume of the fraction in milliliters;
c=Dilution factor of the fraction (for example, if 2 milliliters of
the fraction are diluted to 10 milliliters for reading, c will be 5);
20.08=Absorptivity (1 milligram per milliliter, 1 centimeter) of
4-epianhydrotetracycline in chloroform at 438 nanometers.
Total weight of 4-epianhydrotetracycline in the sample=Sum of weights
of 4-epianhydrotetracycline in the fractions labeled
4-epianhydrotetracycline Number of milliliters in the sample solution
Percent 4-epianhydrotetracycline in tetracycline, tetracycline
hydrochloride, tetracycline phosphate complex bulk packaged for
repacking or for use in the manufacture of another drug=
Percent 4-epianhydrotetracycline in dosage forms=
(39 FR 18944, May 30, 1974, as amended at 40 FR 22251, May 22, 1975;
43 FR 11153, Mar. 17, 1978)
21 CFR 436.310 Thin layer chromatography identity test for mitomycin.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 9 9 3.5 inches, lined with filter paper and with a
solvent trough on the bottom.
(2) Plates. Use 20 by 20 centimeter thin layer chromatography plates
coated with silica gel G or equivalent, to a thickness of 250 microns.
(b) Reagents -- (1) Developing solvent. Mix n-butanol, glacial
acetic acid, and water in volumetric proportions of 4:2:1, respectively.
(2) Spray solution. Prepare a one-percent solution of ninhydrin in
ethanol.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 1 milligram of mitomycin
per milliliter, in water.
(d) Procedure. Pour the developing solvent into the solvent trough
on the bottom of the tank and onto the paper lining the walls of the
tank. Cover and seal the tank. Allow it to equilibrate for 30 minutes.
Prepare a plate as follows: Apply spotting solutions on a line 2.5
centimeters from the base of the silica gel plate and at points 2.0
centimeters apart. Apply approximately 2 microliters of the working
standard solution to points 1 and 3. When these spots are dry, apply
approximately 2 microliters of sample solution to points 2 and 3. After
all spots are thoroughly dry, place the silica gel plate into the trough
in the chromatography tank. Cover and seal the tank tightly. Allow the
solvent front to travel about 10 centimeters from the starting line.
Remove the plate and allow it to air dry. After the plate is dry, spray
lightly with the spray solution. Heat the plate in an oven at 110 C.
for 10-15 minutes. Mitomycin appears as a pink spot.
(e) Evaluation. The sample and standard should have spots of
corresponding Rf value (approximately 0.51), and standard and sample
combined should appear as a single spot of corresponding Rf value.
(39 FR 18944, May 30, 1974, as amended at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.311 Thin layer chromatography identity test for amoxicillin.
Using the sample solution prepared as described in the section for
the antibiotic drug to be tested, proceed as described in paragraphs (a)
through (e) of this section.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top. Line the inside walls of the tank
with Whatman's 3MM chromatographic paper (0.33 millimeters) or
equivalent.
(2) Plates. Use 20- by 20-centimeter thin layer chromatography
plates coated with Silica Gel G or equivalent to a thickness of 250
microns.
(b) Reagents -- (1) Developing solvent. Mix methyl alcohol,
chloroform, pyridine, and distilled water in volumetric proportions of
90:80:10:30, respectively.
(2) Spray solution. Dissolve 300 milligrams of ninhydrin in 100
milliliters of ethyl alcohol.
(c) Preparation of working standard. Weigh an amount of the
amoxicillin working standard equivalent to 200 milligrams of amoxicillin
into a 50-milliliter volumetric flask and bring to volume with 0.1N
hydrochloric acid.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate for at least 2 hours.
Spot duplicate plates by applying approximately 5 microliters each of
standard and sample solutions on a line 1.5 centimeters from the base of
the plate and at intervals of not less than 2.0 centimeters. All
solutions must be spotted within 10 minutes of preparation. Place
spotted plate in a desiccator until solvent has evaporated from spots.
Place the plate into the glass trough at the bottom of the
chromatography tank. Cover the tank. Allow the solvent to reach the
15-centimeter scored mark, remove the plate from the tank and dry with a
current of warm air until there is no detectable solvent odor. Apply
the ninhydrin spray solution to the plate -- do not saturate -- and
place immediately into an oven maintained at 110 C for 15 minutes.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former.
Amoxicillin has anRf value of about 0.53. The sample and standard should
have spots of corresponding Rf values.
(39 FR 34032, Sept. 23, 1974; 48 FR 11427, Mar. 18, 1983, as amended
at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.312 Atomic absorption method for determining the zinc
content of zinc bacitracin.
(a) Equipment. An atomic absorbance spectrophotometer equipped with
a zinc hollow-cathode discharge lamp, an air-acetylene flame, a
nebulizer-burner system for introducing the sample solution into the
flame, an optical dispersing device (such as a monochromator) for
isolating a resonance line of zinc from others produced by the emission
source, and a suitable radiation detector and recorder.
(b) Preparation of working standard and sample solutions -- (1)
Workingstandard solutions. Prepare a standard stock solution containing
10 milligrams of zinc per milliliter as follows: Weigh 3.11 grams of
zinc oxide into a 250-milliliter volumetric flask, add 80 milliliters of
1N HCl, warm to dissolve, cool to room temperature, and dilute to volume
with water. Dilute aliquots of this standard stock solution with 0.001N
HCl to obtain three working standard solutions containing respectively
0.5, 1.5, and 2.5 micrograms of zinc per milliliter.
(2) Sample solution. Accurately weigh approximately 200 milligrams
of the sample into a 100-milliliter volumetric flask. Dissolve and
dilute to volume with 0.01N HCl. Transfer a 2.0-milliliter aliquot of
this solution to a 200-milliliter volumetric flask and dilute to volume
with 0.001N HCl.
(c) Procedure. Using 0.001N HCl as the blank, adjust the absorbance
of the instrument to zero at a detection wavelength of 213.8 nanometers.
Determine the absorbance of each standard solution and the sample
solution at 213.8 nanometers.
(d) Calculations. Plot the absorbance versus the concentration of
each of the working standard solutions. Draw a straight response line
of best fit through these points. Read the concentration of zinc in
micrograms per milliliter corresponding to the absorbance of the sample
solution. Calculate the percent zinc in the sample as follows:
Percent zinc=
where:
C=Concentration of zinc in the sample solution in micrograms per
milliliter;
m=Percent moisture in the sample.
(40 FR 15088, Apr. 4, 1975)
21 CFR 436.316 Determination of penicillin G content.
(a) Reagents. The reagents are freshly prepared every three days and
are of such quality that when used in this procedure with an authentic
sample of penicillin G, not less than 97 percent of penicillin G is
recovered.
(1) Amyl acetate (iso-amyl acetate) solution. Saturate the amyl
acetate (boiling range 138.5 C -- 141.5 C) with the N-ethylpiperidine
salt of penicillin G by adding 2 milligrams of the salt for each 1.0
milliliter of the solvent. Cool this solution to 0 C -- 8 C and
filter it through a sintered-glass filter immediately before use.
(2) Acetone solution. Saturate reagent grade acetone with the
N-ethylpiperidine salt of penicillin G using 3 milligrams of salt for
each 1 milliliter of acetone. Cool this solution to 0 C -- 8 C and
filter it through a sintered-glass filter immediately before use.
(3) N-ethylpiperidine solution. N-ethylpiperidine (boiling range
129.5 C -- 131.0 C) should be stored in brown bottles in a
refrigerator. Dilute 1.0 milliliter of this reagent with 4.0
milliliters of amyl acetate. Saturate this solution with the
N-ethylpiperidine salt of penicillin G, using about 3 milligrams of the
salt for each 1.0 milliliter of solution. Cool this solution to 0 C --
8 C and filter it through a sintered-glass filter immediately before
use.
(4) Phosphoric acid solution. Prepare by dissolving 1.0 milliliter
of reagent grade phosphoric acid (85 percent) in 4.0 milliliters of
water. Cool to 0 C -- 8 C and shake before using.
(5) Silica gel. Use dry silica gel (mesh size 6-16, Tyler standard).
Place about 0.5 gram of the silica gel in a micro filter funnel
(approximately 10-millimeter diameter) having a fritted-glass disc of
medium porosity.
(b) Procedure. Accurately weigh from 60 to 70 milligrams of the
sample to be tested, except if penicillin G procaine is to be tested
weigh 90 to 100 milligrams of sample, into a glass test tube or glass
vial of approximately 10-milliliter capacity. Add 2.0 milliliters of
water to dissolve or suspend (procaine) the penicillin and cool to 0 C
-- 5 C. Add 2.0 milliliters of amyl acetate solution and 0.5
milliliter of phosphoric acid solution, stopper and shake the container
vigorously for approximately 15 seconds. For penicillin G procaine, add
a second 0.5-milliliter portion of phosphoric acid solution and shake
vigorously. Centrifuge to obtain a clear separation of the two layers
(approximately 20 seconds). If any penicillin procaine remains
undissolved, add a third 0.5-milliliter portion of phosphoric acid
solution, shake the container vigorously, and centrifuge. After
centrifuging, remove as much of the amyl acetate layer as possible,
usually about 1.7 milliliters to 1.8 milliliters, with a suitable
hypodermic needle and syringe and place the portion removed into the
filter funnel containing silica gel, described in paragraph (a)(5) of
this section. Allow the amyl acetate to remain in contact with the
silica gel for exactly 20 seconds, then apply suction and collect the
filtrate in a small test tube placed in a suction flash surrounded by
cracked ice. Pipet a 1.0-milliliter aliquot of the amyl acetate
filtrate into a tared flat-bottom glass tube (approximately 15 x 50
millimeters) containing 1.0 milliliter of acetone solution and 0.5
milliliter of N-ethylpiperidine solution. The time elapsing between
acidification and the addition of the filtrate to the above reagents
should not be more than 3 minutes. Place the glass tube containing the
mixture into a large weighing bottle, stopper the bottle and allow to
stand for not less than 2 hours in a refrigerator at 0 C -- 8 C.
Remove the liquid from the precipitate by means of a tared micro filter
stick and wash with a total of 1.0 milliliter of acetone solution adding
the latter by means of a hypodermic syringe equipped with a fine needle.
Place the filter stick inside the glass tube, dry under vacuum at room
temperature for not less than 1 hour, and weigh. (The N-ethylpiperidine
penicillin G residues can be saved for saturating reagents).
(c) Calculations. Calculate the percent penicillin G content as
follows:
Percent penicillin G content=
(42 FR 59857, Nov. 22, 1977)
21 CFR 436.317 Solubility characteristic test for griseofulvin
(ultramicrosize) tablets.
(a) Apparatus -- (1) Vessel. A cylindrical glass tank. The
approximate dimensions are 40 centimeters in diameter and at least 23
centimeters in height.
(2) Heating system. A 1,500-watt immersion heating element connected
to a partial immersion, contact thermometer and an appropriate control
relay.
(3) Circulating system components. The circulating system consists
of three different circulating devices:
(i) Circulating pump of a centrifugal, immersion type. Tubing
approximately 1 centimeter outside diameter and 46 centimeters in length
is attached to the pump outlet producing a flow rate of approximately
1,600 milliliters per minute when operated as described.
(ii) A ''4-element stirrer'' consisting of a motor and a shaft
approximately 45 centimeters long and 8 millimeters in diameter. The
motor rotates the vertical shaft in a clockwise direction at
approximately 180 revolutions per minute. There are 4 elements or sets
of stirring blades on the shaft. One set, located at the bottom of the
shaft, is a 3-bladed element of 2.5 centimeters overall radius with
circular blades, 1.8 centimeters in diameter and 1 to 2 millimeters in
thickness, pitched at an angle of approximately 45 degrees from the
horizontal plane, so that fluid is propelled downward when the shaft is
rotated in a clockwise direction. The three remaining sets of stirring
blades have 4 blades each, symmetrically positioned about the shaft.
Each set of blades is 3.2 centimeters in overall radius. Each blade is
rectangular in shape, 2.4 centimeters in length, 1.2 centimeters in
height, and 1 to 2 millimeters in thickness. The four sets of blades
are located at 5 centimeter intervals on the shaft, the top three being
fixed in a staggered configuration.
(iii) A rotating basket device consisting of a motor capable of
constant speed of 100 5 revolutions per minute in a clockwise direction,
a shaft, and a cylindrical basket. The shaft and the basket are
fabricated from Type 316 stainless steel. The shaft is 6 millimeters in
diameter and approximately 30 centimeters in length. It must run true
on the motor axis so that the basket rotates smoothly and without
perceptible wobble. The basket consists of two parts, one of which, the
top, is attached to the shaft. It is of solid metal except for a
2-millimeter round vent, and is fitted with three spring clips that
allow the removal of the lower part, or the basket proper, to admit the
test sample. The detachable part of the basket is fabricated of welded
seam stainless steel, 40 mesh woven wire cloth, formed into a cylinder
3.66 centimeters high and 2.5 centimeters in diameter, with a narrow rim
of sheet metal around the top.
(4) Circulating system configuration. All three circulating devices
are located in one half of the tank. In clockwise order they are the
circulating pump, the rotating basket, and the 4-element stirrer. There
is a distance of 12 to 13 centimeters between each of the three devices.
The rotating basket shaft and the stirring shaft are located 9 to 10
centimeters from the tank wall. The 4-element stirrer is positioned 1
to 1.5 centimeters from the bottom of the tank. The rotating basket is
fixed at 7 to 8 centimeters from the bottom. The circulating pump
intake is located approximately 3 centimeters from the top of the fluid
in the tank and 5 to 6 centimeters from the wall of the tank. The
pump's outlet hose is held by a clamp so that hose makes a clockwise arc
around the inside wall of the tank, descending to a point near the
bottom of the tank and 5 to 6 centimeters from the wall, which is 180
degrees from the pump inlet.
(b) Dissolution medium. Distilled water.
(c) Procedure. Place 24 liters of dissolution medium into the vessel
and maintain the temperature at 37 0.5 C by means of the heater,
circulating pump, and the 4-element stirrer. Withdraw a 25-milliliter
portion of the dissolution medium as a sample-blank solution. Place one
tablet into the basket, and lower it into its proper position in the
tank. Rotate the basket at 100 5 revolutions per minute in a clockwise
direction. After 60 minutes, withdraw a second 25-milliliter portion as
the sample solution. Filter the sample-blank solution and the sample
solution through water-washed glass wool, or an equivalent filter,
discarding the first 10 to 15 milliliters of each filtrate. Determine
the amount of griseofulvin dissolved as directed in paragraph (d)(2) of
this section.
(d) Griseofulvin assay -- (1) Preparation of standard solution and
standard-blank solution. Accurately weigh approximately 50 milligrams
of griseofulvin working standard and place into a 100-milliliter
volumetric flask. Dissolve and dilute to volume with methyl alcohol.
Transfer 2.0 milliliters of this solution to a 200-milliliter volumetric
flask and dilute to volume with distilled water. This is the standard
solution. Transfer a 2.0-milliliter portion of methyl alcohol to a
200-milliliter volumetric flask and dilute to volume with distilled
water. This is the standard-blank solution. Filter the standard-blank
solution and the standard solution through water-washed glass wool, or
an equivalent filter, discarding the first 10 to 15 milliliters of each
filtrate.
(2) Procedure. Using a suitable spectrophotometer and distilled
water as the blank, determine the absorbance of the four filtered
solutions at the absorbance peak at approximately 295 nanometers, using
suitable spectrophotometer cells with a 1-centimeter light path.
Determine the exact position of the absorbance peak for the particular
instrument used.
(3) Calculation. Determine the percentage of griseofulvin dissolved
as follows:
Percent griseofulvin dissolved=
Where:
Au=Absorbance of the sample solution minus the absorbance of the
sample-blank solution;
Ws=Weight of the working standard in milligrams;
V=Volume of the dissolution medium in liters;
As=Absorbance of the standard solution minus the absorbance of the
standard-blank solution;
P=Labeled potency of the sample in milligrams of griseofulvin per
tablet.
(e) Evaluation. The tablet passes the solubility characteristic test
if it dissolves to the extent of not less than 50 percent at 60 minutes.
If the tablet fails to meet this requirement, repeat the test on five
additional tablets. The batch passes the solubility characteristic test
if not less than 5 of 6 tablets meet the requirement.
(40 FR 41522, Sept. 8, 1975; 40 FR 45426, Oct. 2, 1975)
21 CFR 436.318 Continuous flow thin layer chromatography identity test.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide equipped with a glass solvent trough in the bottom.
(2) Plates. Use a 20 20 centimeter thin-layer chromatography plate
coated with Silica Gel G or equivalent to a thickness of 250
micrometers.
(3) Cover. A stainless steel cover with a slot, measuring 21 0.6
centimeters, cut in the front edge.
(4) Supporting platform. A platform that can be placed in the bottom
of the chromatography tank so that the solvent trough is elevated about
3.75 centimeters.
(b) Reagents -- (1) Developing solvent. Mix chloroform, redistilled
methanol and concentrated ammonium hydroxide in volumetric proportions
of 25:60:30, respectively.
(2) Spray solution. Dissolve 1 gram of ninhydrin in 100 milliliters
of n-butanol and add 1 milliliter of pyridine.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 6 milligrams of antibiotic
to be tested per milliliter in distilled water.
(d) Procedure. Prepare a plate as follows: On a line 2 centimeters
from the base of the silica gel plate, and at intervals of 1 centimeter,
spot 3 microliters each of the standard solution and the sample
solution. In addition, prepare one spot composed of 3 microliters of
the sample solution and 3 microliters of the standard solution. Place
the supporting platform in the bottom of the tank and place the solvent
trough on it, near the front of the tank. Place a piece of Whatman 3
MM filter paper or equivalent, measuring 20x3 centimeters and folded in
half, lengthwise, over the front edge of the tank to form a cushion and
drying wick for the plate. Place the plate in the solvent trough with
the coated side toward the front of the tank and leaning against the
filter paper at the top. Pour the developing solvent into the trough
and bottom of the tank. Cover the tank. The plate should extend
approximately 1 centimeter beyond the top of the tank and through the
slot in the cover. Seal all the openings in the tank with masking tape,
except where the plate leans against the filter paper. Remove the plate
from the tank after 5.5 hours. Allow the plate to air dry and then heat
it for 15 minutes at 110 C in an oven. Remove the plate from the oven
and immediately spray it with the spray solution. The compound appears
as a pink spot.
(e) Evaluation. The sample and standard should have traveled the
same distance from the origin, and the standard and sample combined
should appear as a single spot that has traveled the same distance as
the sample and standard individually.
(40 FR 57797, Dec. 12, 1975)
21 CFR 436.319 Thin layer chromatography identity test for bacitracin
and bacitracin zinc.
(a) Equipment -- (1) Chromatography tank. A rectangular tank
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top. Line the inside walls of the tank
with Whatman 3MM chromatographic paper or equivalent.
(2) Plates. Use a 20- by 20-centimeter thin layer chromatography
plate coated with silica gel G or equivalent to a thickness of 250
micrometers. Activate the plate by heating for 20 minutes at 110 C.
Allow to cool to room temperature and use immediately.
(b) Reagents -- (1) Developing solvent. Mix n-butanol, water,
pyridine, glacial acetic acid, and ethyl alcohol in volumetric
proportions of 60:10:6:15:5, respectively.
(2) Spray solution. Dissolve 1 gram of ninhydrin in a mixture of 1
milliliter of pyridine and sufficient n-butanol to make 100 milliliters.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 6.0 milligrams of
bacitracin per milliliter in 1 percent disodium ethylenediamine
tetraacetic acid in water.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate for at least 30
minutes. Prepare a plate as follows: On a line 2.0 centimeters from
the base of the silica gel plate, and at intervals of 2.0 centimeters,
spot approximately 1.0 microliter of the standard solution to points 1
and 3. When these spots are dry, apply approximately 1.0 microliter of
sample solution to points 2 and 3. After all spots are thoroughly dry,
place the base of the silica gel plate directly into the glass trough in
the chromatography tank. Cover and seal the tank. Allow the solvent
front to travel approximately 13 centimeters from the starting line.
Remove the plate from the tank, and allow it to air dry. After the
plate is dry, spray lightly with the spray solution. The plate may take
1 hour or more to develop at room temperature. The development may be
speeded up by warming the plate in a 110 C oven.
(e) Evaluation. The sample and standard should have spots of
corresponding Rf value (approximately 0.26) and standard and sample
combined should appear as a single spot of corresponding Rf value.
(42 FR 27228, May 27, 1977)
21 CFR 436.320 Ferric chloride colorimetric assay.
(a) Reagents. (1) 1N hydrochloric acid.
(2) 0.01N hydrochloric acid.
(3) Ferric chloride stock solution. Quickly weigh (very hygroscopic)
5.0 grams of FeCl3 6H2O into a 100-milliliter beaker. Add approximately
10 milliliters of 1N hydrochloric acid and stir to dissolve.
Quantitatively transfer to a 50-milliliter glass-stoppered amber
volumetric flask and make up to volume with water.
(4) Ferric chloride working reagent. Pipette 10.0 milliliters of
ferric chloride stock solution into a 2-liter volumetric flask, add 20
milliliters 1N hydrochloric acid, and bring to volume with water. Check
the pH; it should be between 2.0 and 2.1.
(b) Standard solution. Accurately weigh approximately 50 milligrams
of the working standard of the antibiotic to be tested and dissolve with
25 milliliters of 0.1N hydrochloric acid. Quantitatively transfer to a
250-milliliter volumetric flask and dilute to volume with distilled
water. Keep in a glass-stoppered flask and store under refrigeration.
Discard solution after 7 days.
(c) Sample solution. Accurately weigh approximately 50 milligrams of
the sample and dissolve with 25 milliliters of 0.1N hydrochloric acid.
Quantitatively transfer to a 250-milliliter volumetric flask and dilute
to volume with distilled water.
(d) Procedure. Pipette exactly 10.0 milliliters of the standard
solution and of the sample solution into separate test tubes. To each
tube add exactly 10 milliliters of ferric chloride working reagent, mix,
and allow to stand 15 minutes. Determine the absorbance of each
solution at 490 nanometers in a suitable spectrophotometer against a
blank prepared from 10.0 milliliters of 0.01N hydrochloric acid and 10.0
milliliters of ferric chloride working reagent.
(e) Estimation of potency. Calculate the potency as follows:
Micrograms of antibiotic per milligram=
(43 FR 11154, Mar. 17, 1978; 43 FR 34456, Aug. 4, 1978)
21 CFR 436.321 Griseofulvin gas liquid chromatography.
(a) Equipment. Gas chromatograph equipped with an electronic
integrator and with a flame ionization detector: Hewlett Packard 7600
or equivalent.
(b) Reagents. (1) Chloroform, reagent grade.
(2) Internal standard solution: Prepare a solution containing 1.0
milligram of tetraphenylcyclopentadienone per milliliter in chloroform.
(c) Typical conditions -- (1) Column. 1.2 meters by 4 millimeters
ID, glass, packed with 1 percent OV-17 on Gas Chrom Q (100/120 mesh), or
equivalent.
(2) Temperatures. Column 245 C; detector 260 C; injection port
260 C.
(3) Carrier gas. Helium approximately 60 millimeters per minute and
40 pounds per square inch (1.7 kilograms per square centimeter).
(4) Detector. Hydrogen flame ionization-hydrogen at 12 pounds per
square inch (0.5 kilogram per square centimeter), air at 34 pounds per
square inch (1.43 kilograms per square centimeter).
(5) Sensitivity. Adjusted to obtain peak heights greater than 50
percent full scale deflection.
(d) Preparation of griseofulvin sample and working standard
solutions. Accurately weigh approximately 40 milligrams of both the
sample and the working standard into separate 25-milliliter volumetric
flasks. Add sufficient internal standard solution to dissolve the
contents of each flask with vigorous mixing and then dilute to volume
with internal standard solution and mix. Proceed as directed in
paragraph (e) of this section.
(e) Procedure. Inject 1.0 microliter of this solution into the gas
chromatograph. Use the typical conditions and materials listed in
paragraphs (a), (b), and (c) of this section. The resolution of the
peaks should be complete. The griseofulvin peak will elute before the
internal standard peak. Calculate the griseofulvin content as directed
in paragraph (f) of this section.
(f) Calculations. Calculate the griseofulvin content of the sample
as follows:
Micrograms of griseofulvin per milligram=
where:
Ru=Area of the griseofulvin sample peak (at a retention time equal to
that observed for the griseofulvin standard)/Area of the internal
standard peak;
Rs=Area of the griseofulvin working standard peak/Area of the
internal standard peak;
Ws=Weight of the griseofulvin working standard in milligrams;
Wu=Weight of the sample in milligrams;
f=Potency of the griseofulvin working standard in micrograms per
milligram.
(44 FR 20660, Apr. 6, 1979)
21 CFR 436.322 High-pressure liquid chromatographic assay for
anthracycline antibiotics.
(a) Equipment. A suitable high-pressure liquid chromatograph, such
as a Waters Associates Model 2441 or equivalent equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator;
(6) A 30-centimeter column having an inside diameter of 4.6
millimeters and packed with a suitable reverse phase packing such as:
Waters Associates, Micro-Bondapak C18. 1
(b) Reagents. (1) Solvent mixture: Water: acetonitrile (69:31).
(2) Mobile phase: Water: acetonitrile (69:31) adjusted to pH 2 with
phosphoric acid. Filter the mobile phase through a suitable glass fiber
filter or equivalent that is capable of removing particulate
contamination to 1 micron in diameter. Degas the mobile phase just
prior to its introduction into the chromatograph pumping system.
(3) Internal standard solution: Prepare a
2.0-milligram-per-milliliter solution of 2-naphthalenesulfonic acid in
the solvent mixture.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.5 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the reference standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Procedure. Use the standard and sample solutions prepared as
directed in the individual monographs for the drug being tested. Use
the equipment, reagents, and operating conditions listed in paragraphs
(a), (b), and (c) of this section. Inject 5 microliters of the standard
solution into the chromatograph. Allow an elution time sufficient to
obtain satisfactory separation of expected components (ordinarily this
time is 20 minutes). After separation of the standard solution has been
completed, inject 5 microliters of the sample solution into the
chromatograph and repeat the procedure described for the standard
solution. The elution order is: Void volume, internal standard,
doxorubicin, dihydrodaunomycin, daunomycin, adriamycinone,
dihydrodaunomycinone, bromodaunomycin, daunomycinone, and
bis-anhydrodaunomycinone.
(e) Calculations. Calculate the anthracycline content as directed in
the individual monograph for the drug being tested.
(43 FR 44836, Dec. 29, 1978)
1Available from Waters Associates, Inc., Maple St., Milford, Mass.
10757.
21 CFR 436.323 Continuous flow thin layer chromatography identity test
for cefamandole nafate.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide equipped with a glass solvent trough in the bottom.
(2) Plates. Use a 20 x 20 centimeter thin-layer chromatography plate
coated with silica gel G or equivalent to a thickness of 250
micrometers.
(3) Cover. A stainless steel cover with a slot measuring 21 x 0.6
centimeters, cut in the front edge.
(4) Supporting platform. A platform that can be placed in the bottom
of the chromatography tank so that the solvent trough is elevated about
3.75 centimeters.
(b) Reagents -- (1) Developing solvent. Mix n-butanol, glacial
acetic acid, and water in volumetric proportions of 4:1:1, respectively.
(2) Spray solution. Mix starch iodide solution, glacial acetic acid,
and 0.1 N iodine test solution, U.S.P. in volumetric proportions of
50:3:1. Prepare the starch iodide solution by mixing starch iodide paste
test solution, U.S.P. and water in volumetric proportions of 1:1.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 1 milligram of cefamandole
nafate per milliliter in distilled water.
(d) Procedure. Prepare a plate as follows: On a line 2 centimeters
from the base of the silica gel plate, and at intervals of 1 centimeter,
spot 5 microliters each of the standard solution and the sample
solution. In addition, prepare one spot composed of 5 microliters of
the sample solution and 5 microliters of the standard solution. Place
the supporting platform in the bottom of the tank and place the solvent
trough on it, near the front of the tank. Place a piece of Whatman 3
MM filter paper or equivalent, measuring 20 x 3 centimeters and folded
in half, lengthwise, over the front edge of the tank to form a cushion
and drying wick for the plate. Place the plate in the solvent trough
with the coated side toward the front of the tank and leaning against
the filter paper at the top. Pour the developing solvent into the
trough and bottom of the tank. Cover the tank. The plate should extend
approximately 1 centimeter beyond the top of the tank and through the
slot in the cover. Seal all the openings in the tank with masking tape,
except where the plate leans against the filter paper. Remove the plate
from the tank after 4 hours. Allow the plate to air dry and then heat
it in an oven for 15 minutes at 110 C. Remove the plate from the oven
and immediately spray it with the spray solution. The compound appears
as a white spot on a purple background.
(e) Evaluation. The sample and standard should have traveled the
same distance from the origin, and the combined standard and sample
should appear as a single spot that has traveled the same distance as
the sample and standard individually.
(44 FR 20664, Apr. 6, 1979)
21 CFR 436.324 Polarographic analysis of cefamandole.
(a) Equipment -- (1) Polarograph. Use a polarograph equipped with a
dropping mercury indicating electrode, a platinum auxilliary electrode,
and a saturated calomel reference electrode, such as Princeton Applied
Research Model 1741 or equivalent.
(2) X-Y plotter. Use a suitable X-Y plotter, such as Houston
Omnigraphic Model 2200-3-32 or equivalent.
(3) Nitrogen. Use a nitrogen tank equipped with a pressure-reducing
regulator and a filter to remove traces of oxygen, such as an oxisorb
filter1 or equivalent.
(b) Reagent. pH 2.3 Buffer: Dissolve 3.6 grams of dibasic sodium
phosphate, 39.4 grams of citric acid, and 70.8 grams of potassium
chloride in sufficient distilled water to make 1 liter.
(c) Operating conditions -- (1) Operating mode: Differential pulse.
(2) Scan range: ^0.3 volt to ^1.05 volts.
(3) Scan rate: ^2 millivolts per second.
(4) Sensitivity: 10 to 20 microamperes or equivalent to keep peak on
scale.
(5) Mercury drop time: 1 second per drop.
(6) Modulation amplitude: 25 millivolts.
(7) Display direction: +
(8) Damping: None.
(d) Preparation of sample and working standard solutions. Use the
cefamandole lithium working standard. Accurately weigh approximately 12
milligrams of sample or working standard into a 50-milliliter volumetric
flask. Dissolve the sample or working standard in 4 milliliters of
distilled water. Immediately prior to polarography, add 30 milliliters
of pH 2.3 buffer, dilute to volume with distilled water, and mix.
(e) Procedure. Transfer a portion of the sample or working standard
solution to the polarographic cell. Pass a stream of nitrogen through
the solution for 5 minutes to remove the dissolved oxygen. After 5
minutes, disperse the nitrogen above the sample. Start the mercury
dropping from the mercury dropping electrode, and, using the operating
conditions described in paragraph (c) of this section, record the
polarogram. Compare the polarogram of the sample to that of the working
standard.
(f) Calculations. Calculate the potency of cefamandole as follows:
Micrograms of cefamandole per milligram=
where:
A=The peak height of the sample;
B=The peak height of the working standard.
The peak height is obtained from the polarogram by measuring the
vertical distance from the peak to the baseline of the sample or working
standard.
(44 FR 20664, Apr. 6, 1979, as amended at 47 FR 20756, May 14, 1982)
1Available from Princeton Applied Research Corporation, P.O. Box
2565, Princeton, NJ 08540.
2Available from Houston Instrument, 8500 Cameron Road, Austin, TX
78753.
21 CFR 436.325 High pressure liquid chromatography assay for
vidarabine.
(a) Equipment. A suitable high pressure liquid chromatograph, such
as a Waters Associates Model 2441 or equivalent, equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A 30-centimeter column having an inside diameter of 4 millimeters
and packed with a suitable octadecyl bonded silica phase packing such as
Waters Associates, Micro-Bondapak C18. 1
(b) Mobile phase. (1) Transfer 2.2 grams of sodium dioctyl
sulfosuccinate and 10 milliliters of glacial acetic acid to a 1-liter
volumetric flask. Dissolve with 500 milliliters of methanol, dilute to
volume with distilled water, and mix. Filter the mobile phase through a
suitable glass fiber filter or equivalent that is capable of removing
particulate contamination to 1 micron in diameter.
(2) De-gas the mobile phase just before its introduction into the
chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.5 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the reference standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Preparation of sample and working standard solutions. Accurately
weigh approximately 24 milligrams of sample or working standard into a
200-milliliter volumetric flask. Add about 150 milliliters of distilled
water and heat on a steam bath for 10 minutes. Shake until all the
powder is dissolved. Cool to room temperature and dilute to volume with
distilled water.
(e) Procedure. Using the equipment, mobile phase, and operating
conditions listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the sample or working standard solution
prepared as directed in paragraph (d) of this section into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of expected components. The elution order is void volume, 9-
-D-arabinofuranosylhypoxanthine (if present), vidarabine, and adenine
(if present).
(f) Calculations. Calculate the vidarabine content as follows:
Micrograms of vidarabine per milligram=
where:
A=Area of the vidarabine sample peak (at a retention time equal to
that observed for the standard);
B=Area of the standard peak;
Ws=Weight of standard in milligrams;
Wu=Weight of sample in milligrams; and
f=Potency of standard in micrograms per milligram.
(44 FR 30334, May 25, 1979, as amended at 47 FR 23708, June 1, 1982)
1Available from Waters Associates, Inc., Maple St., Milford, MA
10757.
21 CFR 436.326 Thin layer chromatographic identity test for cefoxitin
sodium.
Using the sample solution prepared as described in the section for
the antibiotic drug to be tested, proceed as described in paragraphs
(a), (b), (c), (d), and (e) of this section.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top. Line the inside walls of the tank
with Whatman 3 MM, chromatographic paper or equivalent.
(2) Plates. Use a 20 20 centimeter thin layer chromatography plate
coated with silica gel G or equivalent to a thickness of 250
micrometers.
(b) Developing solvent. Mix ethyl acetate, pyridine, n-butanol,
acetic acid, and water in volumetric proportions of 42:21:21:6:10,
respectively.
(c) Spray solution. Immediately before use, mix 100 milliliters of a
1-percent ferric chloride solution in 1 percent hydrochloric acid with
100 milliliters of a 1-percent potassium ferricyanide solution and 75
milliliters of methanol.
(d) Preparation of working standard solution. Prepare a solution
containing approximately 2.5 milligrams per milliliter of cefoxitin
working standard in distilled water.
(e) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate for 1 hour. Prepare a
plate as follows: On a line 2 centimeters from the base of the silica
gel plate, and at intervals of 2 centimeters, spot 10 microliters each
of the standard solution and the sample solution. After all spots are
thoroughly dry, place the silica gel plate directly into the glass
trough. Cover and seal the tank. Allow the solvent front to travel
about 15 centimeters from the starting line. Remove the plate from the
tank and heat it for 1 hour at 60 C in a circulating air oven. Remove
the plate from the oven and allow it to cool at room temperature. Apply
the spray solution and allow it to air dry. After approximately 15
minutes, the compound appears as a blue spot on a yellow-green
background.
(f) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
sample and standard should have spots of corresponding Rf values.
(44 FR 10373, Feb. 20, 1979, as amended at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.327 Thin layer chromatographic identity test for
cyclacillin.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 x 23 x 9 centimeters, with a glass solvent trough on
the bottom and a tight-fitting cover.
(2) Plates. Use 20 x 20 centimeter thin layer chromatography plates
coated with Silica Gel G or equivalent to a thickness of 250 microns.
(b) Reagents -- (1) Developing solvent. One percent ammonium formate
aqueous solution.
(2) Spray solution. Dilute starch iodide paste TS (U.S.P. XIX) with
an equal volume of water. Mix diluted starch iodide paste, glacial
acetic acid, and 0.1N iodine in volumetric proportions of 50:3:1,
respectively.
(c) Assay solutions -- (1) Preparation of working standard solution.
Accurately weigh an amount of cyclacillin working standard and dissolve
the material with sufficient 0.1N sodium hydroxide to obtain a solution
containing 1 milligram per milliliter. Allow the solution to stand for
15 minutes before using.
(2) Preparation of sample solution. Using the sample solution
prepared as described in the section for the antibiotic to be tested,
proceed as described in paragraphs (d) and (e) of this section.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank. Cover and seal the tank. Allow it to
equilibrate. Prepare a plate as follows: On a line 2 centimeters from
the base of the thin layer chromatography plate and at intervals of 2
centimeters, spot 5 microliters each of the working standard solution
and sample solution. Dry the spots thoroughly with a stream of dry air.
Place the plate in the trough in the chromatography tank. Cover and
seal the tank. Allow the solvent front to travel about 15 centimeters
from the starting line and then remove the plate from the tank. Dry the
plate by heating for 30 minutes at 80 C in a circulating air oven.
Visualize the spots by applying the spray solution.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line, and the distance the spots are from the starting
line. Divide the latter by the former to calculate the Rf value. The
sample and standard should appear as white spots against a blue
background at an Rf of approximately 0.6. The test is satisfactory if
the Rf value of the sample compares with that of the working standard.
(46 FR 2981, Jan. 13, 1981, as amended at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.328 High pressure liquid chromatographic assay for
sulfisoxazole acetyl content.
(a) Equipment. A suitable high pressure liquid chromatograph, such
as a Waters Associates Model 2441 or equivalent equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with a suitable reverse phase packing such as:
Waters Associates, Micro-Bondapak C18;1 and
(6) A suitable integrator.
(b) Reagents -- (1) Mobile phase. Mix acetonitrile (high pressure
liquid chromatography grade): water (40:60). Filter the mobile phase
through a suitable glass fiber filter or equivalent which is capable of
removing particulate contamination to 1 micron in diameter. De-gas the
mobile phase just prior to its introduction into the chromatograph
pumping system.
(2) Internal standard solution. Dissolve 0.33 milligram of
benzanilide per milliliter in acetonitrile (high pressure liquid
chromatography grade). Filter the solution through a suitable glass
fiber filter or equivalent which is capable of removing particulate
contamination to 1 micron in diameter.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.2 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for reference standard that
is at least 50 percent of scale. The minimum between peaks must be no
more than 2 millimeters above the baseline.
(d) Preparation of the working standard and sample solutions -- (1)
Working standard solution. Prepare a solution containing 1.0 milligram
per milliliter of sulfisoxazole acetyl in the internal standard
solution.
(2) Sample solution. Reconstitute the sample as directed in the
labeling. Allow to stand for 1 hour. Shake gently and transfer 5.0
milliliters of the sample to a separatory funnel. Extract the
suspension three times with 75-milliliter portions of chloroform.
Collect the chloroform layers in a 250-milliliter volumetric flask.
Dilute the flask to volume with chloroform and mix. Filter a portion of
the solution through a suitable glass fiber filter or equivalent which
is capable of removing particulate contamination to 1 micron in
diameter. Transfer a 4.0-milliliter aliquot of the filtrate into a
25-milliliter glass-stoppered flask and evaporate to dryness under a
stream of dry air. Dissolve the residue in 10.0 milliliters of the
internal standard solution, stopper, and mix.
(e) Procedure. Using the equipment, reagents, and operating
conditions listed in paragraphs (a), (b), and (c) of this section,
inject 5 microliters of sample or working standard solution prepared as
described in paragraph (d) of this section, into the chromatograph.
Allow an elution time sufficient to obtain satisfactory separation of
expected components. The elution order is void volume, sulfisoxazole
acetyl and benzanilide.
(f) Calculations. Calculate the sulfisoxazole content as follows:
Milligrams of sulfisoxazole per milliliter of sample=
where:
A=Area of sample peak (at a retention time equal to that of the
standard) divided by the area of the internal standard peak;
B=Area of the standard peak divided by the area of the internal
standard peak;
0.864=The molecular weight of sulfisoxazole divided by the molecular
weight of sulfisoxazole acetyl.
(46 FR 2990, Jan. 13, 1981)
1Available from: Waters Associates, Inc., Maple Street, Milford, MA
10757.
21 CFR 436.329 High-pressure liquid chromatographic assay for
meclocycline.
(a) Equipment. A suitable high-pressure liquid chromatograph, such
as a Waters Associates Model 2441 or equivalent equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 340 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator;
(6) A column approximately 25 centimeters in length having an inside
diameter of approximately 4 millimeters and packed with a suitable
reverse-phase packing such as: 10 micrometer silica gel particles
bonded to octadecyl silane, Vydac 201 TP Reverse Phase2 or equivalent.
(b) Reagents -- (1) 0.001M Ammonium (ethylenedinitrilo) tetraacetate.
Moisten 293 milligrams of (ethylenedinitrilo) tetraacetic acid with 1
milliliter of methanol and dissolve in 7 milliliters of concentrated
ammonium hydroxide. Dilute to 900 milliliters with distilled water,
adjust the pH to 6.6 with glacial acetic acid, and dilute to 1,000
milliliters with distilled water.
(2) Mobile phase. Mix 150 milliliters of tetrahydrofuran
(high-pressure liquid chromatography grade) with 850 milliliters of
0.001M ammonium (ethylenedinitrilo) tetraacetate. Filter the mobile
phase through a suitable glass fiber filter or equivalent that is
capable of removing particulate contamination to 1 micron in diameter.
Degas the mobile phase just prior to its introduction into the
chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 0.8 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the reference standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Preparation of sample and working standard solutions. Accurately
weigh an amount of sample or working standard equivalent to
approximately 25 milligrams of meclocycline into a 50-milliliter
volumetric flask. Dissolve and dilute to volume with methanol and mix.
Transfer exactly 3.0 milliliters of this solution to a 25-milliliter
volumetric flask, dilute to volume with mobile phase, and mix.
(e) Procedure. Using the equipment, reagents, and operating
conditions listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the sample or working standard solution
prepared as described in paragraph (d) of this section into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of expected components. The elution order is void volume,
oxytetracycline (if present), demeclocycline (if present), methacycline
(if present), and meclocycline.
(f) Calculations. Calculate the meclocycline content as follows:
Micrograms of meclocycline per milligram=
where:
A=Area or peak height of the sample peak (at a retention time equal
to that observed for the standard);
B=Area or peak height of the standard peak.
(46 FR 3836, Jan. 16, 1981)
1Available from: Waters Associates, Inc., Maple St., Milford, MA
10757.
2Available from: The Separations Group, 16640 Spruce St., Hesperia,
CA 92345.
21 CFR 436.330 Thin layer chromatographic identity test for
bacampicillin.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 23 9 centimeters, with a glass solvent trough on
the bottom and a tight-fitting cover, lined with Whatman's 3MM
chromatographic paper (0.3 millimeter) or equivalent.
(2) Plates. Use 20 20 centimeter thin layer chromatography plates
coated with Silica Gel 60F 254 or equivalent to a thickness of 250
microns.
(b) Reagents -- (1) Developing solvent. Mix methylene chloride,
chloroform, and 95 percent ethyl alcohol in volumetric proportions of
100:10:10, respectively.
(2) Spray solution. Dissolve 1 gram of ninhydrin in 100 milliliters
of n-butanol and add 1 milliliter of pyridine.
(c) Spotting solutions -- (1) Preparation of working standard
solution. Dissolve and dilute a weighed amount of the bacampicillin
hydrochloride working standard with sufficient 95 percent ethyl alcohol
to obtain a solution containing 2 milligrams per milliliter.
(2) Preparation of sample solution. Dissolve and dilute a weighed
amount of the sample with sufficient 95 percent ethyl alcohol to obtain
a solution containing 2 milligrams per milliliter. Proceed as described
in paragraphs (d) and (e) of this section.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate for one hour. Prepare
a plate as follows: On a line 2.5 centimeters from the base of the thin
layer chromatography plate and at intervals of 2.0 centimeters, spot 5
microliters of the working standard solution to positions 1 and 3. When
these spots are dry, apply 5 microliters of the sample solution to
points 2 and 3. After all the spots are thoroughly dry, place the plate
into the trough in the bottom of the tank. Cover and tightly seal the
tank, allow the solvent front to travel about 15 centimeters from the
starting line (about 30 minutes) and then remove the plate from the
tank. Air dry the plate. Visualize the spots by spraying with spray
solution and heating in an oven at 100 C for approximately 10 minutes.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line, and the distance the spots are from the starting
line. Divide the latter by the former to calculate the Rf value.
Bacampicillin appears as a purple spot at an Rf value of approximately
0.52. The test is satisfactory if the Rf value of the sample compares
with that of the working standard. The combined spot should appear as a
single spot of corresponding Rf value.
(46 FR 25602, May 8, 1981, as amended at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.331 High-pressure liquid chromatographic assay for
dactinomycin.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers to 10 micrometers in
diameter, U.S.P. XX.
(b) Mobile phase. Mix acetonitrile (high-pressure liquid
chromatography grade): water (60:40). Filter the mobile phase through a
suitable glass fiber filter or equivalent that is capable of removing
particulate contamination to 1 micron in diameter. Degas the mobile
phase just prior to its introduction into the chromatograph pumping
system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2.5 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Preparation of working standard and sample solutions -- (1)
Preparation of working standard solution. Prepare a solution containing
0.25 milligram per milliliter of dactinomycin in mobile phase.
(2) Preparation of sample solution. Prepare the sample solution as
described in the individual monograph for the drug being tested.
(e) Procedure. Use the equipment, mobile phase, operating
conditions, and working standard and sample solutions described in
paragraphs (a), (b), (c), and (d) of this section, and proceed as
directed in paragraph (e)(1) of this section.
(1) System suitability test. Equilibrate and condition the column by
passage of about 10 to 15 void volumes of mobile phase followed by two
or more replicate injections of 10 microliters each of the working
standard solution. Allow an elution time sufficient to obtain
satisfactory separation of expected components after each injection.
Record the peak responses and, calculate the relative standard deviation
as described for system suitability tests in the U.S.P. XX General
Chapter 621 chromatography. Proceed as directed in paragraph (e)(2) of
this section if the minimum performance requirement for the relative
standard deviation is not more than 1.0 percent. If the minimum
performance requirement is not met, adjustment must be made to the
system to obtain satisfactory operation before proceeding as described
in paragraph (e)(2) of this section.
(2) Determination of the chromatogram. Inject 10 microliters of the
working standard solution into the chromatograph. Allow an elution time
sufficient to obtain satisfactory separation of the expected components.
After separation of the working standard solution has been completed,
inject 10 microliters of the sample solution into the chromatograph and
repeat the procedure described for the working standard solution.
(f) Calculations. Calculate the dactinomycin content as described in
the individual monograph for the drug being tested.
(49 FR 24017, June 11, 1984, as amended at 50 FR 5749, Feb. 12, 1985)
21 CFR 436.332 High-pressure liquid chromatographic assay for
moxalactam.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter,
U.S.P. XX;
(5) A suitable recorder of at least 25.4 centimeter deflection;
(6) A suitable integrator.
(b) Mobile phase. Mix 0.01M ammonium acetate:methanol (19:1).
Filter the mobile phase through a suitable glass fiber filter or
equivalent that is capable of removing particulate contamination to 1
micron in diameter. Degas the mobile phase just prior to its
introduction into the chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 0.5 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard solution. Transfer the contents
of an ampoule of working standard to a tared weighing bottle. Place the
unstoppered weighing bottle in a desiccator containing a saturated
aqueous solution of potassium carbonate to provide an atmosphere of 42
percent relative humidity. Allow the moisture content of the working
standard to equilibrate for 16 hours. Determine the moisture content as
described in 436.201 of this chapter. Equilibrated standard material
must be kept in a closed weighing bottle and used within 36 hours of
equilibration. Dissolve approximately 50 milligrams of the working
standard, accurately weighed and corrected for moisture, with sufficient
distilled water to obtain a solution containing 0.5 milligram of
moxalactam per milliliter. Use the prepared solution immediately.
(e) Preparation of sample solution. Mix contents of vial thoroughly.
Dissolve an accurately weighed portion of approximately 50 milligrams
of sample with distilled water to obtain a concentration of 0.5
milligram per milliliter (estimated); also, reconstitute the sample as
directed in the labeling. Then using a suitable hypodermic needle and
syringe, remove all of the withdrawable contents if it is represented as
a single dose container; or, if the labeling specifies the amount of
potency in a given volume of the resultant preparation, remove an
accurately measured representative portion from each container. Further
dilute an aliquot of this solution with distilled water to obtain a
concentration of 0.5 milligram per milliliter (estimated). Use the
prepared solution immediately.
(f) Procedure. Using the equipment, reagents, and operating
conditions as listed in paragraphs (a), (b), and (c) of this section,
inject 5 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of the expected components. After separation of the working
standard solution has been completed, inject 5 microliters of the sample
solution into the chromatograph and repeat the procedure described for
the working standard solution.
(g) Calculations. (1) Calculate the moxalactam content in micrograms
per milligram as follows:
Micrograms of moxalactam per milligram of sample=
where:
Ru=Sum of the areas of the moxalactam sample R-isomer and the
S-isomer peaks;
Rs=Sum of the areas of the moxalactam working standard R-isomer and
the S-isomer peaks;
Wu=Weight of the sample in milligrams;
Ws=Weight of the moxalactam working standard in milligrams;
P=Potency of the moxalactam working standard in micrograms per
milligram, corrected for moisture.
(2) Calculate the moxalactam content of the vial as follows:
Milligrams of moxalactam per vial=
where:
Ru=Sum of the areas of the moxalactam R-isomer and the S-isomer
peaks;
Rs=Sum of the areas of the moxalactam working standard R-isomer and
the S-isomer peaks;
Ws=Weight of the moxalactam working standard in milligrams;
P=Potency of the moxalactam working standard in micrograms per
milligram, corrected for moisture;
d=Dilution factor.
(3) Calculate the ratio of R-isomer to S-isomer as follows:
Ratio of R-isomer to S-isomer=
(46 FR 61069, Dec. 15, 1981)
21 CFR 436.333 Thin layer chromatographic identity test for moxalactam.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top. Line the inside walls of the tank
with Whatman 3MM chromatographic paper or equivalent.
(2) Plates. Use a 20x20 centimeter thin layer chromotagraphy plate
coated with silca gel G or equivalent to a thickness of 250 micrometers.
(b) Developing solvent. Mix ethyl acetate, glacial acetic acid,
acetonitrile, and water in volumetric proportions of 42:14:14:18,
respectively.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 10 milligrams per
milliliter of moxalactam in distilled water.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate for 1 hour. Prepare a
plate as follows: On a line 2 centimeters from the base of the silica
gel plate, and at intervals of 2 centimeters, spot 10 microliters each
of the standard solution and the sample solution. After all spots are
thoroughly dry, place the silica gel plate directly into the glass
trough. Cover and seal the tank. Allow the solvent front to travel
about 15 centimeters from the starting line. Remove the plate from the
tank and air dry. Expose the plate to iodine vapors for 40 minutes.
Immediately circumscribe all spots using a suitable marker.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
sample and standard should have spots of corresponding Rf values and
intensity.
(46 FR 61070, Dec. 15, 1981, as amended at 49 FR 2242, Jan. 19, 1984)
21 CFR 436.334 High-pressure liquid chromatographic assay for
piperacillin.
(a) Equipment. A high-pressure liquid chromatograph equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator;
(6) A 25-centimeter column having an inside diameter of 4.6
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter
(United States Pharmacopeia XX).
(b) Reagents. (1) 0.2M monobasic sodium phosphate: Dissolve 27.60
grams of monobasic sodium phosphate with sufficient water to make 1,000
milliliters.
(2) 10 percent tetrabutylammonium hydroxide in water.
(3) Ampicillin-piperacillin solution: Dissolve and dilute 25
milligrams of ampicillin and 5 milligrams of piperacillin monohydrate
with sufficient mobile phase to obtain 100 milliliters, and mix.
(c) Mobile phase. Methanol:water:0.2M monobasic sodium phosphate:10
percent tetrabutylammonium hydroxide (450:447:100:3) adjusted to pH 5.5
0.02 with phosphoric acid. The concentration of reagents may be varied
to obtain acceptable operation of the system. De-gas the mobile phase
just prior to its introduction into the chromatograph pumping system.
(d) Preparation of working standard and sample solutions -- (1)
Working standard solution. Place approximately 20 milligrams of the
working standard, accurately weighed, into a 50-milliliter volumetric
flask. Add 25 to 30 milliliters of mobile phase. Shake until
dissolved. Dilute to volume with mobile phase.
(2) Sample solution -- (i) Micrograms per milligram. Place
approximately 20 milligrams of the sample, accurately weighed, into a
50-milliliter volumetric flask. Add 25 to 30 milliliters of mobile
phase. Shake until dissolved. Dilute to volume with mobile phase.
(ii) Milligrams per vial. Reconstitute as directed in the labeling.
Withdraw the total contents and dilute with mobile phase to a
concentration of 0.4 milligram of piperacillin per milliliter.
(e) Procedure. Use the equipment, reagents, mobile phase, and
working standard and sample solutions described in paragraphs (a), (b),
(c), and (d) of this section and proceed as directed in paragraph (e) of
this section.
(1) Systems suitability test. Chromatograph three replicate samples
of ampicillin-piperacillin solution as directed in paragraph (e)(2) of
this section. Allow an elution time sufficient to obtain satisfactory
separation of expected components after each injection. Record the peak
responses and calculate the resolution factor as described for system
suitability tests in the United States Pharmacopeia XX General Chapter
621 for gas chromatography. The resolution factor between ampicillin
and piperacillin is not less than 15. If the resolution factor does not
meet this limit, adjustments must be made to the system to obtain
satisfactory operation before proceeding as described in paragraph
(e)(2) of this section.
(2) Determination of the chromatogram. Operate the high-pressure
liquid chromatograph at ambient temperature at a flow rate of one
milliliter per minute. Use a detector sensitivity setting that gives a
peak height for the reference standard that is at least 50 percent of
scale. Purge the column with mobile phase until a steady baseline is
established. Inject 10 microliters of the working standard solution
into the chromatograph. Allow an elution time sufficient to obtain
separation of the expected components. After separation of the working
standard solution has been completed, inject 10 microliters of the
sample solution into the chromatograph and repeat the procedure
described for the working standard solution.
(f) Calculations -- (1) Calculate the piperacillin content in
micrograms per milligram as follows:
Micrograms of piperacillin per milligram of sample =
where:
A=Area of the sample peak (at a retention time equal to that observed
for the standard);
B=Area of the standard peak.
(2) Calculate the piperacillin content in grams per vial as follows:
Grams of piperacillin per vial =
where:
A=Area of the sample peak (at a retention time equal to that observed
for the standard);
B=Area of the standard peak;
d=Dilution factor.
(47 FR 15768, Apr. 13, 1982; 47 FR 33493, Aug. 3, 1982)
21 CFR 436.335 High-pressure liquid chromatographic assay for
chloramphenicol palmitate.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 280 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter,
U.S.P. XX.
(b) Mobile phase. Mix methanol:water:glacial acetic acid (170:30:1).
Degas the mobile phase just prior to its introduction into the
chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2.0 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the reference standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Preparation of sample and working standard solutions. Accurately
weigh approximately 65 milligrams of sample or chloramphenicol palmitate
working standard each into a 50-milliliter volumetric flask. Add
approximately 35 milliliters of methanol and 1 milliliter of glacial
acetic acid. Place in an ultrasonic bath for 10 minutes and dilute to
volume with methanol.
(e) Procedure. Using the equipment, mobile phase, and operating
conditions listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of expected components. After separation of the working
standard solution has been completed, inject 10 microliters of the
sample solution into the chromatograph and repeat the procedure
described for the working standard solution.
(f) Calculations. Calculate the chloramphenicol content as follows:
where:
A=Area of chloramphenicol palmitate sample peak (at a retention time
equal to that observed for the standard);
B=Area of the working standard peak;
Ws=Weight of standard in milligrams;
Wu=Weight of sample in milligrams; and
f=Micrograms of chloramphenicol activity per milligram of
chloramphenicol palmitate working standard.
(49 FR 6091, Feb. 17, 1984)
21 CFR 436.336 Thin layer chromatographic identity test for azlocillin.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top.
(2) Iodine vapor chamber. A rectangular tank approximately 23
centimeters long, 23 centimeters high, and 9 centimeters wide, with a
suitable cover, containing iodine crystals.
(3) Plates. Use 20 x 20 centimeter thin layer chromatography plates
coated with Silica Gel G or equivalent to a thickness of 250 microns.
(b) Reagents -- (1) Buffer. Dissolve 9.078 grams of potassium
phosphate, monobasic (KH2PO4) in sufficient distilled water to make
1,000 milliliters (solution A). Dissolve 17.88 grams of sodium
phosphate, dibasic, heptahydrate (Na2HPO4.7H2O) in sufficient distilled
water to make 1,000 milliliters (solution B). Place 12.1 milliliters of
solution B into a 100-milliliter volumetric flask and dilute to volume
with solution A.
(2) Developing solvent. Place 50 milliliters of n-butyl acetate, 9
milliliters of n-butanol, 25 milliliters of glacial acetic acid, and 15
milliliters of buffer into a separatory funnel. Shake well and allow
the layers to separate. Discard the lower phase and use the upper phase
as the developing solvent.
(c) Preparation of spotting solutions. Prepare solutions of the
sample and working standard, each containing 20 milligrams of azlocillin
per milliliter in distilled water.
(d) Procedure. Pour developing solvent into the glass trough on the
bottom of the chromatography tank to a depth of about 1 centimeter. Use
the chamber immediately. Prepare plate as follows: Apply spotting
solutions on a line 2.5 centimeters from the base of the silica gel
plate and at points 2.0 centimeters apart. Apply approximately 10
microliters of the working standard solution to points 1 and 3. When
these spots are dry, apply approximately 10 microliters of sample
solution to points 2 and 3. Place spotted plate in a desiccator until
solvent has evaporated from spots. Place the plate into the glass
trough at the bottom of the chromatography tank. Cover the tank. Allow
the solvent to travel about 15 centimeters from the starting line.
Remove the plate from the tank and allow to air dry. Warm the iodine
vapor chamber to vaporize the iodine crystals and place the dry plate in
the iodine vapor chamber until the spots are visible, usually about 10
minutes.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
azlocillin sample and the standard should have spots of corresponding Rf
values (approximately 0.4), and standard and sample combined should
appear as a single spot for azlocillin. The penicilloate and penilloate
of azlocillin as well as ampicillin appear as additional spots with Rf
values of approximately 0.15, 0.3, and 0.25, reectively.
(47 FR 53348, Nov. 26, 1982)
21 CFR 436.337 High-pressure liquid chromatographic assay for
cephradine.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 8 millimeters;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder that is compatible with the detector output;
(5) A suitable integrator (optional); and
(6) A 25-centimeter column having an inside diameter of 4.6
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 10 micrometers in diameter, U.S.P. XX.
(b) Reagents. (1) 4 percent glacial acetic acid.
(2) 3.86 percent sodium acetate.
(c) Mobile phase. 4 percent glacial acetic acid:3.86 percent sodium
acetate:methanol:distilled water (3:15:200:782). Filter the mobile phase
through a suitable glass fiber filter or equivalent that is capable of
removing particulate contamination to 1 micron in diameter. Degas the
mobile phase prior to its introduction into the chromatograph pumping
system. The distilled water:methanol ratio may be varied to obtain
acceptable operation of the system.
(d) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.2 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the cephradine in the
cephradine working standard that is about 75 percent of full scale.
(e) Preparation of working standard and sample solutions -- (1)
Preparation of cephradine working standard solution. Place an
accurately weighed portion of the cephradine working standard into a
suitably sized container. Add 5.0 milliliters of distilled water and
place in an ultrasonic bath to facilitate dissolution. Dilute with a
sufficient amount of mobile phase to obtain a solution containing 0.8
milligram of cephradine activity per milliliter.
(2) Preparation of cephalexin working standard solution. Dissolve an
accurately weighed portion of the cephalexin working standard with
mobile phase to obtain a solution containing 0.02 milligram of
cephalexin activity per milliliter. Place in an untrasonic bath to
facilitate dissolution.
(3) Preparation of sample solutions -- (i) Product not packaged for
dispensing (micrograms of cephradine per milligram). Dissolve an
accurately weighed portion of the sample with mobile phase to obtain a
solution containing 0.8 milligram per milliliter. Place in an
ultrasonic bath to facilitate dissolution. Using this sample solution,
proceed as directed in paragraph (f)(1) of this section.
(ii) Product packaged for dispensing. Determine both micrograms of
cephradine per milligram of the sample and milligrams of cephradine per
container. Use separate containers for preparation of each sample
solution as described in paragraphs (e)(3)(ii) (a) and (b) of this
section.
(a) Micrograms of cephradine per milligram. Dissolve an accurately
weighed portion of the sample with mobile phase to obtain a solution
containing 0.8 milligram per milliliter. Place in an ultrasonic bath to
facilitate dissolution. Using this sample solution, proceed as directed
in paragraph (f)(1) of this section.
(b) Milligrams of cephradine per container. Reconstitute the sample
as directed in the labeling. Then, using a suitable hypodermic needle
and syringe, remove all of the withdrawable contents if it is
represented as a single-dose container; or, if the labeling specifies
the amount of potency in a given volume of the resultant preparation,
remove an accurately measured representative portion from each
container. Dilute the solution thus obtained with mobile phase to
obtain a solution containing 0.8 milligram per milliliter. Using this
sample solution, proceed as directed in paragraph (f)(1) of this
section.
(f) Procedure -- (1) Cephradine content. Using the equipment,
reagents, mobile phase, and operating conditions as listed in paragraphs
(a), (b), (c), and (d) of this section, inject 10 microliters of the
cephradine working standard solution into the chromatograph. Allow an
elution time sufficient to obtain satisfactory separation of the
expected components. After separation of the working standard solution
has been completed, inject 10 microliters of the sample solution
prepared as described in paragraph (e)(3)(i) of this section into the
chromatograph and repeat the procedure described for the working
standard solution. The elution order is void volume, cephalexin, and
cephradine. If the sample is packaged for dispensing, repeat the
procedure for each sample solution prepared as described in paragraphs
(e)(3)(ii) (a) and (b) of this section.
(2) Cephalexin content. Proceed as directed in paragraph (f)(1) of
this section, except:
(i) Use a detector sensitivity setting that gives a peak height for
the cephalexin in the cephalexin working standard that is about 75
percent of full scale; and
(ii) Use the cephalexin working standard in lieu of the cephradine
working standard.
(g) Calculations. (1) Calculate the micrograms of cephradine per
milligram of sample as follows:
where:
Au=Area of the cephradine peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard);
As=Area of the cephradine peak in the chromatogram of the cephradine
working standard;
Ps=Cephradine activity in the cephradine working standard solution in
micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(2) Calculate the cephradine content of the vial as follows:
where:
Au=Area of the cephradine peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard);
As=Area of the chephradine peak in the Chromatogram of the cephradine
working standard;
Ps=Cephradine activity in the cephradine working standard solution in
micrograms per milliliter;
Cs=Milligrams of the standard per milliliter; and
d=Dilution factor of the sample.
(3) Calculate the percent cephalexin content of the sample as
follows:
where:
Aa=Area of the cephalexin peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard);
Ab=Area of the cephalexin peak in the chromatogram of the cephalexin
working standard;
Wb=Milligrams of cephalexin per milliliter of cephalexin working
standard solution;
Wu=Milligrams of cephradine per milliliter of sample solution;
Pb=Micrograms of cephalexin per milligram of cephalexin working
standard; and
m=Percent moisture content of the sample.
(49 FR 47483, Dec. 5, 1984)
21 CFR 436.338 High-pressure liquid chromatographic assay for
cefoperazone.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator;
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter,
United States Pharmacopeia XX.
(b) Mobile phase. Mix 1.2 milliliters 1M triethylammonium acetate,
2.8 milliliters 1M acetic acid, and 120 milliliters acetonitrile in a
one liter flask and dilute to volume with distilled water. Filter the
mobile phase through a suitable glass fiber filter or equivalent that is
capable of removing particulate contamination to 1 micron in diameter.
Degas the mobile phase just prior to its introduction into the
chromatographic pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2.0 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard solution. Dissolve approximately
40 milligrams of working standard, accurately weighed, with mobile phase
to obtain a solution containing 0.16 milligram of cefoperazone activity
per milliliter.
(e) Preparation of sample solutions -- (1) Product not packaged for
dispensing (micrograms of cefoperazone per milligram). Dissolve an
accurately weighed portion of the sample with sufficient mobile phase to
obtain a solution containing 0.16 milligram of cefoperazone activity per
milliliter. Using this sample solution, proceed as directed in
paragraph (f) of this section.
(2) Product packaged for dispensing. Determine both micrograms of
cefoperazone per milligram of the sample and milligrams of cefoperazone
per container. Use separate containers for preparation of each sample
solution as described in paragraph (e)(2)(i) and (ii) of this section.
(i) Micrograms of cefoperazone per milligram. Dissolve and
accurately weighed portion of the sample with sufficient mobile phase to
obtain a solution containing 0.16 milligram of cefoperazone activity per
milliliter. Using this sample solution, proceed as directed in
paragraph (f) of this section.
(ii) Milligrams of cefoperazone per container. Reconstitute the
sample as directed in the labeling. Then using a suitable hypodermic
needle and syringe, remove all of the withdrawable contents if it is
represented as a single-dose container; or, if the labeling specifies
the amount of potency in a given volume of the resultant preparation,
remove an accurately measured representative portion from each
container. Further dilute and aliquot of this solution with mobile
phase to a concentration of 0.16 milligram of cefoperazone activity per
milliliter. Using this sample solution, proceed as directed in
paragraph (f) of this section.
(f) Procedure. Using the equipment, reagents, and operating
conditions as listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of the expected components. After separation of the working
standard solution has been completed, inject 10 microliters of the
sample solution prepared as described in paragraph (e)(1) of this
section into the chromatograph and repeat the procedure described for
the working standard solution. If the sample is packaged for
dispensing, repeat the procedure for each sample solution prepared as
described in paragraphs (e)(2)(i) and (ii) of this section.
(g) Calculations -- (1) Calculate the micrograms of cefoperazone per
milligram of sample as follows:
Micrograms of cefoperazone per milligram=
where:
Au=Area of the cefoperazone sample peak (at a retention time equal to
that observed for the standard);
As=Area of the cefoperazone working standard peak;
Ps=Cefoperazone activity in the cefoperazone working standard
solution in micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(2) Calculate the cefoperazone content of the vial as follows:
Milligrams of cefoperazone per vial =
where:
Au=Area of the cefoperazone sample peak (at a retention time equal to
that observed for the standard);
As=Area of the cefoperazone working standard peak;
Ps=Cefoperazone activity in the cefoperazone working standard
solution in micrograms per milliliter; and
d=Dilution factor of the sample.
(48 FR 789, Jan. 7, 1983; 48 FR 7439, Feb. 22, 1983; 48 FR 28250,
June 21, 1983)
21 CFR 436.339 High-pressure liquid chromatographic assay for bleomycin
fractions.
(a) Equipment. A high-pressure liquid chromatograph equipped with:
(1) Two solvent pumps;
(2) A solvent programmer;
(3) A low dead volume cell 8 to 20 microliters;
(4) A light path length of 1 centimeter;
(5) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(6) A suitable recorder;
(7) A suitable integrator; and
(8) A suitable-sized column approximately 25 centimeters in length
having an inside diameter of 4.6 millimeters and packed with octadecyl
silane chemically bonded to porous silica or ceramic microparticles, 5
to 10 micrometers in diameter, USP XX.
(b) Reagents -- (1) 0.005M 1-pentanesulfonic acid in 0.5 percent
acetic acid adjusted to pH 4.3 with concentrated ammonium hydroxide.
Filter and degas before using.
(2) Methanol, spectrophotometric grade. Filter and degas before
using.
(3) Mobile phase. Adjust the solvent programmer for linear gradient
development starting with a mixture of 0.005M 1-pentanesulfonic
acid:methanol (9:1) and ending with a mixture of 0.005M
1-pentanesulfonic acid:methanol (6:4) in 1 hour at a flow rate of 1.2
milliliters per minute. Minor flow rate and gradient changes can be
made as necessary depending on column and instrument conditions.
Disodium ethylenediaminetetraacetic acid USP at a concentration of
0.005M may be added to the mobile phase if necessary for satisfactory
performance.
(c) Preparation of sample solution. Reconstitute the vial with 6
milliliters of deaerated water.
(d) Procedure. Using the equipment and reagents listed in paragraphs
(a) and (b) of this section, start pumping the mobile solvent at the
initial conditions. Inject 10 microliters of the sample solution into
the chromatograph and begin the linear gradient pumping program. After
the final mobile phase conditions are reached (1 hour) continue to pump
the solvent mixture for an additional 20 minutes or until the
demethylbleomycin A2 is eluted. The elution order is void volume,
bleomycinic acid, bleomycin A2, bleomycin A5, bleomycin B2, bleomycin
B4, and demethylbleomycin A2.
(e) Calculations. Calculate the percentage of each bleomycin by
comparing its peak area contribution to that of the total response of
all the bleomycins.
(48 FR 51912, Nov. 15, 1983)
21 CFR 436.340 High-pressure liquid chromatographic assay for
tetracycline hydrochloride content and 4-epitetracycline hydrochloride
content.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles.
(b) Mobile phase. Dissolve 0.55 gram of monobasic ammonium phosphate
in 900 milliliters of water. Adjust the pH to 1.8 with concentrated
phosphoric acid and dilute to 1 liter with water. Mix 800 milliliters
of this solution with 200 milliliters of methanol. Filter the mobile
phase through a suitable glass fiber filter that is capable of removing
particulate contamination to 1 micron in diameter. Degas the mobile
phase just prior to its introduction into the chromatography pumping
system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.0 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the 4-epitetracycline
peak that is at least 50 percent of scale.
(d) Preparation of working standard and sample solutions -- (1)
Working standard solution. Accurately weigh approximately 18 milligrams
of the tetracycline hydrochloride working standard into a 50-milliliter
volumetric flask. Into the same flask, accurately weigh approximately
38 milligrams of the 4-epitetracycline working standard. Dissolve and
dilute to volume with a methanol:water mixture (7:18).
(2) Sample solution. Reconstitute the sample as directed in the
labeling. Transfer 10.0 milliliters of the reconstituted sample into a
50-milliliter volumetric flask and dilute to volume with a
methanol:water mixture (7:18).
(e) Procedure. Using the equipment, reagents, and operating
conditions as listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain separation of
the expected components. After separation of the working standard
solution has been completed, inject 10 microliters of the sample
solution into the chromatograph and repeat the procedure described for
the working standard solution. The elution order is 4-epitetracycline
followed by tetracycline.
(f) Calculations. Calculate the tetracycline hydrochloride and
4-epitetracycline hydrochloride content as follows:
where:
A1=Area of the tetracycline sample peak (at a retention time equal to
that observed for tetracycline in the tetracycline working standard);
A2=Area of the tetracycline peak in the tetracycline working
standard;
A3=Area of the 4-epitetracycline sample peak (at a retention time
equal to that observed for the 4-epitetracycline peak in the
4-epitetracycline working standard);
A4=Area of the 4-epitetracycline peak in the 4-epitetracycline
working standard;
Wt=Milligrams of the tetracycline working standard;
We=Milligrams of the 4-epitetracycline working standard;
B=Percent tetracycline hydrochloride in the tetracycline working
standard;
C=Percent tetracycline hydrochloride in the 4-epitetracycline working
standard;
D=Percent 4-epitetracycline hydrochloride in the 4-epitetracycline
working standard; and
E=Percent 4-epitetracycline hydrochloride in the tetracycline working
standard.
(48 FR 51290, Nov. 8, 1983)
21 CFR 436.341 High-pressure liquid chromatographic assay for
plicamycin.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 280 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator; and
(6) A 25-centimeter column having an inside diameter of 4.6
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers to 10 micrometers in
diameter, U.S.P. XX.
(b) Reagents -- (1) 0.01M phosphoric acid.
(2) Mobile phase. Mix acetonitrile (high-pressure liquid
chromatography grade):0.01M phosphoric acid (350:650). Filter the mobile
phase through a suitable glass fiber filter or equivalent that is
capable of removing particulate contamination to 1 micron in diameter.
Degas the mobile phase just prior to its introduction into the
chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.0 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard and sample solutions -- (1)
Preparation of working standard solution. Place approximately 5
milligrams of the plicamycin working standard, accurately weighed, into
a 50-milliliter, amber volumetric flask and dilute to volume with mobile
phase and mix.
(2) Preparation of sample solution. Prepare the sample solution as
described in the individual monograph for the drug being tested.
(e) Procedure. Use the equipment, reagents, operating conditions,
and working standard and sample solutions described in paragraphs (a),
(b), (c), and (d) of this section, and proceed as directed in paragraph
(e)(1) of this section.
(1) System suitability test. Equilibrate and condition the column by
passage of about 10 to 15 void volumes of mobile phase followed by two
or more replicate injections of the working standard solution. Allow an
elution time sufficient to obtain satisfactory separation of expected
components after each injection. Record the peak responses and
calculate the relative standard deviation as described for system
suitability tests in the U.S.P. XX General Chapter 621 chromatography.
Proceed as directed in paragraph (e)(2) of this section if the minimum
performance requirement for the relative standard deviation is not more
than 2.0 percent. If the minimum performance requirement is not met,
adjustment must be made to the system to obtain satisfactory operation
before proceeding as described in paragraph (e)(2) of this section.
(2) Determination of the chromatogram. Inject 10 microliters of the
working standard solution into the chromatograph. Allow an elution time
sufficient to obtain satisfactory separation of expected components.
After separation of the working standard has been completed, inject 10
microliters of the sample solution into the chromatograph and repeat the
procedure described for the working standard solution.
(f) Calculations. Calculate the plicamycin content as described in
the individual monograph for the drug being tested.
(49 FR 24017, June 11, 1984, as amended at 50 FR 5749, Feb. 12, 1985)
21 CFR 436.342 High-pressure liquid chromatographic assay for
cefazolin.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection; and
(5) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter, USP
XX.
(b) Reagents -- (1) Buffer solution, pH 3.6. Transfer 0.9 gram of
sodium phosphate, dibasic USP and 1.298 grams of citric acid USP to a
1-liter volumetric flask. Dissolve and dilute to volume with distilled
water and mix.
(2) Buffer solution, pH 7.0. Transfer 5.68 grams of sodium phosphate,
dibasic USP and 3.63 grams of potassium phosphate monobasic to a 1-liter
volumetric flask. Dissolve and dilute to volume with distilled water
and mix.
(3) Mobile phase. Mix buffer solution, pH 3.6: acetonitrile (9:1).
Filter through a suitable glass fiber filter or equivalent that is
capable of removing particulate contamination to 1 micron in diameter.
Degas the mobile phase just prior to its introduction into the
chromatograph pumping system.
(4) Internal standard solution. Transfer 1.2 grams of salicylic acid
to a 200-milliliter volumetric flask. Dissolve in 10 milliliters of
methyl alcohol, dilute to volume with buffer solution, pH 7.0, and mix.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the initial baseline.
(d) Preparation of working standard and sample solutions -- (1)
Working standard solution. Place approximately 50 milligrams of
cefazolin working standard, accurately weighed, into a 50-milliliter
volumetric flask. Dissolve and dilute to volume with buffer solution,
pH 7.0, and mix. Transfer 4.0 milliliters of this solution to a
200-milliliter volumetric flask, add 5.0 milliliters of internal
standard solution, dilute to volume with buffer solution, pH 7.0, and
mix.
(2) Sample solution. Place approximately 50 milligrams of the
sample, accurately weighed, into a 50-milliliter volumetric flask.
Dissolve and dilute to volume with buffer solution, pH 7.0, and mix.
Transfer 4.0 milliliters of this solution to a 200-milliliter volumetric
flask, add 5.0 milliliters of internal standard solution, dilute to
volume with buffer solution, pH 7.0, and mix.
(e) Procedure. Using the equipment, mobile phase, and operating
conditions listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution prepared as
directed in paragraph (d)(1) of this section into the chromatograph.
After separation of the working standard solution has been completed,
inject 10 microliters of the sample solution prepared as described in
paragraph (d)(2) of this section into the chromatograph and repeat the
procedure described for the working standard solution. Allow an elution
time sufficient to obtain satisfactory separation of the expected
components. The elution order is void volume, salicylic acid and
cefazolin.
(f) Calculation. Calculate the micrograms of cefazolin per milligram
of sample as follows:
where:
Ru = Area of the cefazolin peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard) /Area of
internal standard peak;
Rs = Area of the cefazolin peak in the chromatogram of the cefazolin
working standard/Area of internal standard peak;
Ps = Cefazolin activity in the cefazolin working standard solution in
micrograms per milliliter;
Cu = Milligrams of sample per milliliter of sample solution; and
m = Percent moisture content of the sample.
(48 FR 33478, July 22, 1983; 48 FR 34947, Aug. 2, 1983)
21 CFR 436.343 High-pressure liquid chromatographic assay for
cefuroxime.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator; and
(6) A 15-centimeter column having an inside diameter of 4.6
millimeters and packed with hexyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers in diameter.
(b) Reagents -- (1) Acetate buffer, pH 3.4. Place 50 milliliters of
0.1M sodium acetate into a 1,000-milliliter volumetric flask and dilute
to volume with 0.1M acetic acid. Mix.
(2) Mobile phase. Mix 0.1M acetate buffer, pH 3.4:acetonitrile
(10:1). Filter the mobile phase through a suitable glass fiber filter or
equivalent that is capable of removing particulate contamination to 1
micron in diameter. Degas the mobile phase just prior to its
introduction into the chromatograph pumping system.
(3) Internal standard solution. Prepare a 1.5 milligram per
milliliter solution of orcinol monohydrate in water.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2.0 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard and sample solutions -- (1)
Preparation of working standard solution. Dissolve an accurately
weighed portion of the cefuroxime working standard with sufficient
distilled water to obtain a stock solution containing 1.0 milligram of
cefuroxime per milliliter. Immediately transfer 5.0 milliliters of the
stock solution to a 100-milliliter volumetric flask, add 20.0
milliliters of internal standard solution and dilute to 100 milliliters
with distilled water and mix. Store the solution in a refrigerator and
use within 6 hours.
(2) Preparation of sample solutions -- (i) Product not packaged for
dispensing (micrograms of cefuroxime per milligram). Dissolve an
accurately weighed portion of the sample with sufficient distilled water
to obtain a stock solution containing 1.0 milligram of cefuroxime per
milliliter. Immediately transfer 5.0 milliliters of the stock solution
to a 100-milliliter volumetric flask, add 20.0 milliliters of internal
standard solution and dilute to 100 milliliters with distilled water and
mix. Store the solution in a refrigerator and use within 6 hours.
Using this sample solution, proceed as directed in paragraph (e) of this
section.
(ii) Product packaged for dispensing. Determine both micrograms of
cefuroxime per milligram of the sample and milligrams of cefuroxime per
container. Use separate containers for preparation of each sample
solution as described in paragraphs (d)(2)(ii) (a) and (b) of this
section.
(a) Micrograms of cefuroxime per milligram. Dissolve an accurately
weighed portion of the sample with sufficient distilled water to obtain
a stock solution containing 1.0 milligram of cefuroxime per milliliter.
Immediately transfer 5.0 milliliters of the stock solution to a
100-milliliter volumetric flask, add 20.0 milliliters of internal
standard solution and dilute to 100 milliliters with distilled water and
mix. Store the solution in a refrigerator and use within 6 hours.
Using this sample solution, proceed as directed in paragraph (e) of this
section.
(b) Milligrams of cefuroxime per container. Reconstitute the sample
as directed in the labeling. Then using a suitable hypodermic needle
and syringe, remove all of the withdrawable contents if it is
represented as a single-dose container; or, if the labeling specifies
the amount of potency in a given volume of the resultant preparation,
remove an accurately measured representative portion from each
container. Dilute the solution thus obtained with distilled water to
obtain a stock solution of 1.0 milligram per milliliter. Immediately
transfer 5.0 milliliters of the stock solution to a 100-milliliter
volumetric flask, add 20.0 milliliters of internal standard solution and
dilute to 100 milliliters with distilled water and mix. Store the
solution in a refrigerator and use within 6 hours. Using this sample
solution, proceed as directed in paragraph (e) of this section.
(e) Procedure. Using the equipment, reagents, and operating
conditions as listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of the expected components. After separation of the working
standard solution has been completed, inject 10 microliters of the
sample solution prepared as described in paragraph (d)(2)(i) of this
section into the chromatograph and repeat the procedure described for
the working standard solution. If the sample is packaged for
dispensing, repeat the procedure for each sample solution prepared as
described in paragraphs (d)(2)(ii)(a) and (d)(2)(ii)(b) of this section.
(f) Calculations -- (1) Calculate the micrograms of cefuroxime per
milligram of sample as follows:
where:
Ru=Area of the cefuroxime peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard)/Area of
internal standard peak;
Rs=Area of the cefuroxime peak in the chromatogram of the cefuroxime
working standard/Area of internal standard peak;
Ps=Cefuroxime activity in the cefuroxime working standard solution in
micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(2) Calculate the cefuroxime content of the vial as follows:
where:
Ru=Area of the cefuroxime peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard)/Area of
internal standard peak;
Rs=Area of the cefuroxime peak in the chromatogram of the cefuroxime
working standard/Area of internal standard peak;
Ps=Cefuroxime activity in the cefuroxime working standard solution in
micrograms per milliliter; and
d=Dilution factor of the sample.
(48 FR 38460, Aug. 24, 1983; 48 FR 40704, Sept. 9, 1983)
21 CFR 436.344 Thin layer chromatographic identity test for cefuroxime.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 23 9 centimeters, with a glass solvent trough on the
bottom and a tight-fitting cover. Line the inside walls of the tank
with Whatman 3MM chromatographic paper or equivalent.
(2) Plates. Use 20 20 centimeter thin layer chromatography plates
coated with Silica Gel F or equivalent to a thickness of 250 microns.
(b) Developing solvent. Mix chloroform, methanol, and formic acid in
volumetric proportions of 90:16:4, respectively.
(c) Preparation of the spotting solutions. Dissolve approximately
200 milligrams each of the working standard and sample in 5 milliliters
of a 50 percent aqueous acetone solution.
(d) Procedure. Pour the developing solvent into the glass trough at
the bottom of the chromatography tank. Cover and seal the tank. Allow
it to equilibrate for 1 hour. Prepare a plate as follows: On a line 2
centimeters from the base of the plate, and at intervals of 2
centimeters, spot 5 microliters each of the sample and working standard
solutions. After all spots are thoroughly dry, place the plate directly
into the glass trough of the chromatography tank. Cover and seal the
tank tightly. Allow the solvent front to travel a minimum of 15
centimeters from the starting line. Remove the plate from the tank and
allow it to air dry. Observe under ultraviolet light (254 nanometers).
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
sample and standard should have spots of corresponding Rf values.
(48 FR 38461, Aug. 24, 1983)
21 CFR 436.345 High-pressure liquid chromatographic assay for
ceftizoxime.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 to 10 micrometers in diameter, USP
XX.
(b) Reagents -- (1) pH 3.6 buffer solution. Transfer 2.31 grams of
sodium phosphate diabasic dodecahydrate and 1.42 grams of citric acid
monohydrate to a 1-liter volumetric flask. Dissolve and dilute to
volume with distilled water.
(2) pH 7.0 buffer solution. Transfer 14.33 grams of sodium phosphate
dibasic dodecahydrate and 3.63 grams of potassium phosphate monobasic to
a 1-liter volumetric flask. Dissolve and dilute to volume with
distilled water.
(3) Mobile phase. Mix pH 3.6 buffer solution:acetonitrile (9:1).
Filter the mobile phase through a suitable glass fiber filter or
equivalent that is capable of removing particulate contamination to 1
micron in diameter. Degas the mobile phase just prior to its
introduction into the chromatograph pumping system.
(4) Internal standard solution. Place 1.2 grams of salicyclic acid
in a 200-milliliter volumetric flask. Dissolve in 10 milliliters of
methyl alcohol, dilute to volume with pH 7.0 buffer solution and mix.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 2.0 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard solution. Dissolve an accurately
weighed portion of the ceftizoxime working standard with sufficient pH
7.0 buffer solution to obtain a solution containing 1,000 micrograms of
ceftizoxime activity per milliliter. Transfer 2.0 milliliters of this
solution to a 100-milliliter volumetric flask, add 5.0 milliliters of
internal standard solution, dilute to volume with pH 7.0 buffer solution
and mix.
(e) Preparation of sample solutions -- (1) Product not packaged for
dispensing (micrograms of ceftizoxime per milligram). Dissolve an
accurately weighed portion of the sample with sufficient pH 7.0 buffer
solution to obtain a concentration of 1.0 milligram per milliliter.
Transfer 2.0 milliliters of this solution to a 100-milliliter volumetric
flask, add 5.0 milliliters of internal standard solution, dilute to
volume with pH 7.0 buffer solution and mix. Using this sample solution,
proceed as directed in paragraph (f) of this section.
(2) Product packaged for dispensing. Determine both micrograms of
ceftizoxime per milligram of the sample and milligrams of ceftizoxime
per container. Use separate containers for preparation of each sample
solution as described in paragraphs (e)(2) (i) and (ii) of this section.
(i) Micrograms of ceftizoxime per milligram. Dissolve an accurately
weighed portion of the sample with sufficient pH 7.0 buffer solution to
obtain a concentration of 1.0 milligram of ceftizoxime per milliliter.
Transfer 2.0 milliliters of this solution to a 100-milliliter volumetric
flask, add 5.0 milliliters of internal standard solution, dilute to
volume with pH 7.0 buffer solution and mix. Using this sample solution,
proceed as directed in paragraph (f) of this section.
(ii) Milligrams of ceftizoxime per container. Reconstitute the
sample as directed in the labeling. Then using a suitable hypodermic
needle and syringe, remove all of the withdrawable contents if it is
represented as a single-dose container; or, if the labeling specifies
the amount of potency is a given volume of the resultant preparation,
remove an accurately measured representative portion from each
container. Further dilute an aliquot of the solution thus obtained with
sufficient pH 7.0 buffer solution to obtain a concentration of 1.0
milligram per milliliter. Transfer 2.0 milliliters of this solution to
a 100-milliliter volumetric flask, add 5.0 milliliters of internal
standard solution, dilute to volume with pH 7.0 buffer solution and mix.
Using this sample solution, proceed as directed in paragraph (f) of
this section.
(f) Procedure. Using the equipment, reagents, and operating
conditions as listed in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain satisfactory
separation of the expected components. The elution order is void
volume, ceftizoxime, and internal standard. After separation of the
working standard solution has been completed, inject 10 microliters of
the sample solution prepared as described in paragraph (e)(1) of this
section into the chromatograph and repeat the procedure described for
the working standard solution. If the sample is packaged for
dispensing, repeat the procedure for each sample solution prepared as
described in paragraphs (e)(2) (i) and (ii) of this section.
(g) Calculations -- (1) Calculate the micrograms of ceftizoxime per
milligram of sample as follows:
Where:
Ru=Area of the ceftizoxime peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard)/Area of
internal standard peak;
Rs=Area of the ceftizoxime peak in the chromatogram of the
ceftizoxime working standard/Area of internal standard peak;
Ps=Ceftizoxime activity in the ceftizoxime working standard solution
in micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(2) Calculate the ceftizoxime content of the vial as follows:
where:
Ru=Area of the ceftizoxime peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard)/Area of
internal standard peak;
Rs=Area of the ceftizoxime peak in the chromatogram of the
ceftizoxime working standard/Area of internal standard peak;
Ps=Ceftizoxime activity in the ceftizoxime working standard solution
in micrograms per milliliter; and
d=Dilution factor of the sample.
(48 FR 46270, Oct. 12, 1983; 48 FR 49656, Oct. 27, 1983)
21 CFR 436.346 High-pressure liquid chromatographic assay for
cyclosporine.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A suitable pump capable of reproducibly delivering a liquid to a
pressure of 4,500 pounds per square inch and a flow rate of at least 5
milliliters per minute;
(2) A suitable ultraviolet detection system operating at a wavelength
of 210 nanometers;
(3) A suitable recorder;
(4) A suitable integrator;
(5) An oven or water bath capable of maintaining the column at an
operating temperature of 70 C;
(6) A steel capillary tube, 1 meter in length, having an inside
diameter of 0.25 millimeter. This tube is inserted between the injection
system and the chromatographic column and is equilibrated to 70 C; and
(7) A sample injection valve on which the loop determines the sample
size.
(b) Columns. The chromatographic column is packed with
microparticulate (3 to 10 micrometers in diameter) reversed phase
packing materials that exhibit some degree of polarity such as the
hydrocarbon bonded silicas with dimethyl, trimethyl, or octyl groups.
Connect a saturation column gravity packed with similarly bonded silica
particles 40 to 60 microns in diameter to the inlet of the analytical
column.
(c) Mobile phase. Mix acetonitrile, water, methanol, and
o-phosphoric acid (900:525:75:0.075 by volume). Degas by passing
through a 0.5-micrometer filter with vacuum and ultrasonicate for no
less than 2 minutes before use. The mobile phase may be sparged
perceptibly with helium through a 2-micrometer metal filter for the
duration of the analysis. Adjust the ratio of acetonitrile to aqueous
buffer as necessary to obtain satisfactory retention of the peaks.
(d) Operating conditions. Perform the assay at a constant operating
temperature of 70 C with a typical flow rate of 2.0 milliliters per
minute. Use a detector sensitivity setting that gives a peak height for
the working standard that is at least 50 percent of scale with a typical
chart speed of 2.5 millimeters per minute. Obtain chromatograms for
performance parameters at a chart speed of not less than 25 millimeters
per minute to allow a more accurate measurement of peak geometry.
(e) Preparation of working standard and sample solutions. Prepare
the working standard and sample solutions as directed in the individual
monographs for cyclosporine.
(f) Systems suitability. Equilibrate and condition the column by
passage of about 10 to 15 void volumes of mobile phase followed by about
5 injections of not less than 10 microliters each of working standard
solution. Proceed with the analysis when the following minimum
performance requirements have been met or exceeded.
(1) Capacity ratio factor. Calculate the capacity ratio (k) of the
cyclosporine peak as follows:
where:
t=Retention time of solute; and
tm=Retention time of solvent or unretained substance.
The capacity ratio is satisfactory if it is not less than 3 or not
more than 10.
(2) Coefficient of variation. The coefficient of variation of at
least five replicate injections is less than 1 percent.
(3) Efficiency. Calculate the efficiency (n) as follows:
where:
t=Retention time of solute; and
W0.5=Peak width at half height. Both t and W0.5 must be measured in
the same units.
The efficiency is satisfactory if it is greater than 1,500
theoretical plates when assaying cyclosporine and greater than 700
theoretical plates when assaying finished dosage forms.
(4) Asymmetry factor. Calculate the asymmetry factor (As) as
follows:
where:
W0.1=Horizontal distance measured from a point on the cyclosporine
peak ascent 10 percent above the baseline to an intercept with the
cyclosporine peak descent; and
f=Horizontal distance from point of 10 percent ascent above the
baseline of the cyclosporine peak to point of maximum peak height.
The asymmetry factor is satisfactory if it is not more than 1.5.
(5) Resolution. Calculate the resolution (Rs) as follows:
where:
t=Retention time of solute; and the subscripts i and j designate two
different peaks and where tj is larger than ti; and
W=Width of peak at baseline as determined by extrapolating the
relative straight sides to the baseline. Both t and W must be measured
in the same units.
Resolution between the cyclosporine peak and any other peak must be
at least 1.1.
(g) Procedure. Using the equipment, columns, mobile phase, operating
conditions and the working standard and sample solutions listed in
paragraphs (a), (b), (c), (d), and (e) of this section, inject 20
microliters of the working standard solution into the chromatograph.
Allow an elution time sufficient to obtain satisfactory separation of
expected components. After separation of the working standard solution
has been completed, inject 20 microliters of the sample solution into
the chromatograph and repeat the procedure described for the working
standard solution.
(h) Calculations. Calculate the cyclosporine content of cyclosporine
and its dosage forms as directed in the individual monographs.
(49 FR 22631, May 31, 1984; 49 FR 27489, July 5, 1984)
21 CFR 436.347 High-pressure liquid chromatographic assay for
cefoxitin.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4 centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers to 10 micrometers in
diameter, U.S.P. XX.
(b) Reagents -- (1) One percent potassium phosphate buffer, pH 6.0.
Prepare as described in 436.101(a)(1).
(2) Mobile phase. Mix distilled water:glacial acetic
acid:acetonitrile (800:10:190). Filter the mobile phase through a
suitable glass fiber filter or equivalent that is capable of removing
particulate contamination to 1 micron in diameter. Degas the mobile
phase just prior to its introduction into the chromatograph pumping
system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.0 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale. The minimum between peaks must be
no more than 2 millimeters above the baseline.
(d) Preparation of working standard and sample solutions. Use the
working standard and sample solutions prepared as described in the
individual monographs for the drug being tested.
(e) Procedure. Using the equipment, reagents, and operating
conditions as described in paragraphs (a), (b), and (c) of this section,
inject 10 microliters of the working standard solution into the
chromatograph. Allow an elution time sufficient to obtain separation of
the expected components. After separation of the working standard
solution has been completed, inject 10 microliters of the sample
solution into the chromatograph and repeat the procedure described for
the working standard solution.
(f) Calculations. Calculate the cefoxitin content as described in
the individual monographs for the drug being tested.
(49 FR 47827, Dec. 7, 1984)
21 CFR 436.348 High-pressure liquid chromatographic assay for
ceforanide.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A low dead volume cell 8 to 20 microliters;
(2) A light path length of 1 centimeter;
(3) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(4) A suitable recorder of at least 25.4-centimeter deflection;
(5) A suitable integrator; and
(6) A 30-centimeter column having an inside diameter of 4.0
millimeters and packed wth octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers to 10 micrometers in
diameter, U.S.P. XX. A particular column used for analysis of ceforanide
should not be used for the analysis of other drugs. --
(b) Mobile phase. Mix 18.0 milliliters of 10 percent aqueous
tetrabutylammonium hydroxide and 8.56 milliliters of 11N potassium
hydroxide. Add the mixture to approximately 700 milliliters of
distilled water. Add 200 milliliters of reagent grade methanol. Adjust
the pH of the mixture to pH 7.0 with concentrated phosphoric acid and
dilute to 1,000 milliliters with distilled water. Prepare fresh daily.
Filter the mobile phase through a suitable glass fiber filter or
equivalent which is capable of removing particulate contamination to 1
micron in diameter. Degas the mobile phase just prior to its
introduction into the chromatograph pumping system.
(c) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1 milliliter per minute. Use a detector
sensitivity setting that gives a peak height for the working standard
that is at least 50 percent of scale.
(d) Preparation of working standard and sample solutions -- (1)
Preparation of working standard solution. Prepare a solution containing
1,000 micrograms of ceforanide activity per milliliter in mobile phase.
Inject working standard solution within 5 minutes after dissolution.
(2) Preparation of sample solution. Prepare the sample solution as
directed in the individual monograph for the drug being tested. Inject
sample solution within 5 minutes after dissolution.
(e) Procedure. Use the equipment, mobile phase, operating
conditions, and working standard and sample solutions described in
paragraphs (a), (b), (c), and (d) of this section, and proceed as
directed in paragraph (e)(1) of this section.
(1) System suitability test. Equilibrate and condition the column by
passage of about 10 to 15 void volumes of mobile phase followed by three
replicate injections of 10 microliters each of the working standard
solution. Allow an elution time sufficient to obtain satisfactory
separation of expected components after each injection. Record the peak
responses and calculate the tailing factor, efficiency of the column,
coefficient of variation, and capacity factor as described for system
suitability tests in the U.S.P. XX General Chapter 621 chromatography.
Proceed as directed in paragraph (e)(2) of this section if the following
minimum performance requirements have been met:
(i) Tailing factor. The tailing factor is satisfactory if it is not
more than 1.2;
(ii) Efficiency of the column. The efficiency of the column is
satisfactory if it is greater than 1,900 theoretical plates;
(iii) Coefficient of variation. The coefficient of variation of at
least three replicate injections is satisfactory if it is not more than
1.5 percent; and
(iv) Capacity factor. The capacity factor is satisfactory if it is
not less than 1.8 and not more than 5.
If the minimum performance requirements are not met, adjustments must
be made to the system to obtain satisfactory operation before proceeding
as described in paragraph (e)(2) of this section.
(2) Determination of the chromatogram. Inject 10 microliters of the
working standard solution into the chromatograph. Allow an elution time
sufficient to obtain satisfactory separation of the expected components.
After separation of the working standard solution has been completed,
inject 10 microliters of the sample solution into the chromatograph and
repeat the procedure described for the working standard solution.
(f) Calculations. Calculate the ceforanide content as directed in
the individual monograph for the drug being tested.
(49 FR 25846, June 25, 1984; 49 FR 34347, Aug. 30, 1984)
21 CFR 436.349 High-pressure liquid chromatographic assay for L-lysine
in ceforanide for injection.
(a) Equipment. A suitable high-pressure liquid chromatograph
equipped with:
(1) A suitable pump capable of reproducibly delivering a liquid to a
pressure of 5,000 pounds per square inch;
(2) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers;
(3) A suitable recorder;
(4) A suitable integrator; and
(5) A 25-centimeter column having an inside diameter of 4.6
millimeters and packed with octadecyl silane chemically bonded to porous
silica or ceramic microparticles, 5 micrometers to 10 micrometers in
diameter, U.S.P. XX.
(b) Reagents -- (1) 2,4-Dinitrofluorobenzene solution. Weigh
accurately approximately 760 milligrams of 2,4-dinitrofluorobenzene into
a 50-milliliter volumetric flask. Dissolve and dilute to volume with
absolute ethyl alcohol.
(2) Tris (hydroxymethyl) aminomethane (THAM) solution. Weigh
accurately approximately 1.44 grams of THAM into a 100-milliliter
volumetric flask. Dissolve and dilute to volume with distilled water.
(c) Mobile phase. Mix methanol and water (62:38), and adjust to pH
3.0 with glacial acetic acid.
(d) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of 1.5 milliliters per minute. Use a detector
sensitivity setting that gives a peak height for the standard that is at
least 50 percent of scale with a typical chart speed of 0.2 inch per
minute.
(e) Preparation of standard and sample solutions -- (1) Preparation
of standard solution. Weigh accurately approximately 36 milligrams of
L-lysine used as the standard into a 100-milliliter volumetric flask.
Dissolve and dilute to volume with distilled water. Transfer 2.0
milliliters of the L-lysine solution into a 10-milliliter volumetric
flask, add 2.0 milliliters of THAM solution and 3.0 milliliters of
2,4-dinitrofluorobenzene solution. Cap tightly and mix well. Place the
flask in a 50 C water bath for 30 minutes. Remove from water bath,
allow the flask to cool to room temperature, and dilute to volume with
methanol. Mix well.
(2) Preparation of sample solution. Weigh accurately approximately
150 milligrams of the sample, ceforanide for injection, into a
100-milliliter volumetric flask. Dissolve and dilute to volume with
distilled water. Transfer 2.0 milliliters of the sample solution into a
10-milliliter volumetric flask, add 2.0 milliliters of THAM solution and
3.0 milliliters of 2,4-dinitrofluorobenzene solution. Cap tightly and
mix well. Place the flask in a 50 C water bath for 30 minutes. Remove
from water bath, allow the flask to cool to room temperature, and dilute
to volume with methanol. Mix well.
(f) Procedure. Use the equipment, reagents, mobile phase, operating
conditions, and standard and sample solutions described in paragraphs
(a), (b), (c), (d), and (e) of this section, and proceed as directed in
paragraph (f)(1) of this section.
(1) System suitability test. Equilibrate and condition the column by
passage of about 10 to 15 void volumes of mobile phase followed by three
replicate injections of 20 microliters each of the standard solution.
Allow an elution time sufficient to obtain satisfactory separation of
the expected components after each injection. Record the peak responses
and calculate the resolution factor, tailing factor, efficiency of the
column, coefficient of variation, and capacity factor as described for
system suitability tests in the U.S.P. XX General Chapter 621
chromatography. Proceed as directed in paragraph (f)(2) of this section
if the following minimum performance requirements have been met:
(i) Resolution factor. The resolution factor between the peak for
derivatized L-lysine and from the peak for the dinitrofluorobenzene
derivatizing reagent is satisfactory if it is not less than 4.5;
(ii) Tailing factor. The tailing factor is satisfactory if it is not
more than 1.3;
(iii) Efficiency of the column. The efficiency of the column is
satisfactory if it is greater than 1,500 theoretical plates;
(iv) Coefficient of variation. The coefficient of variation of at
least three replicate injections is satisfactory if it is not more than
1.5 percent; and
(v) Capacity factor. The capacity factor is satisfactory if it is
not less than 4 and not more than 6.
If the minimum performance requirements are not met, adjustments must
be made to the system to obtain satisfactory operation before proceeding
as described in paragraph (f)(2) of this section.
(2) Determination of the chromatogram. Inject 20 microliters of the
standard solution into the chromatograph. Allow an elution time
sufficient to obtain satisfactory separation of the expected components.
After separation of the standard solution is completed, inject 20
microliters of the sample solution into the chromatograph and repeat the
procedure described for the standard solution.
(g) Calculations. Calculate the percent of L-lysine per milligram of
ceforanide for injection as follows:
where:
Au = Area of the L-lysine peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard);
As = Area of the L-lysine peak in the chromatogram of the L-lysine
standard:
Ps = L-lysine content in the L-lysine standard solution in micrograms
per milliliter; and
Cu = Milligrams of sample per milliliter of sample solution.
(49 FR 25846, June 25, 1984; 49 FR 34347, Aug. 30, 1984; 49 FR
40006, Oct. 12, 1984)
21 CFR 436.350 High-performance liquid chromatographic assay for
cefonicid.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 2.0 milliliters per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the apparatus described in paragraph (a) of
this section; and the reagents and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by five replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. Record the
peak responses and calculate the prescribed system suitability
requirements as follows:
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05 = Width of peak at 5 percent height; and
f = Horizontal distance from point of ascent to a point coincident
with maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
wh=Peak width at half-height.
(3) Resolution factor. Calculate the resolution factor (R), between
desacetyl cefonicid and cefonicid, as follows:
where:
t1=Retention time of desacetyl cefonicid;
t2=Retention time of cefonicid; and
w1 and w2=Widths of the bases of the corresponding peaks obtained by
extrapolating the relatively straight sides of the peaks to the
baseline.
(4) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using the sample solution in
lieu of the working standard solution.
(49 FR 34347, Aug. 30, 1984, as amended at 49 FR 44460, Nov. 7, 1984;
50 FR 29209, July 18, 1985)
21 CFR 436.351 High-performance liquid chromatographic assay for
amoxicillin and clavulanic acid.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 10 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 2.0 milliliters per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the apparatus described in paragraph (a) of
this section; and the reagents and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by five replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. The
retention times for amoxicillin and clavulanic acid are about 2.1 and
1.0 minutes, respectively, under these prescribed conditions. Record
the peak responses and calculate the prescribed system suitability
requirements as follows:
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factors for the amoxicillin and clavulanic acid peaks.
Calculate the tailing factors (T), from distances measured along the
horizontal line at 5 percent of the peak height above the baseline, as
follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of amoxicillin or clavulanic acid peaks; and
wh=Corresponding peak width at half-height.
(3) Resolution factor. Calculate the resolution factor (R) as
follows:
where:
t1=Retention time of amoxicillin peak;
t2=Retention time of clavulanic acid peak; and
w1 and w2=Widths of the bases of the corresponding peaks obtained by
extrapolating the relatively straight sides of the peaks to the
baseline.
(4) Coefficient of variation (Relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using the sample solution in
lieu of the working standard solution.
(49 FR 39671, Oct. 10, 1984)
21 CFR 436.352 High-performance liquid chromatographic assay for
determining clavam-2-carboxylate content in clavulanate potassium.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, approximately 30 centimeters in length,
packed with a material as defined in the monograph for the drug being
tested.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 0.5 milliliter per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the apparatus described in paragraph (a) of
this section; and the mobile phase and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by five replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. The
retention times for clavam-2-carboxylic acid and clavulanic acid are
about 10 and 14 minutes, respectively, under these prescribed
conditions. The sample solution should be injected at least in
duplicate and an average should be taken. For each such series of
samples injected, two injections of standard should be made, one before
and one after the sample series, and an average should be taken. Record
the peak responses and calculate the prescribed system suitability
requirements as follows:
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of clavam-2-carboxylic acid peak; and
wh=Corresponding peak width at half-height.
(3) Resolution factor. Calculate the resolution factor (R) as
follows:
where:
t1=Retention time of clavam-2-carboxylic acid peak;
t2=Retention time of clavulanic acid peak; and
w1 and w2=Widths of the bases of the corresponding peaks obtained by
extrapolating the relatively straight sides of the peaks to the
baseline.
(4) Coefficient of variation (Relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using the sample solution in
lieu of the working standard solution.
(49 FR 39671, Oct. 10, 1984)
21 CFR 436.353 High-performance liquid chromatographic assay for
amdinocillin.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 2.0 milliliters per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the apparatus described in paragraph (a) of
this section; and the reagents and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by five replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. Record the
peak responses and calculate the prescribed system suitability
requirements as described for the system suitability test in paragraph
(c) of this section.
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column by either of the following formulas:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute;
wh=Peak width at half-height; and
W=Width of the base of the peak obtained by extrapolating the
relatively straight sides of the peak to the baseline.
(3) Resolution factor. Calculate the resolution factor (R) as
follows:
where:
tRj=Retention time for a solute eluting after i (tRj is larger than
tRi);
tRi=Retention time for any solute;
wi=Width of peak at baseline for any solute; and
wj=Width of peak at baseline for any solute eluting after i.
(4) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using the sample solution in
lieu of the working standard solution.
(50 FR 7764, Feb. 26, 1985; 50 FR 10220, Mar. 14, 1985; 50 FR
18243, Apr. 30, 1985)
21 CFR 436.354 High-performance liquid chromatographic assay for
ceftriaxone.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested.
(b) Procedure. Perform the assay at the temperature specified in the
monograph for the drug being tested with a flow rate not to exceed 2.0
milliliters per minute, Use a detector sensitivity setting that gives a
peak height for the working standard that is at least 50 percent of
scale. Use the apparatus described in paragraph (a) of this section;
and also, use the system suitability requirements, reagents, working
standard, test and sample solutions, and calculations as directed in the
individual monograph for the drug being tested. Equilibrate and
condition the column by passage of 10 to 15 void volumes of mobile phase
followed by five replicate injections of 20 microliters each of the test
solution. Allow an operating time sufficiently long to obtain
satisfactory separation and elution of the expected components after
each injection. Record the peak responses and calculate the prescribed
system suitability requirements as described for the system suitability
test in paragraph (c) of this section.
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Capacity factor. Calculate the capacity factor (k) as follows:
where:
tR=Retention time of solute; and
tM=Retention time of solvent or unretained substance.
(2) Resolution. Calculate the resolution (R) as follows:
Where:
tRj=Retention time for a solute eluting after i (tRj is larger than
tRi);
tRi=Retention time for any solute;
wi=Width of peak at baseline for any solute; and
wj=Width of peak at baseline for any solute eluting after i.
(3) Asymmetry factor. Calculate the asymmetry factor (As), measured
at a point 10 percent of the peak height from the baseline, as follows:
where:
a=Horizontal distance from point of ascent to point of maximum peak
height; and
b=Horizontal distance from point of maximum peak height to point of
descent.
(4) Efficiency of the column. Calculate the efficiency of the column
(reduced plate height) (hr) as follows:
(i)
(ii)
(iii)
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute;
wh=Peak width at half-height;
h=Efficiency, as height equivalent to one theoretical plate;
L=Length of column; and
dp=Average diameter of particle in column.
(5) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
The complete operating system is acceptable for assay if it meets the
system suitability requirements of the monograph for the drug being
tested. If the complete operating system is acceptable, proceed as
described in paragraph (b) of this section using the sample solution in
lieu of the test solution. Calculate the drug content as described in
the individual monograph for the drug being tested.
(50 FR 9999, Mar. 13, 1985)
21 CFR 436.355 High-performance liquid chromatographic assay for
ticarcillin-clavulanic acid.
(a) Equipment. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being testing;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 10 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 2.0 milliliters per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the equipment described in paragraph (a) of
this section; and the reagents and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by five replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. The
clavulanic acid peak is sharp and the chromatograms of standard and
sample solutions show baseline separations between it and any
neighboring peaks. The retention times for clavulanic acid and
ticarcillin are approximately 3 minutes and 14 minutes, respectively.
Record the peak responses and calculate the prescribed system
suitability requirements described for the system suitability test in
paragraph (c) of this section.
(c) System suitability test. Using the equipment and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factors for the ticarcillin and clavulanic acid peaks.
Calculate the tailing factors (T), from distances measured along the
horizontal line at 5 percent of the peak height above the baseline, as
follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of ticarcillin or clavulanic acid peaks; and
wh=Corresponding peak width at half-height.
(3) Resolution factor. Calculate the resolution factor (R) as
follows
where:
t1=Retention time of clavulanic acid peak;
t2=Retention time of ticarcillin peak; and
w1 and w2=Widths of the bases of the corresponding peaks obtained by
extrapolating the relatively straight sides of the peaks to the
baseline.
When using the method to assay clavulanic acid alone, the resolution
factor is not applicable.
(4) Coefficient of variation (Relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using the sample solution in
lieu of the working standard solution.
(50 FR 33517, Aug. 20, 1985; 50 FR 43384, Oct. 25, 1985)
21 CFR 436.356 High-performance liquid chromatographic assay for
ceftazidime.
(a) Equipment. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, flow rate, and
calculations specified in the monograph for the drug being tested. Use
a detector sensitivity setting that gives a peak height for the working
standard that is at least 50 percent of scale with typical chart speed
of not less than 2.5 millimeters per minute. Use the equipment
described in paragraph (a) of this section. Use the reagents, working
standard solution, and sample solution described in the monograph for
the drug being tested. Equilibrate and condition the column by passage
of 10 to 15 void volumes of mobile phase followed by five replicate
injections of the same volume (between 10 and 20 microliters) of the
working standard solution for the system suitability test. Allow an
operating time sufficiently long to obtain satisfactory separation and
elution of the expected components after each injection. Record the
peak responses and calculate the prescribed system suitability
requirements described for the system suitability test in paragraph (c)
of this section.
(c) System suitability test. Select the system suitability
requirements specified in the monograph for the drug being tested.
Then, using the equipment and procedure described in this section, test
the chromatographic system for assay as follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
wh=Peak width at half-height.
(3) Resolution. Calculate the resolution (R) as follows:
where:
tRj=Retention time of a solute eluting after i(tRj is larger than
tRi);
tRi=Retention time of any solute;
wi=Width of peak at baseline measured by extrapolating the relatively
straight sides to the baseline of any solute; and
wj=Width of peak at baseline measured by extrapolating the relatively
straight sides to the baseline of any solute eluting after i.
(4) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, except alternate injections
of the working standard solution with injections of the sample solution.
(50 FR 48397, Nov. 25, 1985)
21 CFR 436.357 Atomic absorption test for sodium carbonate content.
(a) Equipment. A suitable atomic absorbance spectrophotometer
equipped with:
(1) A suitable sodium hollow-cathode discharge lamp;
(2) An oxidizing air-acetylene flame;
(3) A nebulizer-burner system;
(4) An optical dispersing device capable of isolating a resonance
line of sodium from other wavelengths produced by the emission source;
and
(5) A suitable radiation detector.
(b) Ionization buffer. Dissolve and dilute 19.07 grams of potassium
chloride in distilled water to 1,000 milliliters.
(c) Preparation of reference standard and sample solutions -- (1)
Reference standard solution. Accurately weigh approximately 140
milligrams of sodium chloride, which has been previously dried for 40 to
50 minutes at a temperature of 500 to 650 C. Dissolve and dilute with
sufficient distilled water to obtain a stock solution containing 5.5
micrograms of sodium per milliliter. Mix 10 milliliters of the stock
solution with 10 milliliters of ionization buffer and dilute the mixture
with distilled water to obtain a solution containing 0.55 microgram of
sodium per milliliter.
(2) Sample solution. Dilute the stock sample solution, prepared as
directed in the monograph for the drug being tested, with distilled
water to obtain a solution containing 5.5 micrograms of sodium per
milliliter (estimated). Mix 10 milliliters of this solution with 10
milliliters of ionization buffer and dilute the mixture with distilled
water to obtain a solution containing 0.55 microgram of sodium per
milliliter (estimated).
(3) Procedure. Determine the atomic absorbance of the reference
standard and sample solutions at a wavelength of 589 nanometers, using
the atomic absorbance spectrophotometer and a reagent blank prepared by
diluting 10 milliliters of ionization buffer to 100 milliliters with
distilled water.
(d) Calculations. Calculate the percent sodium carbonate (S) as
follows:
where:
Au=Absorbance of sodium in the sample solution;
As=Absorbance of sodium in the reference standard solution;
Ps=Sodium concentration in the reference standard solution in
micrograms per milliliter; and
Cu=Milligrams of sample per milliliter of sample solution.
(50 FR 48398, Nov. 25, 1985, as amended at 54 FR 20785, May 15, 1989)
21 CFR 436.358 High-performance liquid chromatographic assay for
pyridine.
(a) Equipment. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 15 to 25 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the pyridine content
using the temperature, instrumental conditions, flow rate, and
calculations specified in the monograph for the drug being tested. Use
a detector sensitivity setting that gives a peak height for the working
standard that is at least 25 percent of scale with typical chart speed
of not less than 2.5 millimeters per minute. Use the equipment
described in paragraph (a) of this section. Use the reagents, working
standard solution, and sample solution described in the monograph for
the drug being tested. Equilibrate and condition the column by passage
of 10 to 15 void volumes of mobile phase followed for the system
suitability test by five replicate injections of the same volume
(between 10 and 20 microliters) of the system suitability test solution.
Allow an operating time sufficiently long to obtain satisfactory
separation and elution of the expected components after each injection.
Record the peak responses and calculate the prescribed system
suitability requirements described for the system suitability test in
paragraph (c) of this section.
(c) System suitability test. Select the system suitability
requirements specified in the monograph for the drug being tested.
Then, using the equipment and procedure described in this section, test
the chromatographic system for assay as follows:
(1) Tailing factor. Calculate the tailing factor for the pyridine
peak (T), from distances measured along the horizontal line at 5 percent
of the peak height above the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Resolution. Calculate the resolution (R) as follows:
where:
tRj=Retention time of t-butyl ceftazidime;
tRi=Retention time of pyridine;
wi=Width of pyridine peak at the baseline measured by extrapolating
the relatively straight sides to the baseline; and
wj=Width of t-butyl ceftazidime peak at the baseline measured by
extrapolating the relatively straight sides to the baseline.
(3) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation for the pyridine peak (SR in
percent ) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, except alternate injections
of the working standard solution with injections of the sample solution.
(50 FR 48398, Nov. 25, 1985; 50 FR 53308, Dec. 31, 1985)
21 CFR 436.360 Gel permeation chromatographic assay for high molecular
weight polymer.
(a) Equipment. A suitable gel permeation chromatograph equipped
with.
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 50 centimeters long and 9 millimeters
internal diameter, packed with a material as defined in the monograph
for the drug being tested.
(b) Procedure. Perform the assay and calculate the high molecular
weight polymer content using the temperature, instrumental conditions,
and calculations specified in the monograph for the drug being tested.
Use a detector sensitivity setting that gives a peak height for the
working standard that is at least 10 percent of scale with a typical
chart speed of not less than 2.5 millimeters per minute. Use the
equipment described in paragraph (a) of this section. Use the reagents,
working standard solution, and sample solution described in the
monograph for the drug being tested. Equilibrate and condition the
column by passage of mobile phase for not less than 18 hours, removing
any voids that may form at the top of the column, followed by five
replicate injections of the same volume (100 microliters) of the blue
dextran system suitability test solution. Allow an operating time
sufficiently long to obtain satisfactory separation and elution of the
expected components after each injection. Record the peak responses and
calculate the prescribed system suitability requirements described for
the system suitability test in paragraph (c) of this section.
(c) System suitability test. Select the system suitability
requirements specified in the monograph for the drug being tested.
Then, using the equipment and procedure described in this section, test
the chromatographic system for assay as follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
wh=Peak width at half-height.
(3) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, using two injections of the
same volume (100 microliters) of the working standard solution followed
by one injection of the same volume (100 microliters) of the sample
solution.
(50 FR 48398, Nov. 25, 1985; 51 FR 1367, Jan. 13, 1986)
21 CFR 436.361 High-performance liquid chromatographic assay for
aztreonam.
(a) Equipment. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 40 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, flow rate, and
calculations specified in the monograph for the drug being tested. Use
a detector sensitivity setting that gives a peak height for the working
standard that is at least 50 percent of scale with typical chart speed
of not less than 2.5 millimeters per minute. Use the equipment
described in paragraph (a) of this section. Use the reagents, working
standard solution, and sample solution described in the monograph for
the drug being tested. Equilibrate and condition the column by passage
of 10 to 15 void volumes of mobile phase followed by five replicate
injections of the same volume (between 10 and 20 microliters) of the
working standard solution. Allow an operating time sufficiently long to
obtain satisfactory separation and elution of the expected components
after each injection. Record the peak responses and calculate the
prescribed system suitability requirements described for the system
suitability test in paragraph (c) of this section.
(c) System suitability test. Select the system suitability
requirements specified in the monograph for the drug being tested.
Then, using the equipment and procedure described in this section, test
the chromatographic system for assay as follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
wh=Peak width at half-height.
(3) Resolution. Calculate the resolution (R) as follows:
where:
tRj=Retention time of a solute eluting after i (tRj is larger than
tRi);
tRi=Retention time of any solute;
wi=Width of peak at baseline of any solute; and
wj=Width of peak at baseline of any solute eluting after i.
(4) Coefficient of variation (relative standard deviation).
Calculate the coefficient of variation (SR in percent ) as follows:
where:
X8 is the mean of N individual measurements of Xi.
If the complete operating system meets the system suitability
requirements of the monograph for the drug being tested, proceed as
described in paragraph (b) of this section, except alternate injections
of the working standard solution with injections of the sample solution.
(52 FR 4611, Feb. 13, 1987; 52 FR 8550, Mar. 18, 1987)
21 CFR 436.362 Thin-layer chromatographic test for free erythromycin
content in erythromycin estolate bulk.
(a) Equipment -- (1) Chromatography tank. A rectangular tank
approximately 23 centimeters long, 23 centimeters high, and 9
centimeters wide, equipped with a glass solvent trough in the bottom and
a tight-fitting cover for the top.
(2) Plates. Use a 20- by 20-centimeter precoated silica gel 60 F-254
thin-layer chromatography plate. Before using, place the plate in an
unlined developing chamber containing approximately 100 milliliters of
anhydrous methanol and allow the solvent front to travel to the top of
the plate, marking the direction of travel. Remove the plate and allow
to drip dry. Store in a dry place.
(b) Reagents -- (1) Developing solvent. Mix 15 milliliters of
chloroform and 85 milliliters of anhydrous methanol. Use fresh
developing solvent for each test.
(2) Spray solution. Dissolve 150 milligrams of xanthydrol in a
mixture of 7.5 milliliters of glacial acetic acid and 92.5 milliliters
of 37 percent hydrochloric acid.
(c) Preparation of spotting solutions -- (1) Sample solution.
Prepare a solution of the sample in anhydrous methanol to contain 10
milligrams per milliliter.
Note: It is advisable to prepare the sample and standard solutions
immediately before spotting to minimize the possibility of degradation
in solution.)
(2) Standard solution. Prepare a solution of erythromycin base
reference standard in anhydrous methanol to contain 1 milligram per
milliliter. Weigh 99.5, 99.0, and 97.0 milligrams of erythromycin
estolate (propionyl erythromycin lauryl sulfate) reference standard and
transfer to separate 10-milliliter volumetric flasks. To these flasks
add 0.5, 1.0, and 3.0 milliliters, respectively, of the
1-milligram-per-milliliter solution of erythromycin base reference
standard and dilute to volume with anhydrous methanol. These solutions
contain, respectively, 0.5 percent, 1.0 percent, and 3.0 percent
erythromycin base in erythromycin estolate. Prepare a solution of
erythromycin estolate reference standard in anhydrous methanol to
contain 10 milligrams per milliliter. Prepare a solution of
erythromycin base reference standard in anhydrous methanol to contain
0.1 milligram per milliliter.
(d) Procedure. Pour 100 milliliters of developing solvent into the
glass trough on the bottom of the unlined chromatography tank. Cover
and seal the tank. Allow it to equilibrate while the plate is being
prepared. Prepare a plate as follows: On a line 2.0 centimeters from
the base of the thin-layer plate, apply 1.0 microliter of each of the
following solutions:
(1) 10-milligrams-per-milliliter solution of erythromycin estolate
reference standard, equivalent to 10 micrograms of erythromycin
estolate;
(2) 0.5 percent base-in-estolate solution, equivalent to 0.05
microgram of base and 9.95 micrograms of estolate;
(3) 1.0 percent base-in-estolate solution, equivalent to 0.10
microgram of base and 9.90 micrograms of estolate;
(4) 3.0 percent base-in-estolate solution, equivalent to 0.30
microgram of base and 9.70 micrograms of estolate;
(5) 0.1-milligram-per-milliliter solution of erythromycin base
reference standard, equivalent to 0.1 microgram of erythromycin base;
and
(6) Sample solution, equivalent to 10 micrograms of erythromycin
estolate. Allow the spots to dry. Place the plate directly in the
chromatograph tank. Cover and seal the tank. Allow the solvent front
to travel a distance of 7 centimeters (about 27 minutes). Remove the
plate from the tank, and allow it to air dry under a hood. With the
plate still under the hood, spray uniformly with the spray solution.
Heat the sprayed plate in an oven at 100 C for 5 minutes. (CAUTION:
Avoid exposure to the acid fumes while removing the plate from the
oven.)
(e) Evaluation. Erythromycin base and erythromycin estolate appear
as reddish-violet spots on the sprayed and heated plate. Better
visualization of the erythromycin base spots may be gained by viewing
the plate under long-wavelength (366 nanometers) ultraviolet light,
erythromycin base appearing as dark spots on a yellow-green fluorescent
background. Erythromycin base has an Rf value of about 0.3.
Erythromycin estolate has an Rf value of about 0.7. Compare the size and
intensity of any erythromycin base spots in the sample lane with the
erythromycin base spots in the erythromycin base reference standard lane
and in the 0.5 percent, 1.0 percent, and 3.0 percent base-in-estolate
lanes, and report the percentage of erythromycin base (free
erythromycin) in the sample. For a more accurate determination of free
erythromycin content, it may be necessary to repeat the test using a
different set of standards.
(53 FR 1919, Jan. 25, 1988)
21 CFR 436.363 High-performance liquid chromatographic assay for
cefmenoxime.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable detection system specified in the monograph for the
drug being tested;
(2) A suitable recording device of at least 18-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) An analytical column, 3 to 30 centimeters long, packed with a
material as defined in the monograph for the drug being tested; and if
specified in that monograph, the inlet of this column may be connected
to a guard column, 3 to 5 centimeters in length, packed with the same
material of 30 to 60 micrometers particle size.
(b) Procedure. Perform the assay and calculate the drug content
using the temperature, instrumental conditions, and calculations
specified in the monograph for the drug being tested with a flow rate
not to exceed 2.0 milliliters per minute. Use a detector sensitivity
setting that gives a peak height for the working standard that is at
least 50 percent of scale with typical chart speed of not less than 2.5
millimeters per minute. Use the apparatus described in paragraph (a) of
this section; and the reagents and working standard and sample
solutions described in the monograph for the drug being tested.
Equilibrate and condition the column by passage of 10 to 15 void volumes
of mobile phase followed by 5 replicate injections of the same volume
(between 10 and 20 microliters) of the working standard solution. Allow
an operating time sufficiently long to obtain satisfactory separation
and elution of the expected components after each injection. Record the
peak responses and calculate the prescribed system suitability
requirements described for the system suitability test in paragraph (c)
of this section.
(c) System suitability test. Using the apparatus and procedure
described in this section, test the chromatographic system for assay as
follows:
(1) Tailing factor. Calculate the tailing factor (T), from distances
measured along the horizontal line at 5 percent of the peak height above
the baseline, as follows:
where:
W0.05=Width of peak at 5 percent height; and
f=Horizontal distance from point of ascent to a point coincident with
maximum peak height.
(2) Efficiency of the column. Calculate the number of theoretical
plates (n) of the column as follows:
where:
n=Efficiency, as number of theoretical plates for column;
tR=Retention time of solute; and
wh=Peak width at half-height.
(3) Resolution. Calculate the resolution (R) as follows:
where:
tRJ=Retention time of a solute eluting after i (tRJ is larger than
tRi);
tRi=Retention time of any solute;
wi=Width of peak at baseline of any solute; and
wJ=Width of peak at baseline of any solute eluting after i.
(4) Coefficient of variation (Relative standard deviation).
Calculate the coefficient of variation (SR) in percent) as follows:
Insert illus. 51A
where:
X is the mean of N individual measurements of Xi. If the complete
operating system meets the system suitability requirements of the
monograph for the drug being tested, proceed as described in paragraph
(b) of this section, using the sample solution in lieu of the working
standard solution.
(53 FR 13401, Apr. 25, 1988; 53 FR 19368, May 27, 1988)
21 CFR 436.364 Atomic absorption test for sodium carbonate content of
cefmenoxime hydrochloride for injection.
(a) Apparatus. A suitable atomic absorbance spectrophotometer
equipped with:
(1) A suitable sodium hollow-cathode discharge lamp;
(2) An oxidizing air-acetylene flame;
(3) A nebulizer-burner system;
(4) An optical dispersing device capable of isolating a resonance
line of sodium from other wavelengths produced by the emission source;
and
(5) A suitable radiation detector.
(b) Reagents. Ionization buffer: Dissolve 19.07 grams of potassium
chloride in distilled water and dilute to 1,000 milliliters.
(c) Preparation of reference standard and sample solutions -- (1)
Reference standard solution. Accurately weigh approximately 140
milligrams of sodium chloride which has been previously dired for 40 to
50 minutes at a temperature of 500 to 650 C. Dissolve and dilute with
sufficient distilled water to obtain a stock solution containing 5.5
micrograms of sodium per milliliter. Mix 10 milliliters of the stock
solution with 10 milliliters of ionization buffer and dilute the mixture
with distilled water to obtain a solution containing 0.55 microgram of
sodium per milliliter.
(2) Sample solution. Dilute the sample solution used in
442.222(b)(1)(ii)(B)(1) of this chapter, with sufficient distilled water
to obtain a stock solution containing 5.5 micrograms of sodium per
milliliter (estimated). Mix 10 milliliters of the stock solution with
10 milliliters of ionization buffer and dilute the mixture with
distilled water to obtain a solution containing 0.55 microgram of sodium
per milliliter (estimated).
(3) Procedure. Determine the atomic absorbance of the reference
standard and sample solutions at a wavelength of 589 nanometers, using
the atomic absorbance spectrophotometer and a reagent blank prepared by
diluting 10 milliliters of ionization buffer to 100 milliliters with
distilled water.
(d) Calculations. Calculate the percent sodium carbonate as follows:
where:
Au=Absorbance of sodium in the sample solution;
As=Absorbance of sodium in the reference standard solution;
Ps=Milligrams of sodium chloride per milliliter of the reference
standard solution;
Cu=Milligrams of sample per milliliter of sample solution; and
d=Dilution factor of the sample.
(53 FR 13401, Apr. 25, 1988)
21 CFR 436.365 Thin layer chromatographic identity test for rifampin.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 23 9 centimeters, with a glass solvent trough on the
bottom and a tight-fitting cover, lined with Whatman 3MM
chromatographic paper or equivalent.
(2) Plates. Use 20 20 centimeter thin layer chromatography plates
coated with silica gel 60 F-254 or equivalent to a thickness of 250
microns.
(b) Developing solvent. Mix chloroform and methanol in volumetric
proportions of 90:10, respectively.
(c) Spotting solutions -- (1) Preparation of working standard
solution. Dissolve approximately 50 milligrams of rifampin working
standard in 5 milliliters of chloroform.
(2) Preparation of sample solution. Dissolve the contents of a
sample vial in 60 milliliters of chloroform.
(d) Procedure. Pour the developing solvent into the glass trough on
the bottom of the tank and onto the paper lining the walls of the tank.
Cover and seal the tank. Allow it to equilibrate. Prepare a plate as
follows: On a line 2.5 centimeters from the base of the thin layer
chromatography plate and at intervals of 2.0 centimeters, spot 3
microliters of the working standard solution to points 1 and 3. When
these spots are dry, apply 3 microliters of the sample solution to
points 2 and 3. After all the spots are thoroughly dry, place the plate
into the trough in the bottom of the tank. Cover and tightly seal the
tank. Allow the solvent front to travel about 7 centimeters from the
starting line. Remove the plate from the tank and air dry.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line, and the distance the red spots are from the starting
line. Divide the latter by the former to calculate the Rf value.
Rifampin appears as a red spot. The test is satisfactory if the Rf
value of the sample compares with that of the working standard. The
combined spot should appear as a single spot of corresponding Rf value.
(54 FR 38375, Sept. 18, 1989; 54 FR 42886, Oct. 18, 1989)
21 CFR 436.366 High-performance liquid chromatography assay for
determining chromatographic purity of vancomycin.
(a) Apparatus. A suitable high-performance liquid chromatograph
equipped with:
(1) A suitable ultraviolet detection system operating at a wavelength
of 254 nanometers or preferably 280 nanometers;
(2) A suitable recording device of at least 25-centimeter deflection;
(3) A suitable chromatographic data managing system; and
(4) A 25-centimeter analytical column having an inside diameter of
4.6 millimeters and packed with octadecyl silane chemically bonded to
porous silica or ceramic microparticles; 5 micrometers in diameter.
(b) Reagents. -- (1) 0.2 percent triethylammonium phosphate buffer.
To 2,000 milliliters of distilled water, either add 4 milliliters of
triethylamine or 4 grams of triethylammonium chloride. Adjust the pH to
3.2 with phosphoric acid.
(2) Sample solvents. (i) Vancomycin hydrochloride: Mobile Phase A.
(ii) Vancomycin base: 5 milliliters Mobile Phase A; add 0.1N HCl
dropwise with swirling until sample dissolves: dilute to volume with
Mobile Phase A.
(c) Mobile Phases -- (1) Mobile Phase A. Add 70 milliliters of
acetonitrile and 10 milliliters of tetrahydrofuran to 920 milliliters of
0.2 percent triethylammonium phosphate buffer and mix well. Filter the
mobile phase through a suitable glass fiber filter or equivalent that is
capable of removing particulate contamination to 1 micron in diameter.
Degas the mobile phase, briefly, just prior to its introduction into the
chromatographic pumping system.
(2) Mobile Phase B. Add 290 milliliters of acetonitrile and 10
milliliters of tetrahydofuran to 700 milliliters of 0.2 percent
triethylammonium phosphate buffer and mix well. Filter the mobile phase
through a suitable glass fiber filter or equivalent that is capable of
removing particulate contamination to 1 micron in diameter. Degas the
mobile phase, briefly, just prior to its introduction into the
chromatographic pumping system.
(d) Operating conditions. Perform the assay at ambient temperature
with a typical flow rate of about 2.0 milliliters per minute. Use a
detector sensitivity setting that gives a peak height for the main peak
(Vancomycin B) that is at least 50 percent of scale. The run time is 30
minutes per injection and the gradient conditions are as follows: (0,
12, 12.5, 8, 0, 2)
(e) Preparation of resolution and sample solutions -- (1) Resolution
solution. Prepare a solution of vancomycin hydrochloride reference
standard in water containing 0.5 milligram per milliliter. Heat at 65
C for 24 hours and allow to cool. This procedure generates two
desamido-vancomycin isomers. The first desamido isomer elutes during
the isocratic period and before the vancomycin B peak; the second
desamido isomer elutes during the gradient ramp and is used to
demonstrate the effective performance of this stage.
(2) Sample preparation. In a volumetric flask either dissolve a
representative sample or dilute a representative portion with sample
solvent to give a sample preparation containing approximately 10
milligrams per milliliter. Pipet 2 milliliters of this sample solution
into a separate 50-milliliter volumetric flask and dilute to volume with
sample solvent to give a diluted sample preparation containing
approximately 0.4 milligram per milliliter.
(f) Procedure. Optimize chromatographic conditions under isocratic
conditions by equilibrating the system while pumping 100 percent mobile
phase A through the column. Inject 20 microliters of the resolution
solution onto the column and record the chromatogram. Adjust the
acetonitrile concentration of mobile phase A as needed to provide a
retention time for vancomycin B of 7.5 to 10.5 minutes. Use the
resolution solution to perform the system suitability tests. The
elution order is resolution compound 1, vancomycin B, resolution
compound 2. Return the system to the initial gradient operating
conditions. Separately inject 20 milliliters of each diluted (0.4
milligram per milliliter) and concentrated (10 milligrams per
milliliter) sample solution onto the column and record each
chromatogram.
(g) System suitability test. Using the resolution solution described
in paragraph (e)(1) of this section, test the performance of the
chromatographic system as follows:
(1) Asymmetry factor. Calculate the asymmetry factor (A), measured
at a point that is 10 percent of the vancomycin B peak height from the
baseline, as follows:
where:
a=Horizontal distance from point of ascent to point of maximum peak
height; and
b=Horizontal distance from point of maximum peak height to point of
descent.
The asymmetry factor (Ar) is satisfactory if it is not less than 0.8
and not more than 1.8.
(2) Efficiency of the column. From the number of theoretical plates
(n) calculated as described in 436.216(c)(2) calculate the reduced
plate height (hr) for the vancomycin B peak as follows:
where:
L=Length of the column in centimeters;
n=Number of theoretical plates; and
dp=Average diameter of the particles in the column in micrometers.
The absolute efficiency (hr) is satisfactory if it is not more than
40 for the vancomycin B peak in the resolution solution.
(3) Resolution. The resolution (R) between the vancomycin B peak and
the peak for resolution compound 1 is not less than 3.0. Resolution
compound 2 is eluted between 3 and 6 minutes after the start of the
period when the percentage of mobile phase B is increasing from 0
percent to 100 percent.
(4) Coefficient of variation (relative standard deviation). The
coefficient of variation (SR in percent) of five replicate injections of
the resolution solution is calculated as described in 436.216(c)(4) is
satisfactory if it is not more than 2.0 percent.
(5) Capacity factor (k). Calculate the capacity factor (k) for
vancomycin B as follows:
where:
tr=Retention time of solute; and
tm=Retention time of solvent or unretained substance, calculated as
follows:
where:
D=Column diameter in centimeters;
L=Column length in centimeters;
0.75=Average total column porosity; and
F=Flow rate in milliliters per minute.
The capacity factor (k) for vancomycin B is satisfactory if it is not
less than 2.6 and not more than 3.3.
When the system suitability requirements have been met, then proceed
as described in paragraph (f) of this section. Alternate
chromatographic conditions are acceptable provided that the system
suitability parameters are met. However, the sample preparation
described in paragraph (e)(2) of this section should not be changed.
(h) Calculations. (1) Calculate the percentage of vancomycin B in
the specimen as follows:
where:
AB=Area of the vancomycin B peak in the dilute (0.4 milligram per
milliliter) sample solution; and
ATotal=Area of the vancomycin B peak in the dilute (0.4 milligram per
milliliter) solution+(Area of the total related substances peaks
(exclude the area of the vancomycin B peak) in the concentrated solution
(10 milligrams per milliliter) divided by 25).
(2) Calculate the percentage of each other peak as follows:
where:
Ai=Area of any given peak, other than the main peak in the
concentrated solution (10 milligrams per milliliter); and
ATotal=Area of the vancomycin B peak in the dilute (0.4 milligram per
milliliter) solution+(Area of the total related substances peaks
(exclude the area of the vancomycin B peak) in the concentrated solution
(10 milligrams per milliliter) divided by 25).
(54 FR 20383, May 11, 1989; 54 FR 25849, June 20, 1989)
21 CFR 436.367 Thin-layer chromatographic identity test for cephalexin
hydrochloride.
(a) Equipment -- (1) Chromatography tank. Use a rectangular tank
approximately 23 23 9 centimeters, with a glass solvent trough in
the bottom and a tight-fitting cover. Line the inside walls of the tank
with Whatman 3 MM chromatographic paper or equivalent.
(2) Plates. Use 20 20 centimeter thin layer chromatographic plates
coated with silica gel 60F-254 or equivalent to a thickness of 250
microns.
(b) Developing solvent. Mix ethylacetate, acetonitrile, water and
glacial acetic acid in volumetric proportions of 42:14:18:14,
respectively.
(c) Preparation of the spotting solutions. Prepare a solution of the
sample containing 25 milligrams per milliliter of cephalexin
hydrochloride in water. Prepare a solution of cephalexin monohydrate
reference material at a concentration of 25 milligrams per milliliter.
Add water and 0.1N hydrochloric acid in a dropwise mode until the
material is completely dissolved.
(d) Procedure. Pour the developing solvent into the glass trough at
the bottom of the chromatography tank. Cover and seal the tank. Allow
it to equilibrate for 1 hour. Prepare a plate as follows: On a line 2
centimeters from the base of the plate, and at intervals of 2
centimeters, spot approximately 5 microliters of the standard solution
to points 1 and 3 and approximately 5 microliters of the sample solution
to point 2. After all spots are thoroughly dry, place the plate
directly into the glass trough of the chromatography tank. Cover and
seal the tank. Allow the solvent front to travel approximately 15
centimeters from the starting line. Remove the plate from the tank and
allow it to air dry.
(e) Evaluation. View the dry plate under ultraviolet light (254
nanometers). Measure the distance the solvent front traveled from the
starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The sample
and standard should have spots of corresponding Rf values of
approximately 0.35.
(54 FR 48860, Nov. 28, 1989; 54 FR 51816, Dec. 18, 1989)
21 CFR 436.367 Subpart G -- Chemical Tests for Nonantibiotic Active Ingredients
21 CFR 436.400 Thin layer chromatographic identity test for
iodochlorhydroxyquin.
(a) Equipment -- (1) Chromatography tank. A rectangular tank,
approximately 9 9 3.5 inches with a glass solvent trough on the
bottom.
(2) Plates. Use 20 20 centimeter thin layer chromatography plates
coated with Silica Gel G or equivalent to a thickness of 250 microns.
(b) Developing solvent. Mix benzene and methanol in volumetric
proportions of 90:10.
(c) Preparation of spotting solutions -- (1) Sample solution. Use
the sample solution prepared as described in the section for the
particular product to be tested.
(2) Reference solution. Prepare a solution containing 0.5 milligram
of iodochlorhydroxyquin U.S.P. reference standard per milliliter in
acetone.
(d) Procedure. Pour developing solvent into the glass trough on the
bottom of the chromatography tank. Cover and seal the tank. Allow it
to equilibrate for 1 hour. Spot a plate as follows: Apply
approximately 10 microliters each of the sample solution and of the
reference solution on a line 2.0 centimeters from the base of the silica
gel plate and at intervals of not less than 2.0 centimeters. After all
spots are thoroughly dry, place the silica gel plate directly into the
glass trough of the chromatography tank. Cover and reseal the tank.
Allow the solvent front to travel about 15 centimeters from the starting
line, remove the plate from the tank, and allow to air dry. Examine
under a strong source of ultraviolet light. The sample and standard are
visible as dark spots.
(e) Evaluation. Measure the distance the solvent front traveled from
the starting line and the distance the spots are from the starting line.
Calculate the Rf value by dividing the latter by the former. The
sample and standard should have spots of corresponding Rf values (0.55
to 0.60).
21 CFR 436.400 Subpart H -- Tests for Specific Antibiotic Dosage Forms
21 CFR 436.500 Penicillin in oil and wax.
(a) Potency. Proceed as directed in 440.80a(b)(1) of this chapter
except paragraph (b)(1)(ix) thereof and, in lieu of the directions in
440.80a(b)(1)(iv) of this chapter prepare sample as follows: Liquefy
the sample by warming, thoroughly mix, and withdraw 1.0 milliliter using
a sterile syringe equipped with an 18-gauge needle. Transfer to a
separatory funnel containing approximately 50 milliliters of
peroxide-free ether. Shake the separatory funnel vigorously to bring
about complete mixing of the material with the ether. Shake with a
25-milliliter portion of 1 percent phosphate buffer at pH 6.0. Remove
the buffer layer and repeat the extraction with three 25-milliliter
quantites of buffer. Combine the extracts and make the proper estimated
dilutions in 1 percent phosphate buffer at pH 6.0. The sample may also
be prepared by transferring aseptically 1.0 milliliter of the penicillin
in oil and wax to a blending jar containing 100 milliliters of 1 percent
phosphate buffer at pH 6.0. Using a high-speed blender, blend this
mixture for 1 minute and then make the proper estimated dilutions in 1
percent phosphate buffer at pH 6.0. If the label represents the potency
of the penicillin in oil and wax as 200,000 units per milliliter or
less, it is satisfactory if it is 85 percent or more of the potency so
represented; if represented as more than 200,000 units per milliliter,
it is satisfactory if it is 90 percent or more of the potency so
represented.
(b) Sterility. Proceed as directed in 436.20, using the method
described in paragraph (e)(2) of that section, except using medium B in
lieu of medium A.
(c) Moisture -- (1) Reagents -- (i) KarlFischer reagent. Preserve
the reagent in glass-stoppered bottles and use from an all glass
automatic burette, protecting the solution from the moisture in the air.
(ii) Water-methanol solution. Use methanol containing approximately
1 mg. of water per milliliter. Store the solution in a glass bottle
attached to an automatic burette and protect from moisture in the air at
all times.
(2) Standardization of Karl Fischer reagent. Add a known volume of
the Karl Fischer reagent to a suitable titrating vessel which has been
previously dried at 105 C. and cooled in a desiccator. Introduce a
mechanical stirrer and two platinum electrodes which are connected to a
suitable electrometric apparatus for measurement of the endpoint. Start
the stirrer and titrate with the water-methanol solution until the
endpoint is reached. Calculate the milliliters of Karl Fischer reagent
equivalent to each milliliter of water-methanol. Add an accurately
weighed quantity of water (approximately 50 milligrams) to a dry
titrating vessel, add an excess of the Karl Fischer reagent and back
titrate with the water-methanol solution as above. Calculate the
milligrams of water equivalent to each milliliter of the Karl Fischer
reagent. Standardize the Karl Fischer reagent in this manner daily.
where:
e=milligrams of water equivalent to 1 ml. Karl Fischer reagent.
w=weight of water in milligrams.
v1=volume of Karl Fischer reagent used.
v2=volume of methanol used.
f=volume ratio of Karl Fischer reagent to water-methanol solution.
(3) Procedure. Transfer 1.0 milliliter of the penicillin in oil and
wax to a dry titrating vessel, add 10 milliliters of dry chloroform and
an excess of the Karl Fischer reagent and back titrate with the
water-methanol solution until the endpoint is reached. Transfer 10
milliliters of the dry chloroform used to a dry titrating vessel, add an
excess of Karl Fischer reagent, and titrate with the water-methanol as
above. Calculate the milliliters of Karl Fischer reagent equivalent to
10 milliliters of chloroform.
Percent moisture=
where:
b=milliliters Karl Fischer reagent equivalent to 10 ml. of
chloroform.
s=volume of the sample in milliliters.
(d) Measurement of penicillin particle size. Vigorously shake the
container to obtain an even suspension of the penicillin particles and
immediately withdraw therefrom approximately 0.5 milliliter of the drug
into a clean, dry, tuberculin syringe using a dry 18-gauge needle.
Discard approximately the first 5 drops of the mixture extruded from the
needle and then extrude approximately 1 minim of the remaining mixture
into a test tube containing 3 to 4 milliliters of light mineral oil.
Thoroughly mix the contents of the tube and by means of a
bacteriological loop (2 millimeters inside diameter, 22 gauge wire),
immediately place one loopful of the suspension on each ruled chamber of
a bright line hemocytometer. (It is not necessary to use a cover slip.)
Confirm by means of the low power objective of the microscope the even
distribution of particles over the ruled areas of both chambers and
repeat with another loopful of the suspension if even dispersion is not
obtained. Use a magnification of 430 or 440 diameters and a calibrated
ocular micrometer to measure the penicillin particles. For the purpose
of measurement and calculation, the predominant type of crystals
observed shall be considered to represent the type of crystals present
and the thickness and density of all particles shall be considered
constant. Center a large penicillin particle in the microscopic field;
measure the particle and all other particles in the field and repeat
this operation on other fields until at least 200 particles are
measured. Particles of less than 5 microns in length are disregarded.
The grouping of the particles by length, the midpoint, the ratio of the
midpoints, and the square of the ratio of the midpoints for each group
are tabulated below:
Calculate the percent particles in each group from the total number
measured. Determine the percent relative weight for each group as
follows:
Plate type particles. Relative weight= (ratio)2 % of total particles
in group.
% relative weight=
Rod-shaped particles. In the case of rod-shaped particles measure
the width as well as the length.
Relative weight=ratio average width % of total particles in group
% relative weight=
When examined by the method described in this section not less than
50 percent of the total relative weight of the penicillin in the drug
consists of penicillin having a particle size of not less than 50
microns in length.
21 CFR 436.503 Procaine penicillin and buffered crystalline penicillin
for aqueous injection.
(a) Total potency (except in single-dose container), sterility,
moisture, pyrogens, toxicity, pH. Proceed as directed in 440.274b(b)
of this chapter.
(b) Buffered crystalline penicillin content -- (1) Preparation of the
solution for assay. Add the indicated amount of distilled water to the
contents of a vial of the sample, and shake well. Withdraw one dose of
the suspension with a hypodermic syringe and place in a 10-milliliter
volumetric flask. Add 20-percent sodium sulfate solution almost to the
mark, centrifuge sufficiently to see the meniscus, make to volume with
20-percent sodium sulfate solution, shake well, and centrifuge to obtain
a clear or reasonably clear solution. Dilute a 5.0-milliliter aliquot
of this clear solution with 1-percent phosphate buffer, pH 6.0, to give
a solution for assay of approximately 2,000 units per milliliter.
(2) Iodometric assay for total penicillin in the solution for assay.
Determine the quantity of penicillin in the solution for assay by the
iodometric assay procedure described in 440.80a(b)(5)(iv)(a) of this
chapter.
(3) Colorimetric determination of procaine penicillin in the solution
for assay. Transfer an aliquot of the solution for assay to a
50-milliliter volumetric flask. Determine the quantity of procaine
penicillin in this solution by the following method:
(i) Reagents -- (a) Sodium nitrite solution. Dissolve 0.1 gram of
sodium nitrite in 100 milliliters of distilled water. Prepare fresh
solution every week and store under refrigeration.
(b) Ammonium sulfamate solution. Dissolve 0.5 gram of ammonium
sulfamate in 100 milliliters of distilled water and store under
refrigeration.
(c) N-(1-naphthyl)-ethylenediamine solution. Dissolve 0.1 gram of
N-(1-naphthyl) ethylenediamine dihydrochloride in 100 milliliters of
distilled water. Prepare fresh solutions every week and store under
refrigeration.
(d) Standard procaine solution. Prepare a standard solution
containing 27.55 milligrams of procaine hydrochloride U.S.P. in a liter
of distilled water (each milliliter of the standard solution is
equivalent to 60 units of procaine penicillin).
(ii) Standards. Transfer, respectively, 1.0, 2.0, 3.0, 4.0, and 5.0
milliliters of the standard solution and 5.0 milliliters of distilled
water to each of six 50-milliliter volumetric flasks. Add 4.0, 3.0,
2.0, and 1.0 milliliters of water to the first four flasks,
respectively, to give each a volume to 5.0 milliliters.
(iii) Procedure. To each flask for the standards and the solution
for assay add 0.5 milliliter of 4 N HCl, 1.0 milliliter of the sodium
nitrite solution, 1.0 milliliter of the ammonium sulfamate, and 1.0
milliliter of the N-(1-naphthyl)-ethylenediamine solution. Mix and wait
two minutes after each addition. Make each flask to volume of 50
milliliters with distilled water. Determine the absorbency of the
colored solutions at 550 M in a suitable photo electric colorimeter.
The instrument is balanced so that the zero concentration reads zero
absorbency. Plot the standard curve on coordinate graph paper. Obtain
the procaine penicillin content of the solution for assay directly from
the point on the standard curve corresponding to its absorbency.
(4) The content of buffered crystalline pencillin in one dose of the
product is calculated as follows:
where:
A=buffered crystalline penicillin content of the product.
B=total number of units of penicillin per milliliter as determined in
paragraph (b)(2) of this section.
C=number of units of procaine penicillin per milliliter as determined
in paragaph (b)(3) of this section.
F=appropriate dilution factor depending on the dilution made in the
preparation of the solution for assay.
The content of buffered crystalline penicillin in the batch is
satisfactory when determined by the method described in this paragraph
if it is not less than 85 percent of that which it is represented to
contain.
(c) Procaine penicillin. The procaine penicillin content of the
batch is the difference between the total potency determined by the
method described in paragraph (a) or (d) of this section and the content
of the buffered crystalline penicillin determined by the method
described in paragraph (b) of this section. The procaine penicillin
content of the batch is satisfactory when determined by the method
described in this paragraph if it is not less than 85 percent of that
which it is represented to contain.
(d) Total potency of a one-dose container. Wash out the material
remaining in the 10-milliliter volumetric flask referred to in paragraph
(b)(1) of this section with 1-percent phosphate buffer, pH 6.0. Dilute
to give a concentration of approximately 2,000 units per milliliter, and
assay by the iodometric method described in 440.80a (b)(5)(iv)(a) of
this chapter. Obtain the total potency by adding the number of units
found in this solution (units per milliliter volume) to the number of
units found (units per milliliter volume) in the solution assayed in
accordance with paragraph (b)(2) of this section.
21 CFR 436.504 Penicillin-bacitracin ointment.
(a) Potency -- (1) Penicillin content. Proceed as directed in
540.380a(b)(1) of this chapter, except the last sentence of that
paragraph. Its content of penicillin is satisfactory if it contains not
less than 85 percent of the number of units it is represented to
contain.
(2) Bacitracin content. Proceed as directed in 448.510a(b)(1) of
this chapter, except that sufficient penicillinase is added to the
sample under test to completely inactivate the penicillin present. Its
content of bacitracin is satisfactory if it contains not less than 85
percent of the number of units it is represented to contain.
(b) Moisture. Proceed as directed in 436.201.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 436.505 Penicillin-streptomycin-bacitracin ointment;
penicillin-dihydrostreptomycin-bacitracin ointment;
penicillin-streptomycin-bacitracin methylene disalicylate ointment;
penicillin-dihydrostreptomycin-bacitracin methylene disalicylate
ointment.
(a) Potency -- (1) Content of penicillin, streptomycin, and
dihydrostreptomycin. Proceed as directed in 536.501(a) of this
chapter.
(2) Bacitracin content. Proceed as directed in 448.510a(b)(1) of
this chapter, except that:
(i) Sufficient penicillinase is added to the sample under test to
completely inactivate the penicillin present.
(ii) Use as the test organism the streptomycin dihydrostreptomycin
resistant strain of either Micrococcus flavus (ATCC 10240A)1013 or
Sarcina subflava (ATCC 7468/d),1 grown and maintained in media
containing 500 micrograms of streptomycin or dihydrostreptomycin per
milliliter of media, or calculate from the quantity of streptomycin or
dihydrostreptomycin found, using the method prescribed by paragraph
(a)(1) of this section, the quantity that would be present when the
sample is diluted to contain one unit of bacitracin (labeled potency)
per milliliter. Prepare the bacitracin standard curve by adding the
calculated quantity of streptomycin or dihydrostreptomycin to each
concentration of bacitracin used for the curve. Use this standard curve
to calculate the bacitracin content of the sample.
(3) Bacitracin methylene disalicylate content. Proceed as directed
in paragraph (a)(2) of this section, except prepare the sample as
follows: Place a representative portion of the sample (usually
approximately 1 gram, accurately weighed) or the entire contents of a
single-dose container in blending jar, add 99 milliliters of a
2.0-percent aqueous solution of sodium bicarbonate and 1 milliliter of a
10-percent aqueous solution of polysorbate 80 and blend for 3 minutes in
a high-speed blender. Allow the foam to subside, remove an aliquot of
the solution, and dilute to 1 unit per milliliter with 1.0-percent
phosphate buffer, pH 6.0.
(b) Moisture. Proceed as directed in 436.201.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
0131Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
21 CFR 436.506 Benzathine penicillin G and buffered crystalline
penicillin for aqueous injection.
(a) Total potency (except in single-dose containers). Proceed as
directed in 440.80a(b)(1) of this chapter, except if the bioassay
method is used prepare the sample by diluting 1.0 milliliter of the drug
suspension with sufficient dimethyl formamide, formamide, or methyl
alcohol to dissolve the benzathine penicillin. Make to 100 milliliters
with buffer. Shake well and dilute to 1.0 unit per milliliter. If the
iodometric method is used, proceed as directed in 440.55a(b) of this
chapter, except in preparing the blank solution dilute 1.0 milliliter of
the drug suspension to 250 milliliters with 1-percent phosphate buffer
at pH 6.0. In preparing the solution for inactivation dissolve 1.0
milliliter of the drug suspension in approximately 20 milliliters of 0.5
N NaOH. Allow to stand for 15 minutes. Dilute to 250 milliliters with
distilled water. Pipette a 2.0-milliliter aliquot into a 125-milliliter
glass-stoppered Erlenmeyer flask and add 2.0 milliliters 1.2 N HCl and
10 milliliters 0.01 N iodine.
(b) Buffered crystalline penicillin content. Place 1.0 milliliter of
the drug suspension in a 10-milliliter volumetric flask and add 20
percent sodium sulfate to make 10 milliliters. Shake well and
centrifuge to obtain a clear, or reasonably clear, solution. Dilute a
5.0-milliliter aliquot to 50 milliliters with buffer and proceed as
directed in 440.80a(b)(1) of this chapter to determine the number of
units per milliliter of this solution, and from this value calculate the
number of units per milliliter of the drug. The content of buffered
crystalline penicillin is satisfactory if it is not less than 85 percent
of that which it is represented to contain.
(c) Benzathine penicillin G content. The benzathine penicillin G
content of the batch is the difference between the total potency as
described in paragraph (a) or (d) of this section and the content of
buffered crystalline penicillin determined by the method prescribed in
paragraph (b) of this section. The content of benzathine penicillin G
is satisfactory if it is not less than 85 percent of that which it is
represented to contain.
(d) Total potency of a single-dose container. Add sufficient
distilled water to the material remaining in the 10-milliliter
volumetric flask referred to in paragraph (b) of this section to bring
the volume back to 10 milliliters and determine the number of units per
milliliter of this suspension. If the iodometric method is used,
2.0-milliliter aliquots are placed in 50-milliliter volumetric flasks
(one blank and one to be inactivated). Obtain the total potency by
adding the number of units found in the 10-milliliter volumetric flask
to one-half the content of buffered crystalline penicillin found in
paragraph (b) of this section.
(e) Sterility. Proceed as directed in 436.20 using the method
described in paragraph (e)(2) of that section, except use medium C in
lieu of medium A, and medium F in lieu of medium E. During the period
of incubation, shake the tubes at least once daily.
(f) Moisture. Proceed as directed in 440.74a(b)(5) of this chapter.
(g) Pyrogens. Proceed as directed in 436.500.
(h) Toxicity. Proceed as directed in 440.55a(b)(3) of this chapter.
(i) pH. Proceed as directed in 440.80a(b)(5)(ii) of this chapter,
using the suspension resulting when the product is reconstituted as
directed in the labeling.
21 CFR 436.507 Benzathine - procaine - buffered crystalline penicillins
for aqueous injection.
(a) Potency -- (1) Total potency. Proceed as directed in
440.80a(b)(1) of this chapter, except if the bioassay method is used
prepare the sample by diluting one dose of the drug suspension with
sufficient dimethyl formamide or formamide or methyl alcohol to dissolve
the benzathine penicillin G. Make to 100 milliliters with 1-percent
phosphate buffer, pH 6.0. Shake well, and dilute to 1.0 unit per
milliliter with buffer. If the iodometric method of assay is used, add
the indicated amount of distilled water to the contents of a vial of the
sample, shake well, and proceed as follows (except for single-dose
containers):
(i) Using a standardized hypodermic syringe, withdraw one dose and
dilute with 1-percent phosphate buffer, pH 6.0, to give a concentration
of approximately 2,000 units per milliliter. Use 2.0 milliliters of
this suspension as the blank in the iodometric assay procedure described
in 440.80a(b)(5)(iv)(a) of this chapter.
(ii) Using a standardized hypodermic syringe, withdraw another dose,
place in a flask, and add 20 milliliters of 0.5 N NaOH for each 300,000
units of benzathine penicillin, mix well, being sure that all penicillin
is in solution, and allow to stand for 15 minutes. Add 1 milliliter of
1.2 N HCl for each 2 milliliters of 0.5 N NaOH, mix, and dilute with
distilled water to the same volume as was used in paragraph (a)(1)(i) of
this section. Place 2.0 milliliters in a 125-milliliter glass-stoppered
Erlenmeyer flask, add 10 milliliters of 0.01 N iodine, allow to stand
for 15 minutes, and titrate with 0.01 N sodium thiosulfate as directed
in the iodometric assay procedure in 440.80a (b)(5)(iv)(a) of this
chapter. The total potency of the batch is satisfactory if it contains
not less than 85 percent of that which it is represented to contain.
(2) Procaine penicillin content (except for single-dose containers).
Make suitable dilutions of the solution prepared in paragraph (a)(1)(ii)
of this section to obtain approximately 60 units of procaine penicillin
per milliliter. Determine the procaine penicillin content by the
colorimetric procedure described in 436.503(b)(3). The content of
procaine penicillin is satisfactory if it contains not less than 85
percent of the number of units that it is represented to contain.
(3) Buffered crystalline penicillin content -- (i) Preparation of the
solution for assay. (a) Add the indicated amount of distilled water to
the contents of a vial of the sample, and shake well. Withdraw one dose
of the suspension with a hypodermic syringe and place in a 10-milliliter
volumetric flask. Add 20-percent sodium sulfate solution almost to the
mark, centrifuge sufficiently to see the meniscus, make to volume with
20-percent sodium sulfate solution, shake well, and centrifuge to obtain
a clear or reasonably clear solution; or
(b) If the original product contains more than 600,000 units, place
it in a 50-milliliter volumetric flask, add 20-percent sodium sulfate to
the mark, shake well, place a 10-milliliter portion in a centrifuge
tube, and centrifuge to obtain a reasonably clear solution.
(c) Dilute a 5.0-milliliter aliquot of the clear solution obtained in
paragraph (a) (3)(i) (a) or (b) of this section with 1-percent phosphate
buffer, pH 6.0, to give a solution for assay of approximately 2,000
units per milliliter.
(ii) Iodometric assay for total penicillin in the solution for assay.
Determine the total quantity of penicillin in the solution for assay by
the iodometric assay procedure described in 440.80a (b)(5)(iv)(a) of
this chapter.
(iii) Colorimetric determination of procaine penicillin in the
solution for assay. Proceed as directed in 436.503 (b)(3). The content
of procaine penicillin in the batch is satisfactory if it is not less
than 85 percent of that which it is represented to contain.
(iv) The buffered crystalline penicillin in one dose of the product
is calculated as follows:
where:
A=the buffered crystalline penicillin content of the product.
B=the number of units of penicillin per milliliter as determined in
paragraph (a)(3)(ii) of this section.
C=the number of units of procaine penicillin per milliliter as
determined in paragraph (a)(3)(iii) of this section.
F=the appropriate dilution factor depending on the dilutions made in
the preparation of the solution for assay.
The content of buffered crystalline penicillin is satisfactory if the
batch contains 85 percent of the number of units per milliliter that it
is represented to contain.
(4) Benzathine penicillin content. The sum of the procaine
penicillin content determined under paragraph (a)(2) or (6) of this
section and the buffered crystalline penicillin content determined under
paragraph (a)(3) of this section, subtracted from the total potency
determined in paragraph (a)(1) or (5) of this section, represents the
benzathine penicillin G content. The benzathine penicillin G content is
satisfactory if it is not less than 85 percent of the number of units
that it is represented to contain.
(5) Total potency of a single-dose container. Wash out the material
remaining in the volumetric flask referred to in paragraph (a)(3)(i)(a)
of this section, or combine the contents remaining in the 50-milliliter
volumetric flask and in the centrifuge tube referred to in paragraph
(a)(3)(i)(b) of this section. Dissolve the material by adding 10
milliliters of 1 N NaOH for each 300,000 units of benzathine penicillin
and allow to stand 15 minutes. Add 1 milliliter of 1.2 N HCl for each
milliliter of 1 N NaOH and then dilute with distilled water to give a
concentration of approximately 2,000 units per milliliter. Place 2.0
milliliters in a 125-milliliter glass-stoppered Erlenmeyer flask, add 10
milliliters of 0.01 N iodine, allow to stand for 15 minutes, and then
titrate with 0.01 N sodium thiosulfate as directed in 440.80a
(b)(5)(iv)(a) of this chapter. For the blank determination prepare a
separate sample as directed in paragraph (a)(3)(i) (a) or (b) of this
section and in the first sentence of this paragraph (a)(5), then dilute
with 1 percent phosphate buffer, pH 6.0, to give a concentration of
approximately 2,000 units per milliliter. The total potency of the
one-dose container is equal to the sum of the number of units found in
this assay (units per milliliter volume) and the number of units found
(units per milliliter volume) in the solution for assay in paragraph
(a)(3)(ii) of this section.
(6) Procaine penicillin content of a single-dose container. Make
suitable dilutions of the NaOH-inactivated solution prepared in
paragraph (a)(5) of this section to obtain approximately 60 units of
procaine penicillin per milliliter. Determine the procaine penicillin
content (units per milliliter volume) of this solution by the
colorimetric procedure described under 436.503(b)(3). To this value add
per procaine penicillin content (unit per milliliter volume) of the
solution for assay, as found in paragraph (a)(3)(iii) of this section,
to obtain the procaine penicillin content of the one-dose container.
The content of procaine penicillin in the batch is satisfactory if it is
not less than 85 percent of that which it is represented to contain.
(b) Sterility. Proceed as directed in 436.20, using the method
described in paragraph (e)(2) of that section, except use medium C in
lieu of medium A, and medium F in lieu of medium E. During the period
of incubation, shake the tubes at least once daily.
(c) Pyrogens. Proceed as directed in 440.55a(b)(4) of this chapter.
(d) Toxicity. Proceed as directed in 440.55a(b)(3) of this chapter.
(e) Moisture. Proceed as directed in 440.74a(b)(5) of this chapter.
(f) pH. Proceed as directed in 440.80a(b)(5)(ii) of this chapter,
using the suspension resulting when the product is reconstituted as
directed in the labeling.
21 CFR 436.508 Penicillin - bacitracin - neomycin ointment;
penicillin-bacitracin-neomycin in oil.
(a) Potency -- (1) Penicillin content; bacitracin content. Proceed
as directed in 436.504(a).
(2) Neomycin content. Proceed as directed in 448.510d(b)(1)(ii) of
this chapter, except that sufficient penicillinase is added to the
sample under test to completely inactivate the penicillin present. Its
content of neomycin is satisfactory if it contains not less than 85
percent of the number of milligrams per gram that it is represented to
contain.
(b) Moisture. Proceed as directed in 436.201.
21 CFR 436.509 Procaine penicillin-streptomycin-polymyxin in oil;
procaine penicillin-dihydrostreptomycin-polymyxin in oil; procaine
penicillin-streptomycin-polymyxin ointment; procaine penicillin -
dihydrostreptomycin - polymyxin ointment.
(a) Potency -- (1) Penicillin content. Proceed as directed in
540.380a(b)(1) of this chapter. Its content of penicillin is
satisfactory if it contains not less than 85 percent of the number of
units per milliliter or per gram that it is represented to contain.
(2) Streptomycin content. Proceed as directed in 544.373(b)(1)(i)
of this chapter, except inactivate the penicillin in the combined
extractives with sufficient penicillinase at 37 C. for 30 minutes.
Its content of streptomycin is satisfactory if it contains not less than
85 percent of the number of milligrams per milliliter or per gram that
it is represented to contain.
(3) Dihydrostreptomycin content. Proceed as directed in paragraph
(a)(2) of this section, using the dihydrostreptomycin working standard
as a standard of comparison. Its content of dihydrostreptomycin is
satisfactory if it contains not less than 85 percent of the number of
milligrams per milliliter or per gram that it is represented to contain.
(4) Polymyxin content. Proceed as directed in 444.170a(b)(2)(i) of
this chapter, with the following exceptions:
(i) In lieu of the directions for the preparation of the sample
described in 444.170a(b)(2)(i)(g) of this chapter, prepare the sample
by one of the following techniques:
(a) Extraction. Place a convenient-sized representative quantity of
the sample in a separatory funnel containing approximately 50
milliliters of peroxide-free ether. Shake the sample and ether until
homogeneous. Add 25 milliliters of 10-percent potassium phosphate
buffer (pH 6.0) and shake. Remove the buffer layer and repeat the
extraction with 25-milliliter portions of buffer at least three times
and any additional times that may be necessary to insure complete
extraction of the antibiotic. Combine the extractives. Inactivate the
penicillin with sufficient penicillinase at 37 C. for 30 minutes.
Make the proper estimated dilutions in 10-percent potassium phosphate
buffer (pH 6.0) to give a concentration of 10 units per milliliter
(estimated).
(b) Blending. Place a convenient-sized representative quantity of
the sample in a blending jar containing 1.0 milliliter of polysorbate 80
and sufficient 1-percent phosphate buffer (pH 6.0) to give a final
volume of 200 milliliters. If the sample consists of substantially more
than 1 gram, use sufficient buffer to give a final volume of 500
milliliters. If the concentration of polymyxin in the blend is less
than 200 units per milliliter, 10-percent phosphate buffer (pH 6.0)
should be used in lieu of 1-percent phosphate buffer (pH 6.0). Using a
high-speed blender, blend the mixture for 2 minutes. Inactivate the
penicillin with sufficient penicillinase at 37 C. for 30 minutes and
make the proper estimated dilutions in 10-percent phosphate buffer (pH
6.0) to give a concentration of 10 units per milliliter (estimated).
(ii) The standard curve is prepared in the following concentrations:
6.4, 8.0, 10.0, 12.5, and 15.6 units per milliliter in 10-percent
potassium phosphate buffer, pH 6.0. The 10 units per milliliter
concentration is used as the reference point. Its content of polymyxin
is satisfactory if it contains not less than 85 percent of the number of
units per milliliter or per gram that it is represented to contain.
(b) Moisture. Proceed as directed in 436.201.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975;
41 FR 10886, Mar. 15, 1976)
21 CFR 436.510 Penicillin-streptomycin-erythromycin ointment;
penicillin-dihydro-streptomycin-erythromycin ointment.
(a) Potency -- (1) Penicillin content. Obtain the weight of the
content of a syringe by weighing before and after ejecting the content
into a beaker. Stir until homogeneous. Remove a representative sample
(usually approximately 1.0 gram, accurately weighed) and place in a
separatory funnel containing 50 milliliters of peroxide-free ether. Add
20 milliliters of 0.1 M potassium phosphate buffer (pH 8.0) and shake.
Remove the buffer layer and repeat the extraction with three additional
20-milliliter portions of the buffer. Place the buffer solution in a
second separatory funnel and wash with three 30-milliliter portions of
ether. Discard the ether washes. Remove an aliquot of the buffer
solution and proceed as directed in 440.80a(b) (1) of this chapter,
except 440.80a(b)(1)(iv) and (ix) of this chapter. If the iodometric
chemical assay is used, proceed as directed in 440.80a(b)(5)(iv)(a) of
this chapter, except prepare the sample as directed in 536.501(a)(1) of
this chapter. Its content of penicillin is satisfactory if it contains
not less than 85 percent of the number of units that it is represented
to contain.
(2) Streptomycin content. Using an aliquot of the buffer solution
prepared as directed in paragraph (a)(1) of this section, proceed as
directed in 444.70a (b)(1) through (9) of this chapter, except add
sufficient penicillinase to completely inactivate the penicillin
present. Its content of streptomycin is satisfactory if it contains not
less than 85 percent of the number of milligrams that it is represented
to contain.
(3) Dihydrostreptomycin content. Proceed as directed in paragraph
(a)(2) of this section, using the dihydrostreptomycin working standard
as the standard of comparison. Its content of dihydrostreptomycin is
satisfactory if it contains not less than 85 percent of the number of
milligrams that it is represented to contain.
(4) Erythromycin content. Proceed as directed in
444.570b(b)(1)(i)(b) of this chapter, except prepare the sample as
follows: Place a representative sample (usually approximately 1.0 gram,
accurately weighed), in a glass blending jar containing 99 milliliters
of 0.1 M potassium phosphate buffer, pH 8.0, and 1 milliliter of
polysorbate 80. Using a high-speed blender, blend for 2 to 3 minutes.
Add 100 milliliters of 0.1 M potassium phosphate buffer, pH 8.0, and
blend for an additional 2 to 3 minutes. Prepare an intermediate
dilution by diluting an aliquot of the filtrate with 0.1 M potassium
phosphate buffer (pH 8.0), and add sufficient penicillinase to
inactivate the penicillin. Then further dilute with buffer to give an
erythromycin content of 1.0 microgram per milliliter (estimated). Its
content of erythromycin is satisfactory if it contains not less than 85
percent of the number of milligrams that it is presented to contain.
(b) Moisture. Proceed as directed in 436.500(c).
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 436.511 Penicillin-streptomycin-bacitracin methylene
disalicylate-neomycin ointment;
penicillin-dihydrostreptomycin-bacitracin methylene
disalicylate-neomycin ointment.
(a) Potency -- (1) Penicillin content. Proceed as directed in
540.380a(b)(1) of this chapter. Its penicillin content is satisfactory
if it contains not less than 85 percent of the number of units that it
is represented to contain.
(2) Streptomycin content. Proceed as directed in 436.105 of this
chapter. Its content of streptomycin is satisfactory if it contains not
less than 85 percent of the number of milligrams that it is represented
to contain.
(3) Dihydrostreptomycin content. Proceed as directed in 436.105 of
this chapter. Its content of dihydrostreptomycin is satisfactory if it
contains not less than 85 percent of the number of milligrams that it is
represented to contain.
(4) Bacitracin methylene disalicylate content. Proceed as directed
in 436.505(a)(3). Its potency is satisfactory if it contains not less
than 85 percent of the equivalent number of units of bacitracin that it
is represented to contain.
(5) Neomycin content. Proceed as directed in 436.105 of this
chapter. Its content of neomycin is satisfactory if it contains not
less than 85 percent of the number of milligrams that it is represented
to contain.
(b) Moisture. Proceed as directed in 436.201.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 436.512 Procaine penicillin
G-novobiocin-neomycin-dihydrostreptomycin in oil.
(a) Potency -- (1) Penicillin G content. Proceed as directed in
440.180d (b)(1)(i)(a) of this chapter, using the novobiocin-resistant
strain of Staphylococcus aureus (ATCC 12692),1 except prepare the sample
as follows: Place the equivalent of one dose of sample in a blending
jar, add 1.0 milliliter of polysorbate 80 and a quantity of 1 percent
potassium phosphate buffer, pH 6.0, sufficient to make a total of 500
milliliters. Blend for 5 minutes with a high-speed blender and make
appropriate dilutions, using 1 percent potassium phosphate buffer, pH
6.0. Its content of penicillin G is satisfactory if it contains not less
than 85 percent of the number of units that it is represented to
contain.
(2) Novobiocin content. Proceed as directed in 440.180d(b)(3)(i),
with the following exceptions:
(i) Prepare the sample as follows: Place the equivalent of one dose
of sample in a blending jar, add 1.0 milliliter of polysorbate 80 and a
quantity of 0.1M potassium phosphate buffer, pH 8.0, sufficient to make
a total of 500 milliliters. Blend for 5 minutes with a high-speed
blender. To an aliquot, add sufficient penicillinase to inactivate the
penicillin, further dilute with 10 percent potassium phosphate buffer,
pH 6.0 (solution 6) to give a final concentration of 0.5 microgram
novobiocin per milliliter (estimated), and allow to stand for 1/2-hour
at 37 C. before filling the plates.
(ii) Aseptically add to the seed agar used for this assay, at the
time the bacterial suspension is added, a slurry of Dowex 50 WX-4, Na+
type 200-400 mesh, sufficient to make a total concentration of 2
percent. Prepare the slurry by adding 50 grams of the resin to 30
milliliters of distilled water and sterilize for 15 minutes at 15 pounds
pressure. Mix the slurry thoroughly before adding. Its content of
novobiocin is satisfactory if it contains not less than 85 percent of
the number of milligrams that it is represented to contain.
(3) Neomycin content. Proceed as directed in 436.517(b)(1) of this
chapter, using the Staphylococcus epidermidis (ATCC 12228)1 procedure,
except:
(i) Prepare the sample as follows: Place the equivalent of one dose
of sample in a blending jar, add 1.0 milliliter of polysorbate 80 and a
quantity of 0.1M potassium phosphate buffer, pH 8.0, sufficient to make
a total of 500 milliliters. Blend for 5 minutes with a high-speed
blender. To an aliquot, add sufficient penicillinase to inactivate the
penicillin, further dilute with 0.1M potassium phosphate buffer, pH 8.0,
to give a final concentration of 1.0 microgram neomycin per milliliter
(estimated), and allow to stand for 1/2-hour at 37 C. before filling
the plates.
(ii) Aseptically add to the seed agar used for this assay, at the
time the bacterial suspension is added, a slurry of Dowex 1-X8, Cl type
200-400 mesh, to make a total concentration of 1 percent. Prepare the
slurry by adding 50 grams of the resin to 30 milliliters of distilled
water and sterilize for 15 minutes at 15 pounds pressure. Mix the
slurry thoroughly before adding. Its content of neomycin is
satisfactory if it contains not less than 85 percent of the number of
milligrams that it is represented to contain.
(4) Dihydrostreptomycin content. Proceed as directed in 436.105
except prepare the sample by placing the equivalent of one dose in a
blender, add 1.0 milliliter of polysorbate 80 and a quantity of 0.1M
potassium phosphate buffer, pH 8.0, sufficient to make a total of 500
milliliters. Blend for 5 minutes with a high-speed blender. To an
aliquot, add sufficient penicillinase to inactivate the penicillin,
further dilute with 0.1M potassium phosphate buffer, pH 8.0, to give a
final concentration of 1.0 microgram dihydrostreptomycin per milliliter
(estimated), and allow to stand for 1/2-hour at 37 C. before filling
the plates. Its content of dihydrostreptomycin is satisfactory if it
contains not less than 85 percent of the number of milligrams that it is
represented to contain.
(b) Moisture. Proceed as directed in 436.500(c).
(39 FR 18944, May 30, 1974, as amended at 41 FR 10886, Mar. 15, 1976)
1Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
21 CFR 436.513 Chlortetracycline troches; tetracycline hydrochloride
troches.
(a) Potency. If it is tetracycline hydrochloride proceed as directed
in 446.81a(b)(1) of this chapter and if it is chlortetracycline
hydrochloride troches proceed as directed in 446.10a(b)(1) of this
chapter, except 446.10a(b)(1)(x), and in lieu of the directions in
446.10a(b)(1)(iv) and (viii)(c) of this chapter prepare the sample as
follows: Place 12 troches in a glass blending jar containing 500
milliliters of 0.01N HCl. Using a high-speed blender, blend for 3 to 5
minutes and then make the proper estimated dilutions in the buffer
solution. The average potency of the troches is satisfactory if they
contain not less than 85 percent of the number of milligrams they are
represented to contain.
(b) Moisture. Proceed as directed in 440.80a(b)(5)(i) of this
chapter.
21 CFR 436.514 Chlortetracycline hydrochloride powder topical;
tetracycline hydrochloride powder topical.
(a) Potency -- (1) Dry powder. Using a 3.0-gram sample or the entire
contents of the immediate container for each determination, prepare the
sample as follows: Using a high-speed blender, blend a 3.0-gram sample
in a glass blending jar containing 500 milliliters of 0.01 N HCl (use
0.1 N HCl if it is tetracycline), or reconstitute in the immediate
container as directed in the labeling of the drug. Transfer an
appropriate aliquot of 1.0 milliliter to 5.0 milliliters to a
100-milliliter volumetric flask and make to mark with 0.01 N HCl (use
0.1 N HCl if it is tetracycline). Withdraw an aliquot from the
volumetric flask, and if it is chlortetracycline hydrochloride dilute to
0.06 g. per milliliter, using 0.1 M potassium phosphate buffer, pH 4.5,
and proceed as directed in 446.10a(b)(1) of this chapter. If it is
tetracycline hydrochloride, dilute to 0.24 g. per milliliter, using 0.1
M potassium phosphate buffer, pH 4.5, and proceed as directed in
446.81a(b)(1) of this chapter. The average potency is satisfactory if
it contains not less than 85 percent of the number of milligrams of
chlortetracycline hydrochloride or tetracycline hydrocloride per gram or
per immediate container that it is represented to contain.
(2) Powder packaged with inert gases. Spray, as directed in the
labeling, the entire contents of each container to be tested into a
separate 2-liter Erlenmeyer flask, held in a horizontal position. Add
500 milliliters of 0.1 N HCl and shake to dissolve the contents.
Immediately remove aliquots of this solution and, using 0.1 M potassium
phosphate buffer, pH 4.5, for further dilutions, proceed as directed in
446.10a(b)(1) of this chapter if it is chlortetracycline hydrochloride
powder or 446.81a(b)(1) of this chapter if it is tetracycline
hydrochloride powder. Calculate the average total amount of antibiotic
expelled from the containers. The total potency is satisfactory if it
contains not less than 85 percent of the number of milligrams of
chlortetracycline hydrochloride or tetracycline hydrochloride that it is
represented to contain.
(b) Moisture. Proceed as directed in 440.80a(b)(5)(i) of this
chapter, except if it is packaged with inert gases proceed as directed
in 536.513(c) of this chapter.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
21 CFR 436.515 Capsules tetracycline and oleandomycin phosphate;
capsules tetracycline and troleandomycin; capsules tetracycline
hydrochloride and oleandomycin phosphate; capsules tetracycline
hydrochloride and troleandomycin.
(a) Potency -- (1) Tetracycline or tetracycline hydrochloride content
by turbidimetric assay -- (i) Test culture and media. Maintain the test
organism Escherichia coli (ATCC 10536)1016 on the agar described in
440.80a(b)(1) (ii)(a) of this chapter. For use in the assay, prepare a
suspension of the organism every 2 weeks, as follows: Transfer the
organism to a fresh agar slant and incubate at 37 C. overnight. Wash
the growth from the slant with the aid of 2 milliliters of sterile
distilled water and sterile glass beads into a Roux bottle containing
300 milliliters of the maintenance medium. Incubate overnight at 37 C.
and then harvest the growth with 50 milliliters of sterile distilled
water and sterile glass beads. Standardize this suspension by
determining the dilution that will permit 40-percent light transmission
in a photoelectric colorimeter using a 650-millimicron filter and an
18-millimeter diameter test tube as an absorption cell. Prepare the
daily inoculum by adding 10 milliliters of that dilution to each liter
of nutrient broth, prepared as directed in 440.80a (b)(1)(ii)(c) of
this chapter, needed for the test.
(ii) Working standard and solutions. Dissolve an appropriate amount
of the working standard in sufficient 0.1 N HCl to give a concentration
of 1,000 micrograms per milliliter. This stock solution may be kept in
the refrigerator for 1 week. Make daily dilutions of the stock solution
with 0.1 M potassium phosphate buffer (pH 4.5) to obtain concentrations
of 0.146, 0.187, 0.240, 0.308, and 0.395 micrograms per milliliter. Add
1.0 milliliter of each such concentration to each of three 16
millimeters x 125 millimeters test tubes.
(iii) Preparation of sample. Dissolve the contents of a
representative number of capsules in sufficient 0.1 N HCl to give a
stock solution of convenient concentration. Further dilute the stock
solution with 0.1 M potassium phosphate buffer (pH 4.5) to obtain a
final concentration of 0.24 microgram per milliliter (estimated). Add
1.0-milliliter of this dilution to each of three 16 millimeters x 125
millimeters test tubes.
(iv) Procedure. To each of the 16 millimeters x 125 millimeters test
tubes prepared in paragraph (a)(1)(ii) and (iii) of this section, add
9.0 milliliters of the inoculated nutrient broth described in paragraph
(a)(1)(i) of this section and place immediately in a 37 C. water bath
for 3 to 4 hours. After incubation, add 0.5 milliliter of a 12-percent
formaldehyde solution to each tube and read the absorbance values in a
suitable photoelectric colorimeter using a wavelength of 530
millimicrons. Set the instrument at zero absorbance with clear
uninoculated broth prepared as described in 440.80a(b)(1)(ii)(c) of
this chapter.
(v) Estimation of potency. Plot the average values for each
concentration of the standard on arithmetic graph paper with absorbance
values on the ordinate and tetracycline or tetracycline hydrochloride
concentrations on the abscissa. Construct the best straightline through
the points, either by inspection or by means of the following equations:
where:
L=absorbance value for the lowest concentration of the standard
curve.
H=absorbance value for the highest concentration of the standard
curve.
a, b, c, d, e=average absorbance values for each concentration of the
standard curve.
Plot the values obtained for L and H and connect the points with a
straight line. Average the absorbance values for the sample and read
the tetracycline or tetracycline hydrochloride concentration from the
standard curve. Multiply the concentration by appropriate dilution
factors to obtain the tetracycline or tetracycline hydrochloride content
of the sample. Its potency is satisfactory if it contains the
equivalent of not less than 85 percent of the number of milligrams of
tetracycline hydrochloride that it is represented to contain.
(2) Oleandomycin content. (i) If oleandomycin phosphate is used,
proceed as directed in paragraph (c)(1) of this section, except prepare
the sample as follows: Dissolve the contents of a representative number
of capsules in sufficient 0.1 M potassium phosphate buffer (pH 8.0) to
give a stock solution of convenient concentration. Further dilute with
0.1 M potassium phosphate buffer (pH 8.0) to obtain a final
concentration of 5.0 g. of oleandomycin activity per milliliter
(estimated).
(ii) If troleandomycin is used, proceed as follows: Dissolve the
contents of a representative number of capsules in chloroform to give a
stock solution of 1.0 milligram of oleandomycin activity per milliliter.
Transfer 30 milliliters of the chloroform solution to a glass-stoppered
test tube (200 millimeters x 22 millimeters) and add 20 milliliters of 1
N sodium hydroxide. Shake for 1 minute and centrifuge briefly to aid in
the separation of the layers. With the aid of a syringe and needle,
remove and discard the aqueous layer. Repeat the washing procedure with
two more 20-milliter portions of 1 N sodium hydroxide solution. Filter
the chloroform layer through a pledget of cotton. Dilute an aliquot of
this solution with chloroform to give a solution containing
approximately 25 g. of oleandomycin per milliliter. Transfer a 5.0
milliliter aliquot to a 40 milliliter glass-stoppered centrifuge tube,
dilute to 20 milliliters, with chloroform, and determine the
oleandomycin content as directed in paragraph (d)(1)(i) of this section.
Its content of oleandomycin is satisfactory if it contains not less
than 85 percent of the number of milligrams that it is represented to
contain.
(b) Moisture. Proceed as directed in 440.80a(b)(5)(1) of this
chapter.
(c) Oleandomycin phosphate used in making the capsules -- (1) Potency
-- (i) Cylinders (cups). Used cylinders described in 440.80a(b)(1)(i)
of this chapter.
(ii) Culture media. (a) Use the nutrient agar described in 440.80a
(b)(1)(ii)(a) of this chapter for the seed layer and base layer, except
that its pH after sterilization is 7.8 to 8.0.
(b) Use the nutrient agar described in 440.80a(b)(1)(ii)(a) of this
chapter for maintaining the test organism.
(iii) Working standard. Dissolve a suitable weighed quantity
(usually 25 milligrams or less) of the working standard (obtained from
the Food and Drug Administration) in 2 milliliters of ethanol, then add
sufficient 0.1 M potassium phosphate buffer, pH 8.0, to give a
concentration of 1,000 micrograms of oleandomycin base per milliliter.
This stock solution may be kept in the refrigerator for 3 days.
(iv) Preparation of sample. Dissolve the sample in sufficient 0.1 M
potassium phosphate buffer (pH 8.0) to give a convenient stock solution.
Further dilute in 0.1 M potassium phosphate buffer (pH 8.0) to give a
final concentration of 5.0 micrograms per milliliter (estimated).
(v) Preparation of test organism. The test organism is
Staphylococcus epidermidis (ATCC 12228)1017 which is maintained on
slants or agar described under paragraph (c)(1)(ii)(a) of this section.
Wash the organism from the agar slant with 3 milliliters of sterile
physiological saline solution onto a large agar surface such as that
provided by a Roux bottle containing 300 milliliters of the agar
described in paragraph (c)(1)(ii)(a) of this section. Spread the
suspension of organisms over the entire agar surface with the aid of
sterile glass beads. Incubate for 4 hours at 32 C. and then wash the
resulting growth from the agar surface with about 30 milliliters of
sterile physiological saline solution. Standardize the suspension by
determining the dilution that will give 80-percent light transmission,
using a suitable photoelectric colorimeter with a 650-millimicron filter
and an 18-millimeter-diameter test tube as an absorption cell. Run test
plates to determine the quantity of the diluted suspension (usually 1.5
milliliters) that should be added to each 100 milliliters of agar to
give clear, sharp zones of inhibition of appropriate size.
(vi) Preparation of plates. Add 21 milliliters of the agar prepared
as described in paragraph (c)(1)(ii)(a) of this section to each Petri
dish (20 millimeters 100 millimeters). Distribute the agar evenly in
the plates and allow it to harden. Use the plates the same day they are
prepared. Melt a sufficient amount of the agar described in paragraph
(c)(1)(ii)(a) of this section, cool to 48 C., add the proper amount of
the test organism as described in paragraph (c)(1)(v) of this section
and mix thoroughly. Add 4 milliliters of this inoculated agar to each
Petri dish. Distribute the agar evenly in the plates, cover with
porcelain covers glazed on the outside, and allow to harden. After the
agar has hardened, place 6 cylinders on the agar surface so that they
are at approximately 60 intervals on a 2.8-centimeter radius.
(vii) Standard curve. Prepare the daily standard curve by further
diluting the 1,000 micrograms per milliliter stock solution in 0.1 M
potassium phosphate buffer (pH 8.0) to obtain concentrations of 3.2,
4.0, 5.0, 6.25 and 7.80 micrograms per milliliter. Use 3 plates for the
determination of each point on the curve, except the 5.0 micrograms per
milliliter concentration, a total of 12 plates. On each of 3 plates
fill 3 cylinders with the 5.0 micrograms per milliliter standard, and
the other 3 cylinders with the concentration under test. Thus, there
will be 36 five-microgram determinations and 9 determinations for each
of the other points on the curve. After incubation, read the diameters
of the circles of inhibition in the plates. Average the readings of the
5.0 micrograms per milliliter concentration and the readings of the
point tested for each set of 3 plates and average also all 36 readings
of the 5.0 micrograms per milliliter concentration. The average of the
36 readings of the 5.0 micrograms per milliliter concentration is the
correction point for the curve. Correct the average value obtained for
each point to the figure it would be if the 5.0 micrograms per
milliliter reading for that set of 3 plates were the same as the
correction point. Thus, if in correcting the 4.0-microgram
concentration, the average of the 36 readings of the 5.0-microgram
concentration were 20.0 millimeters, and the average of the
5.0-microgram concentration of this set of 3 plates were 19.8
millimeters, the correction would be +0.2 millimeter. If the average
reading of the 4.0-microgram concentration of these same 3 plates were
19.0 millimeters, the corrected value would be 19.2 millimeters. Plot
these corrected values, including the average of the 5.0 micrograms per
milliliter concentration, on 2-cycle semilog paper, using the
concentration in micrograms per milliliter as the ordinate (the
logarithmic scale) and the diameter of the zone of inhibition as the
abscissa. Draw the standard curve through these points, either by
inspection or by means of the following equations:
where:
L=corrected zone diameter for the lowest concentration of the
standard curve,
H=corrected zone diameter for the highest concentration of the
standard curve,
c=average zone diameter for 36 readings of the 5.0 micrograms per
milliliter standard.
a, b, d, e=corrected average values for the 3.2, 4.0, 6.25, and 7.81
micrograms per milliliter standard solutions, respectively.
Plot the values obtained for L and H and connect with a straight
line.
(viii) Assay. Use 3 plates for each sample. Fill 3 cylinders on
each plate with the standard 5.0 micrograms per milliliter solution and
3 cylinders with the 5.0 micrograms per milliliter (estimated) sample,
alternating standard and sample. Incubate all plates, including those
containing the standard curve, at 32 C.-35 C. overnight, and measure
the diameter of each circle of inhibition. To estimate the potency of
the sample, average the zone readings of the standard and the zone
readings of the sample on the 3 plates used. If the sample gives a
larger zone size than the average of the standard, add the difference
between them to the 5.0 micrograms per milliliter zone on the standard
curve. If the average sample value is lower than the standard value,
subtract the difference between them from the 5.0 micrograms per
milliliter value on the curve. From the standard curve, read the
potencies corresponding to these corrected values of zone sizes.
(2) Toxicity. Proceed as directed in 440.80a(b)(4) of this chapter,
except use physiological salt solution as the diluent, and inject 0.5
milliliter of a solution containing 8 milligrams per milliliter.
(3) Moisture. Proceed as directed in 440.80(b)(5)(i) of this
chapter.
(4) pH. Proceed as directed in 440.80a(b)(5)(ii) of this chapter,
using a solution containing 100 milligrams per milliliter.
(5) Crystallinity. Proceed as directed in 440.80a(b)(5)(iii) of
this chapter.
(d) Troleandomycin used in making the capsules -- (1) Potency -- (i)
Chemical method -- (a) Reagents and equipment. (1) Methyl orange
reagent: Shake 0.5 M boric acid solution for about 12 hours (to insure
saturation) with an excess of methyl orange indicators. An alternative
method is to heat the mixture to about 50 C. and shake for about an
hour. Then allow to cool. Filter the saturated dye solution and wash
three times with chloroform. Store the dye solution over chloroform.
(2) Acid-alcohol solution: Add 2 milliliters of concentrated
sulfuric acid to 98 milliliters of absolute methyl alcohol.
(3) Glycerin: Reagent grade.
(4) Centrifuge tubes: 40 milliliters, glass-stoppered.
(b) Procedure. Prepare a chloroform solution containing 50.0
milligrams activity of standard oleandomycin base in 200 milliliters of
solution. Transfer 10.0 milliliters of the solution to a 100-milliliter
volumetric flask and dilute to volume with chloroform. Transfer 2.0,
4.0, 6.0, and 8.0 milliliters of this solution to glass-stoppered
centrifuge tubes (40-milliliter size) and dilute to a total volume of
20.0 milliliters each with chloroform. To the 20.0 milliliters of the
solution present in each (40-milliliter size) centrifuge tube add 0.2
milliliter of glacial acetic acid, 0.20 milliliter of glycerin, and 0.40
milliliter of methyl orange reagent. Shake for 5 minutes and centrifuge
for 3 minutes. Immediately transfer to another tube a 10.0-milliliter
aliquot from the chloroform (lower) layer. Care must be exercised to
see that no portion of the dye-glycerin-phase is included with the
chloroform aliquot. Add 1.0 milliliter of acid-alcohol solution to this
chloroform aliquot, mix well, and read the absorbancy at 535 m , using a
1-centimeter cell and a suitable photometer and using chloroform,
similarly treated, as a blank. Prepare a standard curve, plotting the
absorbance values of the standard solutions against the concentration
expressed in micrograms per aliquot. Accurately weigh the sample to be
tested to give 50 milligrams (estimated) of oleandomycin activity,
dissolve in chloroform, and make to 200 milliliters with chloroform.
Transfer 10.0 milliliters to a 100-milliliter volumetric flask and make
to volume with chloroform. Transfer 5.0 milliliters to a
glass-stoppered centrifuge tube and proceed as above. Determine the
potency of the sample from the standard curve.
(ii) Microbiological assay. Proceed as directed in paragraph (c)(1)
of this section, except:
(a) In lieu of the directions in paragraph (c)(1)(ii)(a) of this
section, use the nutrient agar described in 440.80a(b)(1)(ii)(a) of
this chapter for the seed and base layers, except add 2.0 milliliters of
polysorbate 80 to each 100 milliliters of agar. Its pH after
sterilization is 7.8 to 8.0.
(b) In lieu of the directions in paragraph (c)(1)(iii) of this
section, dissolve a suitable weighed quantity (usually 25 milligrams or
less) of the troleandomycin working standard (obtained from the Food and
Drug Administration) in sufficient 80 percent isopropyl alcohol-water
solution to give a concentration of 1,000 micrograms per milliliter
(estimated). Use the solution the day that it is prepared.
(c) In lieu of the directions in paragraph (c)(1)(iv) of this
section, dissolve the sample in sufficient 80 percent isopropyl
alcohol-water solution to give a convenient stock solution. Further
dilute in 0.2 M potassium phosphate buffer, pH 10.5 (35 grams of
dipotassium phosphate plus 2 milliliters of 10 N NaOH, q.s. to 1 liter),
to give a final concentration of 15 micrograms per milliliter
(estimated).
(d) In lieu of the directions in paragraph (c)(1)(vi) of this
section, use the agar described in paragraph (d)(1)(ii)(a) of this
section for both layers. Use the plates as soon after seeding as is
practical. If they are not to be used shortly after seeding, then they
should be refrigerated until ready for use.
(e) In lieu of the directions for preparing the standard curve in
paragraph (c)(1)(vii) of this section, prepare the standard curve by
diluting the stock solution in 0.2 M potassium phosphate buffer, pH
10.5, to give concentrations of 9.6, 12.0, 15.0, 18.8, and 23.4
micrograms per milliliter. The 15.0 micrograms per milliliter is the
reference concentration.
(f) In lieu of the directions in paragraph (c)(1)(viii) of this
section, incubate the plates at 37 C. overnight. The concentration of
the sample and standard being tested is 15.0 micrograms per milliliter.
(2) Toxicity. Administer orally, by means of a cannula or other
suitable device, to each of five mice within the weight range of 18
grams to 25 grams, 0.5 milliliter of a suspension containing 200
milligrams per milliliter in normal saline solution. If no animal dies
within 48 hours, the sample is nontoxic. If one or more animals die
within 48 hours, repeat the test, using for each test five or more
previously unused mice weighing 20 grams ( 0.5 gram) each; if the total
deaths within 48 hours is no greater than 10 percent of the total number
of animals tested, including the original test, the sample is nontoxic.
(3) Moisture. Proceed as directed in 440.80a(b)(5)(i) of this
chapter.
(4) pH. Proceed as directed in 440.80a(b)(5)(ii) of this chapter,
using a saturated aqueous-ethanol (1:1) solution prepared by adding 100
milligrams per milliliter.
(5) Paper chromatograph method -- (i) Apparatus and reagents -- (a)
Chromatographic chamber (cylinder glass-stoppered museum jar 11.5 inches
3.5 inches).
(b) Chromatographic paper (8 inches 8 inches Whatman No. 1).
(c) 0.1 N hydrochloric acid.
(d) Resolving solvent: Butyl acetate, benzene, nitromethane,
pyridine (5:5:5:1 by volume).
(e) Spray reagent: 15 grams antimony trichloride per 100 milliliters
of chloroform.
(ii) Procedure. Dissolve the sample in chloroform to give a solution
containing 10 milligrams to 20 milligrams per milliliter. Prepare a
sheet of chromatographic paper by drawing a line of origin parallel to
and 1 inch from the edge of the paper. Wet the paper thoroughly with
the 0.1 N hydrochloric acid and blot it firmly between sheets of
absorbent paper. Starting 2 inches in from the edges and at 1-inch
intervals, apply 3 microliters to 5 microliters of the sample solutions
to the starting line. Allow a few minutes for the paper to dry
partially. While the paper is still damp, form a cylinder by bringing
the outer edges together, allowing about 1-inch overlap, and secure with
a paper clip. Stand the paper in the chromatographic chamber, which has
been filled to a depth of 1/2-inch with the resolving solvent. After
the solvent front rises to a height of 4 inches to 5 inches above the
origin, remove the paper from the tank and hang it up to air dry. Spray
the dried paper with the antimony trichloride reagent. Hang the paper
in a 100 C. oven for 3 minutes. A purple spot becomes visible for
trioleandomycin at an Rf value of about 0.85. The approximate Rf values
for diacetyloleandomycin, monoacetyloleandomycin, and oleandomycin are,
respectively, 0.72, 0.27, and 0.13.
(6) Acetyl determination -- (i) Apparatus and reagents. (a) One
three-necked Pyrex flask of approximately 45 milliliters capacity,
pear-shaped with T-joints, agar inlet tube, glass-stoppered funnel,
glass condenser, and bubble counter.
(b) 50-milliliter Pyrex Erlenmeyer flask.
(c) 10-milliliter burette, calibrated in 0.02 milliliter.
(d) Anhydrous methanol, reagent grade.
(e) 2 N sodium hydroxide solution.
(f) Sulfuric acid solution prepared by adding 100 milliliters of
concentrated H2SO4 to 200 milliliters of water.
(g) 1 N barium chloride solution.
(h) Phenolphthalein solution (1 percent in ethanol).
(i) Water-pumped nitrogen.
(j) NaOH solution, 0.015 N.
(ii) Procedure. Weight accurately (to 0.01 milligram) approximately
30 milligrams of the sample into the three-necked acetyl flask. Add 2.0
milliliters of methanol to dissolve the sample, then add slowly with
gentle swirling, 1.0 milliliter of NaOH solution. Connect the gas inlet
tube with bubble counter attached, and adjust nitrogen flow to about two
bubbles a second. Put glass-stoppered funnel in centerneck of acetyl
flask and put about 5 milliliters of H2O in the funnel. Add a boiling
chip to the solution and attach condenser in the refluxing position with
water cooling. Adjust burner flame under acetyl flask to reflux
solution gently. Reflux for 30 minutes. Cool assembly slightly then
rinse down condenser (still in reflux position) with a few milliliters
of H2O. Reassemble condenser to the distillation position and add water
through the funnel to make a total of approximately 5 milliliters of H2O
added to acetyl flask. Adjust burner flame so that about 5 milliliters
of H2O and methanol is distilled over in approximately 10 minutes.
Discard this distillate. Cool acetyl flask slightly. Acidify solution
in flask by adding 1 milliliter of the sulfuric acid solution through
the funnel. Adjust burner flame and distill over approximately 20
milliliters of distillate into an Erlenmeyer flask in about 20 minutes,
adding water through the funnel as necessary. It is important to keep
the liquid volume in the acetyl flask around 2 milliliters to 3
milliliters in order to obtain a quantitative recovery of the acetic
acid. Collect a second fraction of distillate, about 10 milliliters in
volume. As the second fraction is distilling, process the first
fraction. Heat the first reaction and boil gently about 20 seconds.
Add a few drops of BaCL2 solution to check if any sulfate was distilled
over. If the sulfate is present, discard and repeat the whole
determination. If the sulfate is absent immediately titrate the
solution with the 0.015 N NaOH solution to a faint pink endpoint, using
one drop of phenolphthalein solution as the indicator. Repeat the above
procedure with the second fraction. If the second fraction requires
less than 0.10 milliliter of the 0.015 N NaOH solution and all the
acetic acid has been distilled over, the determination is completed. If
greater than this, collect a third fraction of approximately 10
milliliters and titrate this as before. Total volumes of NaOH used and
calculate results as follows:
(Milliliters of NaOH N NaOH 0.043 100)/Weight sample in
grams=Percent acetyl.
(7) Crystallinity. Proceed as directed in 440.80a(b)(5)(iii) of
this chapter.
0161Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
1Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
21 CFR 436.516 Tetracycline-neomycin complex powder topical;
tetracycline hydrochloride-neomycin sulfate powder topical.
(a) Potency -- (1) Tetracycline-neomycin complex powder -- (i)
Tetracycline content. Proceed as directed in 436.514(a)(2), except use
water in lieu of 0.1 N HCl for dissolving the sample. Its tetracycline
content is satisfactory if it contains not less than 85 percent of the
equivalent number of milligrams of tetracycline hydrochloride that it is
represented to contain.
(ii) Neomycin content. Using 0.1 M potassium phosphate buffer, pH
8.0, dilute an appropriate aliquot of the aqueous solution, prepared as
directed in paragraph (a)(1) of this section, to a final concentration
of 1 g. per milliliter (estimated), and proceed as directed in
436.515(c)(1), except that the neomycin standard stock solution
described 436.517(b)(1)(iii) is used to prepare the standard curve, by
further diluting with pH 8.0 buffer to final concentrations of 0.64,
0.80, 1.0, 1.25, and 1.56 g. per milliliter. The 1.0 g per milliliter
solution is the reference concentration. In lieu of the method
described in this subparagraph, the neomycin content may also be
determined as follows. Using the aqueous solution described, prepare
the sample and proceed as directed in 436.517(b)(1), except use
Staphylococcus aureus (American Type Culture Collection 12715)1018 as
the test organism, which is grown and maintained on agar containing 100
g. of tetracycline hydrochloride per milliliter of agar. Its neomycin
content is satisfactory if it contains not less than 85 percent of the
number of milligrams that it is represented to contain.
(2) Tetracycline hydrochloride-neomycin sulfate powder -- (i)
Tetracycline hydrochloride content. Prepare the sample as directed in
436.514(a)(2). Use an appropriate aliquot and proceed as directed in
446.81a(b)(1) of this chapter. Its tetracycline hydrochloride content
is satisfactory if it contains not less than 85 percent of the number of
milligrams that it is represented to contain.
(ii) Neomycin content. Use an appropriate aliquot of the solution
prepared in paragraph (a)(2)(i) of this section and proceed as directed
in paragraph (a)(1)(ii) of this section. Its neomycin content is
satisfactory if it contains not less than 85 percent of the number of
milligrams that it is represented to contain.
(b) Sterility. Thoroughly cleanse with a suitable disinfectant the
value (do not flame) of each container to be tested. Into each of two
empty, sterile Erlenmeyer flasks stoppered with a cotton plug, spray
quantitites sufficient to yield a residue of approximately the
equivalent of 50 milligrams from 10 separate cans by removing the plug
temporarily and using aseptic technique while spraying; allow
propellant to evaporate, add 250 milliliters to 500 milliliters of
diluting fluid B in lieu of diluting fluid A, and swirl the flasks to
dissolve the contents. Then proceed as directed in 436.20 of this
chapter using the method described in paragraph (e)(1) of that section.
(c) Moisture. Proceed as directed in 536.513(c) of this chapter.
(d) Tetracycline-neomycin complex used in making the drug -- (1)
Potency -- (i) Tetracycline content. Dissolve the sample to be tested
in sufficient water to give a convenient stock solution. Using an
appropriate aliquot, proceed as directed in 446.81a(b)(1).
(ii) Neomycin content. Using an aliquot of the stock solution
prepared as directed in paragraph (d)(1)(i) of this paragraph, proceed
as directed in paragraph (a)(2) of this section, except the last
sentence of that subparagraph.
(2) Toxicity. Proceed as directed in 440.80a(b)(4) of this chapter
using 0.5 milliliter of a solution prepared by diluting the sample with
physiological sodium chloride solution to contain 200 g. of neomycin
per milliliter (estimated).
(3) pH. Using a 1-percent aqueous solution, proceed as directed in
440.80a(b)(5)(ii) of this chapter.
(39 FR 18944, May 30, 1974, as amended at 40 FR 13497, Mar. 27, 1975)
0181Available from: American Type Culture Collection, 12301 Parklawn
Drive, Rockville, MD 20852.
21 CFR 436.517 Bacitracin-neomycin tablets; zinc bacitracin-neomycin
tablets; bacitracin methylene disalicylate-neomycin tablets.
(a) Tablets -- (1) Potency -- (i) Bacitracin, zinc bacitracin, or
bacitracin methylene disalicylate content. Proceed as directed in
448.110a(b)(1). Its content of bacitracin, zinc bacitracin, or
bacitracin methylene disalicylate is satisfactory if it contains not
less than 85 percent of the number of units per tablet that it is
represented to contain.
(ii) Neomycin content. Place 5 tablets in a blending jar and add
thereto 200 milliliters of a 500-milliliter quantity of 0.10-percent
phosphate buffer pH 8.0. After blending for 1 minute with a high-speed
blender, add the remainder of the buffer. Blend again for 1 minute and
make the proper estimated dilutions in the buffer and proceed as
directed in paragraph (b)(1) of this section. Its content of neomycin
is satisfactory if it contains not less than 85 percent of the number of
milligrams of activity that it is represented to contain.
(2) Moisture. Proceed as directed in 440.80a(b)(5)(i) of this
chapter.
(3) Disintegration time. Proceed as directed in 440.180a(b)(3).
(b) Neomycin used in making the tablets -- (1) Potency -- (i)
Cylinders (cups). Use cylinders described under 440.80a(b)(1)(i) of
this chapter.
(ii) Culture medium. Use the medium described in 440.80a(b)(1)
(ii)(a) of this chapter for both the base and seed layers, except its pH
after sterilization is 7.8 to 8.0.
(iii) Working standard. Dry the working standard (obtained from the
U.S.P. Reference Standards Committee, 46 Park Avenue, New York 16, N.Y.)
for 3 hours at 60 C. and a pressure of 5 millimeters or less and weigh
out a sufficient quantity to make a convenient stock solution by
diluting with a 0.1 M potassium phosphate buffer, pH 7.8 to 8.0. The
stock solution, when stored at a temperature of approximately 15 C., or
less, may be used for a period not exceeding 1 month.
(iv) Standard curve. Using the stock solution, prepare a daily
standard curve as directed in 444.70a(b)(1)(iv) of this chapter, using
solutions of the neomycin working standard in 0.1M potassium phosphate
buffer, pH 8.0, in concentrations of 6.4, 8.0, 10.0, 12.5, and 15.6
micrograms per milliliter if the test organism Staphylococcus aureus
(ATCC 6538P),1 or in concentrations of 0.64, 0.80, 1.0, 1.25, and 1.56
micrograms per milliliter if the test organism is Staphylococcus
epidermidis (ATCC 12228). 1 The 10.0 micrograms per milliliter and the
1.0 microgram per milliliter concentrations are used as the reference
points.
(v) Preparation of test organism. The test organism is
Staphylococcus aureus (ATCC 6538P),1 which is maintained on agar
described in 440.80a(b)(1)(ii)(a) of this chapter. From a stock slant
inoculate a Roux bottle containing this same agar and incubate for 24
hours at 32 C.-35 C. Wash the resulting growth from the agar surface
with about 50 milliliters of sterile sodium chloride solution.
Standardize this suspension by determining the dilution that will permit
80 percent light transmission through a filter at 6500 Angstrom units in
a photoelectric colorimeter. The suspension may be used for 2 weeks if
it is stored under refrigeration. Staphylococcus epidermidis (ATCC
12228),1 which is maintained on agar as described in
440.80a(b)(1)(ii)(a) of this chapter, may also be used as the test
organism. From a stock slant, inoculate a Roux bottle containing this
medium and incubate for 24 hours at 32 C.-35 C. Wash the resulting
growth from the agar surface, using approximately 30 milliliters of
sterile sodium chloride solution. Standardize the suspension by
determining the dilution that will permit 80 percent light transmission
through a filter of 6500 Angstrom units in a photoelectric colorimeter.
The suspension may be stored for 2 weeks under refrigeration.
(vi) Preparation of plates. Using the agar described in subdivision
(ii) of this subparagraph and approximately a 0.5 percent inoculum of
the suspension described in paragraph (b)(1)(v) of this section, prepare
the plates as directed in 440.80a(b)(1)(v) of this chapter.
(vii) Assay. Dissolve volumetrically in 0.1 M potassium phosphate
buffer, pH 7.8 to 8.0, the sample to be tested to make a convenient
stock solution. Further dilute volumetrically this solution with 0.1 M
potassium phosphate buffer, pH 7.8 to 8.0, to a final concentration of
10.0 micrograms (estimated) per milliliter, if the test organism is
Staphylococcusaureus or 1.0 microgram per milliliter (estimated) if the
test organism is Staphylococcus epidermidis.
(2) Toxicity. Proceed as directed in 440.80a(b)(4) of this chapter,
using 0.5 milliliter of a solution prepared by diluting the sample to
approximately 200 micrograms per milliliter with physiological salt
solution.
(3) Moisture. In an atmosphere of about 10 percent relative
humidity, transfer about 100 milligrams of the finely powdered sample to
a tared weighing bottle equipped with ground-glass top and stopper.
Weigh the bottle and place it in a vacuum oven, tilting the stopper on
its side so that there is no closure during the drying period. Dry at a
temperature of 60 C. and a pressure of 5 millimeters of mercury or
less for 3 hours. At the end of the drying period fill the vacuum oven
with air dried by passing it through a drying agent such as sulfuric
acid or silica gel. Replace the stopper and place the weighing bottle
in a desiccator over a desiccating agent such as phosphorous pentoxide
or silica gel, allow to cool to room temperature, and reweigh.
Calculate the percent loss.
(4) pH. Proceed as directed in 440.80a(b)(5)(ii) of this chapter,
using a solution containing 33 milligrams per milliliter.
1 See footnote 1 to 436.516.
21 CFR 436.542 Acid resistance/dissolution test for enteric-coated
erythromycin pellets.
(a) Equipment. Use Apparatus 1 as described in the United States
Pharmacopeia XX dissolution test.
(b) Immersion fluids. All immersion fluids may be degassed by
heating immediately prior to use.
(1) Acid resistance medium. Use 0.06N hydrochloric acid, pH 1.2.
(2) Dissolution medium. Dissolve 6.8 grams of monobasic potassium
phosphate in 250 milliliters of water. Add 109 milliliters of 0.2N
sodium hydroxide and 400 milliliters of water and adjust the resulting
solution with 0.2N sodium hydroxide to a pH of 6.8 0.1. Dilute to 1
liter.
(c) Procedure. Warm the immersion fluids to a temperature of 37
5.0 C. Place the contents of one capsule into the basket. Lower the
basket into 900 milliliters of acid resistance medium contained in the
beaker. Ensure that all air is displaced from the immersed basket and
that the pellets remain in the basket. Rotate the basket at the speed
of 50 revolutions per minute for an accurately timed period of 1 hour.
Remove the basket from the fluid and immediately lower the basket into
900 milliliters of dissolution medium contained in the beaker. Again
ensure that all air is displaced from the immersed basket and that the
pellets remain in the basket. Rotate the basket at 50 revolutions per
minute for an accurately timed dissolution period of 45 minutes.
Withdraw a 25-milliliter sample of the dissolution medium from a point
midway between the stirring shaft and the wall of the vessel and
approximately midway in depth. Filter the sample through a Whatman 541
filter paper or equivalent, discarding the first 2 milliliters. Assay
for erythromycin using the filtrate as the test solution as directed in
436.105. Repeat the test on five additional capsules.
(d) Evaluation. Use the interpretation described in the United
States Pharmacopeia XX dissolution test.
(46 FR 16678, Mar. 13, 1981, as amended at 50 FR 47213, Nov. 15,
1985; 52 FR 35912, Sept. 24, 1987; 54 FR 41824, Oct. 12, 1989)
21 CFR 436.543 Acid resistance test for pellet-filled doxycycline
hyclate capsules.
(a) Equipment. Use Apparatus 1 as described in the United States
Pharmacopeia XXI dissolution test.
(b) Acid resistance medium. Use 0.06N hydrochloric acid, pH 1.2.
May be degassed by heating immediately prior to use.
(c) Procedure. Warm the acid resistance medium to a temperature of
37 2.0 C. Place the contents of one pellet-filled capsule into the
basket. Lower the basket into a beaker containing 900 milliliters of
acid resistance medium. Ensure that all air is displaced from the
immersed basket and that the contents of the pellet-filled capsule
remain in the basket.
Rotate the basket at the speed of 50 revolutions per minute for an
accurately timed period of 20 minutes. Withdraw a 5-milliliter sample
of the acid resistance medium from a point midway between the stirring
shaft and the wall of the vessel and approximately midway in depth (this
is the sample solution). Assay the sample solution for doxycycline as
described in paragraph (d) of this section. Repeat the test on five
additional pellet-filled capsules.
(d) Doxycycline content -- (1) Preparation of working standard
solution. Dissolve an accurately weighed portion of doxycycline hyclate
working standard with 0.1M hydrochloric acid to obtain a concentration
of 0.01 milligram per milliliter.
(2) Preparation of sample solution. Dilute the 5-milliliter sample
portion to 25 milliliters with 0.1M hydrochloric acid.
(3) Procedure. Using a suitable spectrophotometer and 0.1M
hydrochloric acid as the blank, determine the absorbance of each
standard and sample solution at the absorbance peak at approximately 345
nanometers. Determine the exact position of the absorption peak for the
particular instrument used.
(4) Calculations. Determine the total amount of doxycycline
dissolved as follows:
where:
Au=Absorbance of sample;
As=Absorbance of standard;
c=Concentration of working standard in milligrams; and
d=Dilution factor of sample withdrawn from beaker.
*If more than 15 milliliters of dissolution medium is removed,
correct for the volume removed.
(e) Evaluation. The pellet-filled capsule passes the test if no more
than 50 percent of the drug is dissolved at 20 minutes. If one
pellet-filled capsule fails to meet this requirement, repeat the test on
six additional pellet-filled capsules. No more than 2 pellet-filled
capsules in 12 may exceed 50 percent of the drug dissolved at 20
minutes.
(50 FR 41679, Oct. 15, 1985; 50 FR 45603, Nov. 1, 1985)
21 CFR 436.544 Dissolution test for pellet-filled doxycycline hyclate
capsules.
(a) Equipment. Use Apparatus 1 as described in the United States
Pharmacopeia XXI dissolution test.
(b) Dissolution medium. Prepare the dissolution medium as follows:
Dissolve 10.21 grams of potassium biphthalate and 1.4 grams of sodium
hydroxide in approximately 950 milliliters of distilled water and adjust
the pH to 5.5 using 1M sodium hydroxide solution. Dilute with distilled
water to 1,000 milliliters.
(c) Procedure. Proceed as directed in the United States Pharmacopeia
XXI dissolution test. Ensure that all air is displaced from the
immersed basket and that the contents of the pellet-filled capsule
remain in the basket. Rotate the basket at the speed of 50 revolutions
per minute for an accurately timed period of 30 minutes. Withdraw a
5-milliliter sample of the dissolution medium from a point midway
between the stirring shaft and the wall of the vessel and approximately
midway in depth (this is the sample solution). Assay the sample
solution for doxycycline as described in paragraph (d) of this section.
Repeat the test on five additional pellet-filled capsules.
(d) Doxycycline content -- (1) Preparation of working standard
solution. Dissolve an accurately weighed portion of doxycycline hyclate
working standard with 0.1M hydrochloric acid to obtain a concentration
of 0.01 milligram per milliliter.
(2) Preparation of sample solution. Dilute the 5-milliliter sample
portion to 25 milliliters with 0.1M hydrochloric acid.
(3) Procedure. Using a suitable spectrophotometer and 0.1M
hydrochloric acid as the blank, determine the absorbance of each
standard and sample solution at the absorbance peak at approximately 345
nanometers. Determine the exact position of the absorption peak for the
particular instrument used.
(4) Calculations. Determine the total amount of doxycycline
dissolved as follows:
where:
Au=Absorbance of sample;
As=Absorbance of standard;
c=Concentration of working standard in milligrams; and
d=Dilution factor of sample withdrawn from beaker.
*If more than 15 milliliters of dissolution medium is removed,
correct for the volume removed.
(e) Evaluation. Use the dissolution acceptance table and
interpretation in the United States Pharmacopeia XXI.
(50 FR 41679, Oct. 15, 1985)
21 CFR 436.545 Acid resistance test for erythromycin particles in
tablets.
(a) Equipment. Use Apparatus 2 as described in the United States
Pharmacopeia XXI dissolution test.
(b) Acid resistance medium. Use 0.1N hydrochloric acid, 500
milliliters.
(c) Procedure. Warm the immersion fluid to a temperature of 37 0.5
C. Place one tablet into a vessel containing 500 milliliters of acid
resistance medium. Rotate the paddle at the speed of 50 revolutions per
minute for an accurately timed period of 1 hour. Withdraw a
50-milliliter sample of the dissolution medium from a point midway
between the stirring shaft and the wall of the vessel and approximately
midway in depth. Filter the sample through a Whatman No. 1 filter
paper or equivalent, discarding the first 5.0 milliliters. Assay for
dissolved erythromycin as directed in paragraph (d) of this section
using the filtrate as the sample solution. Repeat the test on five
additional tablets.
(d) Arsenomolybdate colorimetric assay for dissolved erythromycin --
(1) Apparatus. Automatic analyzer consisting of (i) a liquid sampler,
(ii) a proportioning pump, (iii) suitable spectrophotometers equipped
with matched flow cells and analysis capability at 660 nanometers, (iv)
a means of recording spectrophotometric readings, and (v) a manifold
consisting of the components illustrated in the diagram in paragraph
(d)(4) of this section.
(2) Reagents -- (i) Arsenomolybdate solutions -- (a) Stock solution.
Dissolve 100 grams of ammonium molybdate in approximately 1,700
milliliters of water contained in a 2-liter volumetric flask. Insert an
inert plastic coated stirring bar into the flask, and begin mixing.
While mixing, slowly add 84 milliliters of sulfuric acid (temperature of
solution should not exceed 50 C). Dissolve 12 grams of sodium arsenate
in 100 milliliters of water, and add to the solution in the flask.
Remove the stirring bar, dilute with water to volume, and mix. Store in
an amber bottle for 24 hours before using. (This solution should not be
allowed to come into contact with rubber.)
(b) Working solution. Dilute 1 part of stock solution with 2 parts
of water, and mix. This solution is freshly prepared on the day of use.
(ii) Acetate buffer, pH 4.8. Dissolve 133 grams of ACS grade sodium
acetate crystals in about 3.5 liters of water. Adjust the pH to 4.8 0.1
with glacial acetic acid. Dilute with water to 4,000 milliliters, and
mix.
(iii) 9N Sulfuric acid. Place a 2-liter volumetric flask containing
an inert plastic coated magnetic stirring bar and about 1,500
milliliters of water in an ice bath, and begin mixing. While mixing,
cautiously add 300 milliliters of sulfuric acid. Allow the solution to
cool. Remove the stirring bar, dilute with water to volume, and mix.
(3) Preparation of working standard solutions -- (i) Working standard
stock solution. Accurately weigh approximately 400 milligrams of USP
Erythromycin Reference Standard, previously dried at 60 C for 3 hours
under vacuum (pressure of 5 millimeters of mercury or less), and
transfer to a 100-milliliter volumetric flask. Dissolve and dilute with
acetate buffer, pH 4.8 to volume, and mix.
(ii) Working standard solutions. Pipet 5, 10, 15, and 20 milliliters
of the standard stock solution into separate 500-milliliter volumetric
flasks, add acetate buffer, pH 4.8 to volume, and mix. The approximate
concentrations of these solutions (before adjusting for the standard
potency) are 40, 80, 120, and 160 micrograms of erythromycin per
milliliter, respectively.
(4) Procedure. Use the working standard solutions prepared as
described in paragraph (d)(3) of this section. The arrangement of the
apparatus and flow of the samples and reagents are shown in the manifold
diagram set forth following this paragraph. The sampler rate is usually
60 per hour, but may be varied. Establish a steady state by pumping
reagents until the record trace becomes constant. Place cups containing
the four concentrations of working standard solutions in the sampler
followed by no more than 12 cups of sample solutions. Then place four
more cups containing the four concentrations of working standard
solutions in the sampler. Repeat the sequence above for additional
samples by bracketing standards around no more than 12 sample solutions
at a time.
Insert Illus. 0049
(5) System suitability test. Perform a linear regression analysis of
absorbance versus concentration in micrograms per milliliter of the
standards. The system is suitable for calculation if the beginning
baseline and the ending baseline after assaying a series of standard and
sample solutions does not vary by more than 2 percent transmittance, and
the correlation coefficient for each standard curve is greater than
0.995.
(6) Calculations. (i) Calculate the concentration of each standard
curve solution in micrograms of erythromycin per milliliter as follows:
(ii) Calculate the percent of labeled amount of erythromycin released
in 60 minutes as follows:
(51 FR 37721, Oct. 24, 1986)
21 CFR 436.545 Pt. 440
21 CFR 436.545 PART 440 -- PENICILLIN ANTIBIOTIC DRUGS
21 CFR 436.545 Subpart A -- Bulk Drugs
Sec.
440.1a Sterile azlocillin sodium.
440.2a Sterile amdinocillin.
440.3 Amoxicillin trihydrate.
440.5 Ampicillin.
440.7 Ampicillin trihydrate.
440.7a Sterile ampicillin trihydrate.
440.9a Sterile ampicillin sodium.
440.8 Bacampicillin hydrochloride.
440.10 Benzylpenicilloyl-polylysine concentrate.
440.11 Carbenicillin indanyl sodium.
440.13a Sterile carbenicillin disodium.
440.15 Cloxacillin sodium monohydrate.
440.17 Cyclacillin.
440.19 Dicloxacillin sodium monohydrate.
440.19a Sterile dicloxacillin sodium monohydrate.
440.25 Hetacillin.
440.29 Hetacillin potassium.
440.29a Sterile hetacillin potassium.
440.36a Sterile methicillin sodium monohydrate.
440.37a Sterile mezlocillin sodium monohydrate.
440.41 Nafcillin sodium monohydrate.
440.41a Sterile nafcillin sodium monohydrate.
440.49 Oxacillin sodium monohydrate.
440.49a Sterile oxacillin sodium monohydrate.
440.55a Sterile penicillin G benzathine.
440.71 Penicillin V.
440.73 Penicillin V potassium.
440.74a Sterile penicillin G procaine.
440.80 Penicillin G potassium.
440.80a Sterile penicillin G potassium.
440.81a Sterile penicillin G sodium.
440.83a Sterile piperacillin sodium.
440.90a Sterile ticarcillin disodium.
440.91 Ticarcillin monosodium monohydrate.
21 CFR 436.545 Subpart B -- Oral Dosage Forms
440.103 Amoxicillin oral dosage forms.
440.103a Amoxicillin trihydrate capsules.
440.103b Amoxicillin trihydrate for oral suspension.
440.103c Amoxicillin trihydrate chewable tablets.
440.103d Amoxicillin trihydrate and clavulanate potassium tablets.
440.103e Amoxicillin trihydrate and clavulanate potassium for oral
suspension.
440.105 Ampicillin oral dosage forms.
440.105a Ampicillin tablets.
440.105b Ampicillin chewable tablets.
440.105c Ampicillin capsules.
440.105d Ampicillin for oral suspension.
440.107 Ampicillin trihydrate oral dosage forms.
440.107a Ampicillin trihydrate chewable tablets.
440.107b Ampicillin trihydrate capsules.
440.107c Ampicillin trihydrate for oral suspension.
440.107d Ampicillin trihydrate-probenecid for oral suspension.
440.107e Ampicillin trihydrate-probenecid capsules.
440.108 Bacampicillin hydrochloride dosage forms.
440.108a Bacampicillin hydrochloride tablets.
440.108b Bacampicillin hydrochloride for oral suspension.
440.111 Carbencillin indanyl sodium tablets.
440.115 Cloxacillin sodium monohydrate oral dosage forms.
440.115a Cloxacillin sodium monohydrate capsules.
440.115b Cloxacillin sodium monohydrate for oral solution.
440.117 Cyclacillin oral dosage forms.
440.117a Cyclacillin tablets.
440.117b Cyclacillin for oral suspension.
440.119 Dicloxacillin sodium monohydrate oral dosage forms.
440.119a Dicloxacillin sodium monohydrate capsules.
440.119b Dicloxacillin sodium monohydrate for oral suspension.
440.125 Hetacillin oral dosage forms.
440.125a Hetacillin chewable tablets.
440.125b Hetacillin for oral suspension.
440.129 Hetacillin potassium capsules.
440.141 Nafcillin sodium monohydrate oral dosage forms.
440.141a Nafcillin sodium monohydrate tablets.
440.141b Nafcillin sodium monohydrate capsules.
440.141c Nafcillin sodium monohydrate for oral solution.
440.149 Oxacillin sodium monohydrate oral dosage forms.
440.149a Oxacillin sodium monohydrate capsules.
440.149b Oxacillin sodium monohydrate for oral solution.
440.155 Penicillin G benzathine oral dosage forms.
440.155a -- 440.155b (Reserved)
440.155c Penicillin G benzathine oral suspension.
440.155d Penicillin G benzathine tablets.
440.171 Penicillin V oral dosage forms.
440.171a Penicillin V capsules.
440.171b Penicillin V for oral suspension.
440.171c Penicillin V tablets.
440.173 Penicillin V potassium oral dosage forms.
440.173a Penicillin V potassium capsules.
440.173b Penicillin V potassium chewable wafers.
440.173c Penicillin V potassium tablets.
440.173d Penicillin V potassium for oral solution.
440.180 Penicillin G potassium oral dosage forms.
440.180a Penicillin G potssium tablets.
440.180c Penicillin G potassium capsules.
440.180f Penicillin G potassium for oral solution.
440.180g Penicillin G potassium tablets for solution.
21 CFR 436.545 Subpart C -- Injectable Dosage Forms
440.201 Sterile azlocillin sodium.I26440.202 Sterile amdinocillin.
440.202 Sterile amdinocillin.
440.207 Sterile ampicillin trihydrate for suspension.
440.209 Ampicillin sodium injectable dosage forms.
440.209a Sterile ampicillin sodium.
440.209b Sterile ampicillin sodium and sulbactam sodium.
440.210 Benzylpenicilloyl-polylysine injection.
440.213 Sterile carbenicillin disodium.
440.219 Dicloxacillin sodium monohydrate injectable dosage forms.
440.219a Sterile dicloxacillin sodium monohydrate.
440.219b Dicloxacillin sodium monohydrate for injection.
440.229 Hetacillin potassium injectable dosage forms.
440.229a Sterile hetacillin potassium.
440.229b Hetacillin potassium for injection
440.236 Methicillin sodium for injection.
440.237 Sterile mezlocillin sodium monohydrate.
440.241 Nafcillin sodium injectable dosage forms.
440.241a Nafcillin sodium monohydrate for injection.
440.241b Nafcillin sodium injection.
440.249 Oxacillin sodium injectable dosoge forms.
440.249a Oxacillin sodium monohydrate for injection.
440.249b Oxacillin sodium injection.
440.255 Penicillin G benzathine injectable dosage forms.
440.255b Sterile penicillin G benzathine suspension.
440.255c Sterile penicillin G benzathine-penicillin G procaine
suspension.
440.255d Sterile penicillin G benzathine for suspension.
440.274 Penicillin G procaine injectable dosage forms.
440.274a Sterile penicillin G procaine with aluminum stearate
suspension.
440.274b Sterile penicillin G procaine suspension.
440.274c Sterile penicillin G procaine for suspension.
440.280 Penicillin G potassium injectable dosage forms.
440.280a Sterile penicillin G potassium.
440.280b Penicillin G potassium for injection.
440.280c Penicillin G potassium injection.
440.281 Penicillin G sodium injectable dosage forms.
440.281a Sterile penicillin G sodium.
440.281b Penicillin G sodium for injection.
440.283 Sterile piperacillin sodium.
440.290 Ticarcillin disodium injectable dosage forms.
440.290a Sterile ticarcillin sodium.
440.290b Sterile ticarcillin disodium and clavulanate potassium.
440.290c Ticarcillin disodium and clavulanate potassium injection.
21 CFR 436.545 Subparts D-J -- (Reserved)
21 CFR 436.545 Subpart K -- Bulk Drug Formulations for Repacking or for
Manufacturing Use
440.1080a Sterile penicillin G potassium buffered.
440.1081a Sterile penicillin G sodium, buffered.
Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 357).
21 CFR 436.545 Subpart A -- Bulk Drugs
21 CFR 440.1a Sterile azlocillin sodium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Sterile azlocillin sodium is the sodium
salt of 4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,
3,3-dimethyl-7-oxo-6-(((((2-oxo-1-imidazolidinyl)carbonyl)amino)phenyla
c-etyl)amino)-(2S-(2a,5a,6b(S*)))-. It is so purified and dried that:
(i) If the azlocillin sodium is not packaged for dispensing, its
azlocillin content is not less than 859 micrograms and not more than
1,000 micrograms of azlocillin per milligram on an anhydrous basis. If
the azlocillin sodium is packaged for dispensing, its azlocillin content
is not less than 859 micrograms and not more than 1,000 micrograms of
azlocillin per milligram on an anhydrous basis and also, each container
contains not less than 90 percent and not more than 115 percent of the
number of milligrams of azlocillin that it is represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) Its moisture content is not more than 2.5 percent.
(v) Its pH in an aqueous solution containing 100 milligrams of
azlocillin per milliliter is not less than 6.0 and not more than 8.0.
(vi) Its specific rotation in an aqueous solution containing 10
milligrams of azlocillin per milliliter is +170 to +200 .
(vii) It gives a positive identity test for azlocillin.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, moisture, pH, specific rotation, and identity.
(ii) Samples, if required by the Director, Center for Drug Evaluation
and Research:
(a) If it is packaged for repacking or for use in the manufacture of
another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams; and 5 packages, each containing
approximately 1 gram.
(2) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) If it is packaged for dispensing:
(1) For all tests except sterility: A minimum of 15 immediate
containers.
(2) For sterility testing: 20 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
in 442.40(b)(1)(ii) of this chapter, except:
(i) Dilute Brij 35 solution. In lieu of the hydroxylamine
hydrochloride solution described in 442.40(b)(1)(ii)(b)(1) of this
chapter, use dilute Brij 35 solution in the reference channel. Prepare
dilute Brij 35 solution as follows: Place 1 milliliter of Brij 35, 30
percent solution, into a 1-liter volumetric flask containing 900
milliliters of distilled water. Swirl gently and dilute to volume
slowly with distilled water. Mix well.
(ii) Buffer. In lieu of the buffer described in
442.40(b)(1)(ii)(b)(2) of this chapter, use the buffer prepared as
follows: Dissolve 200 grams of primary standard tris (hydroxymethyl)
aminomethane in sufficient distilled water to make 1 liter. Filter
before use.
(iii) Preparation of working standard solution. Dissolve and dilute
an accurately weighed portion of the azlocillin working standard with
sufficient distilled water to obtain a concentration of 1.0 milligram of
azlocillin per milliliter.
(iv) Preparation of sample solutions -- (a) Product not packaged for
dispensing (micrograms of azlocillin per milligram). Dissolve and
dilute an accurately weighed portion of the sample with sufficient
distilled water to obtain a stock solution of 1.0 milligram of
azlocillin per milliliter (estimated).
(b) Product packaged for dispensing. Determine both micrograms of
azlocillin per milligram of the sample and milligrams of azlocillin per
container. Use separate containers for preparation of each sample
solution as described in paragraphs (b)(1)(iv)(b)(1) and (2) of this
section.
(1) Micrograms of azlocillin per milligram. Dissolve and dilute an
accurately weighed portion of the sample with sufficient distilled water
to obtain a stock solution of 1.0 milligram of azlocillin per milliliter
(estimated).
(2) Milligrams of azlocillin per container. Reconstitute as directed
in the labeling using distilled water in lieu of the reconstituting
fluid. Then, using a suitable hypodermic needle and syringe, remove all
of the withdrawable contents if it is represented as a single-dose
container; or, if the labeling specifies the amount of potency in a
given volume of the resultant preparation, remove an accurately measured
representative portion from each container. Dilute with distilled water
to obtain a stock solution of convenient concentration. Further dilute
an aliquot of the stock solution with distilled water to a concentration
of 1.0 milligram of azlocillin per milliliter (estimated).
(v) Calculations -- (a) Calculate the micrograms of azlocillin per
milligram of sample as follows:
Micrograms of azlocillin per milligram of sample
Au Ps 100
= --------------------
As Cu (100^m)
where:
Au=Absorbance of sample solution;
Ps=Potency of working standard solution in micrograms per milliliter;
As=Absorbance of working standard solution;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture in sample.
(b) Calculate the azlocillin content of the single-dose vial as
follows:
Milligrams of azlocillin per vial
Au Ps d
= ----------------
As 1,000
where:
Au=Absorbance of sample solution;
Ps=Potency of working standard solution in micrograms per milliliter;
As=Absorbance of working standard solution; and
d=Dilution factor of the sample.
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(b) of this chapter,
using a solution containing 100 milligrams of azlocillin per milliliter.
(4) Moisture. Proceed as directed in 436.201 of this chapter, using
the titration procedure and calculations described in paragraph (e)(2)
of that section and preparing the sample as follows: Weigh the vial.
Rapidly transfer a portion of the powder into the titration vessel, add
the Karl Fischer reagent and restopper the vial immediately. Reweigh
the vial to obtain the sample weight. A nitrogen purged glove bag or
glove box should be used for preparing the sample.
(5) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 100 milligrams of azlocillin per milliliter.
(6) Specific rotation. Proceed as directed in 436.210 of this
chapter, using an aqueous solution containing 10 milligrams of
azlocillin per milliliter and a 1.0-decimeter polarimeter tube.
Calculate the specific rotation on an anhydrous basis.
(7) Identity. Proceed as directed in 436.336 of this chapter.
(47 FR 53348, Nov. 26, 1982, as amended at 50 FR 1504, Jan. 11, 1985;
55 FR 11582, Mar. 29, 1990)
21 CFR 440.2a Sterile amdinocillin.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Sterile amdinocillin is
4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,
6-(((hexahydro-1H-azepin-1-yl)-methylene)amino)-3,3-dimethyl-7-oxo-,
(2S-2a,5a,6b))-. It is so purified and dried that:
(i) If the amdinocillin is not packaged for dispensing, its
amdinocillin potency is not less than 950 micrograms and not more than
1,050 micrograms of amdinocillin per milligram on an anhydrous basis.
If the amdinocillin is packaged for dispensing, its amdinocillin potency
is not less than 950 micrograms and not more than 1,050 micrograms of
amdinocillin per milligram on an anhydrous basis and also, each
container contains not less than 90 percent and not more than 120
percent of the number of milligrams of amdinocillin that it is
represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) Its moisture content is not more than 0.5 percent.
(v) Its pH in an aqueous solution containing 100 milligrams of
amdinocillin per milliliter is not less than 4.0 and not more than 6.2.
(vi) It is crystalline.
(vii) It gives a positive identity test for amdinocillin.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for amdinocillin
potency, and if packaged for dispensing, amdinocillin potency and
container content, sterility, pyrogens, moisture, pH, crystallinity, and
identity.
(ii) Samples, if required by the Director, Center for Drug Evaluation
and Research:
(a) If it is packaged for repacking or for use in the manufacture of
another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams.
(2) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) If it is packaged for dispensing:
(1) For all tests except sterility: A minimum of 15 immediate
containers.
(2) For sterility testing: 25 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Amdinocillin potency and
container content. Proceed as directed in 436.353 of this chapter,
using ambient temperature, an ultraviolet detection system operating at
a wavelength of 220 nanometers, a column packed with microparticulate (3
to 10 micrometers in diameter) reversed phase packing material such as
octadecyl hydrocarbon bonded silicas, e.g., a Whatman ODS-3 column
(25-centimeter column having an inside diameter of 4.6 millimeters and 5
micrometer particle size or equivalent), a flow rate of 1.0 milliliter
per minute, and an injection volume of 20 microliters. Reagents,
working standard and sample solutions, system suitability requirements,
and calculations are as follows:
(i) Reagents -- (a) Buffer solution 0.01M pH 5.0. Transfer 1.36 grams
of monobasic potassium phosphate in sufficient water to make 1,000
milliliters of solution. Adjust the pH to 5.0 0.1 with 18N phosphoric
acid or 10N sodium hydroxide.
(b) Mobile phase. Mix acetonitrile (high-pressure liquid
chromatography grade): 0.01M pH 5.0 phosphate buffer (15:85).
(ii) Working standard and sample solutions -- (a) Preparation of
working standard solution. Prepare the working standard solution fresh
before injection by dissolving an accurately weighed portion of the
amdinocillin working standard with sufficient distilled water to obtain
a stock solution containing approximately 100 micrograms of amdinocillin
per milliliter.
(b) Preparation of sample solutions -- (1) Product not packaged for
dispensing (micrograms of amdinocillin per milligram). Dissolve an
accurately weighed portion of the sample with sufficient distilled water
to obtain a solution containing 100 micrograms of amdinocillin per
milliliter (estimated).
(2) Product packaged for dispensing. Determine both micrograms of
amdinocillin per milligram of the sample and milligrams of amdinocillin
per container. Use separate containers for preparation of each sample
solution as described in paragraphs (b)(1)(ii)(b)(2) (i) and (ii) of
this section.
(i) Micrograms of amdinocillin per milligram. Dissolve an accurately
weighed portion of the sample with sufficient distilled water to obtain
a solution containing 100 micrograms of amdinocillin per milliliter
(estimated).
(ii) Milligrams of amdinocillin per container. Reconstitute the
sample as directed in the labeling. Then, using a suitable hypodermic
needle and syringe, remove all of the withdrawable contents if it is
represented as a single-dose container; or, if the labeling specifies
the amount of potency in a given volume of the resultant preparation,
remove an accurately measured representative portion from each
container. Dilute the solution thus obtained with sufficient distilled
water to obtain a solution containing 100 micrograms of amdinocillin per
milliliter (estimated).
(iii) System suitability requirements -- (a) Tailing factor. The
tailing factor (T) is satisfactory if it is not more than 2.5 at 5
percent of peak height:
(b) Efficiency of the column. The efficiency of the column (n) is
satisfactory if it is greater than 1,500 theoretical plates.
(c) Resolution factor. The resolution factor (R) between the peak
for amdinocillin and its nearest eluting impurity is satisfactory if it
is not less than 2.5.
(d) Coefficient of variation. The coefficient of variation (SR in
percent) of five replicate injections is satisfactory if it is not more
than 2.0 percent.
If the system suitability parameters have been met, then proceed as
described in 436.353(b) of this chapter.
(iv) Calculations. (a) Calculate the micrograms of amdinocillin per
milligram of sample as follows:
where:
Au=Area of the amdinocillin peak in the chromatogram of the sample
(at a retention time equal to that observed for the standard);
As=Area of the amdinocillin peak in the chromatogram of the
amdinocillin working standard;
Ps=Amdinocillin activity in the amdinocillin working standard
solution in micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(b) Calculate the amdinocillin content of the container as follows:
where:
Au=Area of the amdinocillin peak in the chromatogram of the sample
(at a retention time equal to that observed for the standard);
As=Area of the amdinocillin peak in the chromatogram of the
amdinocillin working standard:
Ps=Amdinocillin activity in the amdinocillin working standard
solution in micrograms per milliliter; and
d=Dilution factor of the sample.
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(a) of this chapter,
using a solution containing 40 milligrams of amdinocillin per
milliliter.
(4) Moisture. Proceed as directed in 436.201 of this chapter.
(5) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 100 milligrams of amdinocillin per
milliliter.
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
a potassium bromide disc containing 1 milligram of amdinocillin in 300
milligrams of potassium bromide, prepared as described in paragraph
(b)(l) of that section.
(50 FR 7765, Feb. 26, 1985; 50 FR 10220, Mar. 14, 1985; 50 FR
18243, Apr. 30, 1985; 55 FR 11582, Mar. 29, 1990)
21 CFR 440.3 Amoxicillin trihydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Amoxicillin trihydrate is the trihydrate
form of D(^) a-amino-p-hydroxybenzyl penicillin. It is so purified and
dried that:
(i) Its potency is not less than 900 micrograms and not more than
1,050 micrograms of amoxicillin per milligram on an anhydrous basis.
(ii) (Reserved)
(iii) Its moisture content is not less than 11.5 percent and not more
than 14.5 percent.
(iv) Its pH in an aqueous solution containing 2 milligrams per
milliliter is not less than 3.5 and not more than 6.0.
(v) Its amoxicillin content is not less than 90 percent on an
anhydrous basis.
(vi) The acid-base titration concordance is such that the difference
between the percent amoxicillin content when determined by nonaqueous
acid titration and by nonaqueous base titration is not more than 6. The
potency-acid titration concordance is such that the difference between
the potency value divided by 10 and the percent amoxicillin content of
the sample determined by the nonaqueous acid titration is not more than
6. The potency-base titration concordance is such that the difference
between the potency value divided by 10 and the percent amoxicillin
content of the sample determined by the nonaqueous base titration is not
more than 6.
(vii) It is crystalline.
(viii) It gives a positive identity test for amoxicillin trihydrate.
(2) Labeling. In addition to the labeling requirements of 432.5 of
this chapter, each package shall bear on its outside wrapper or
container and the immediate container the following statement: ''For
use in the manufacture of nonparenteral drugs only''.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, amoxicillin content, concordance, crystallinity, and identity.
(ii) Samples required: 12 packages, each containing approximately
500 milligrams.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the iodometric
assay shall be conclusive:
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient
sterile distilled water to give a stock solution containing 1.0
milligram of amoxicillin per milliliter (estimated). Further dilute an
aliquot of the stock solution with solution 3 to the reference
concentration of 0.1 microgram of amoxicillin per milliliter
(estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except in paragraph (d) of that section, add 3 drops of 1.2N
hydrochloric acid to both the sample and working standard solutions
after the addition of 0.01N iodine solution.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 2 milligrams per milliliter.
(5) Amoxicillin content. Proceed as directed in 436.213 of this
chapter using both the titration procedures described in paragraphs (e)
(1) and (2) of that section. Calculate the percent amoxicillin content
as follows:
(i) Acid titration.
Percent amoxicillin content=
where:
A=Milliliters of lithium methoxide reagent used in titrating the
sample.
B=Milliliters of lithium methoxide reagent used in titrating the
blank.
m=Percent moisture content of the sample.
Calculate the difference between the potency and the amoxicillin
content as follows:
Difference =
(ii) Base titration.
Percent amoxicillin content=
where:
A=Milliliters of perchloric acid reagent used in titrating the
sample.
B=Milliliters of perchloric acid reagent used in titrating the blank.
m=Percent moisture content of the sample.
Calculate the difference between the potency and the amoxicillin
content as follows:
Difference =
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
a 0.5 percent potassium bromide disc prepared as described in paragraph
(b)(1) of that section.
(39 FR 34032, Sept. 23, 1974, as amended at 46 FR 16682, Mar. 13,
1981; 49 FR 3458, Jan. 27, 1984; 50 FR 19918, May 13, 1985)
21 CFR 440.5 Ampicillin.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Ampicillin is 6-(D-a-aminobenzyl)
penicillin. It is a white powder. It is so purified and dried that:
(i) It contains not less than 900 micrograms and not more than 1,050
micrograms of ampicillin per milligram on an anhydrous basis.
(ii) (Reserved)
(iii) Its loss on drying is not more than 2.0 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 3.5 and not more than 6.0.
(v) Its ampicillin content is not less than 90 percent on an
anhydrous basis.
(vi) The acid-base titration concordance is such that the difference
between the percent ampicillin content when determined by nonaqueous
acid titration and by nonaqueous base titration is not more than six.
The potency-acid titration concordance is such that the difference
between the potency value divided by 10 and the percent ampicillin
content of the sample determined by the nonaqueous acid titration is not
more than six. The potency-base titration concordance is such that the
difference between the potency value divided by 10 and the percent
ampicillin content of the sample determined by the nonaqueous base
titration is not more than six.
(vii) It is crystalline.
(viii) It gives a positive identity test for ampicillin.
(2) Labeling. In addition to the labeling requirements prescribed by
432.5(b) of this chapter, each package shall bear on its outside
wrapper or container and the immediate container the following
statement, ''For use in the manufacture of nonparenteral drugs only''.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, loss on
drying, pH, ampicillin content, concordance, crystallinity, and
identity.
(ii) Samples required: 10 packages, each containing approximately
300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Assay for potency by
any of the following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive.
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient
sterile distilled water to give a stock solution containing 0.1
milligram of ampicillin per milliliter (estimated). Further dilute an
aliquot of the stock solution with 0.1M potassium phosphate buffer, pH
8.0 (solution 3), to the reference concentration of 0.1 microgram of
ampicillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except in paragraph (d) of that section, add 3 drops of 1.2N
hydrochloric acid to both the sample and working standard solutions
after the addition of 0.01N iodine solution.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) (Reserved)
(3) Loss on drying. Proceed as directed in 436.200(a) of this
chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Ampicillin content. Proceed as directed in 436.213 of this
chapter, using both the titration procedures described in paragraphs (e)
(1) and (2) of that section. Calculate the percent ampicillin content
as follows:
(i) Acid titration.
Percent ampicillin content=
where:
A=Milliliters of lithium methoxide reagent used in titrating the
sample;
B=Milliliters of lithium methoxide reagent used in titrating the
blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=
(ii) Base titration.
Percent ampicillin content=
where:
A=Milliliters of perchloric acid reagent used in titrating the
samples;
B=Milliliters of perchloric acid reagent used in titrating the blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
a 0.5 percent potassium bromide disc, prepared as described in paragraph
(b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 41 FR 42649, Sept. 28,
1976; 46 FR 16682, Mar. 13, 1981; 49 FR 3458, Jan. 27, 1984; 50 FR
19918, May 13, 1985)
21 CFR 440.7 Ampicillin trihydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Ampicillin trihydrate is the trihydrate
form of D(^)a-amino-benzyl penicillin. It is so purified and dried
that:
(i) It contains not less than 900 micrograms and not more than 1,050
micrograms of ampicillin per milligram on an anhydrous basis.
(ii) (Reserved)
(iii) Its loss on drying is not less than 12 percent and not more
than 15 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 3.5 and not more than 6.0.
(v) Its ampicillin content is not less than 90 percent on an
anhydrous basis.
(vi) The acid-base titration concordance is such that the difference
between the percent ampicillin content when determined by nonaqueous
acid titration and by nonaqueous base titration is not more than 6. The
potency-acid titration concordance is such that the difference between
the potency value divided by 10 and the percent ampicillin content of
the sample determined by the nonaqueous acid titration is not more than
6. The potency-base titration concordance is such that the difference
between the potency value divided by 10 and the percent ampicillin
content of the sample determined by the nonaqueous base titration is not
more than 6.
(vii) It is crystalline.
(viii) It gives a positive identity test for ampicillin trihydrate.
(2) Labeling. In addition to the labeling requirements prescribed by
432.5(b) of this chapter, this drug shall be labeled ''ampicillin'' and
each package shall bear on its outside wrapper or container and the
immediate container the following statement ''For use in the manufacture
of nonparenteral drugs only''.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, loss on
drying, pH, ampicillin content, concordance, crystallinity, and
identity.
(ii) Samples required: 10 packages each containing approximately 300
milligrams.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive.
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient
sterile distilled water to give a stock solution containing 0.1
milligram of ampicillin per milliliter (estimated). Further dilute an
aliquot of the stock solution with 0.1M potassium phosphate buffer, pH
8.0 (solution 3), to the reference concentration of 0.1 microgram of
ampicillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except in paragraph (d) of that section, add 3 drops of 1.2N
hydrochloric acid to both the sample and working standard solutions
after the addition of 0.01N iodine solution.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) (Reserved)
(3) Loss on drying. Proceed as directed in 436.200(a) of this
chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Ampicillin content. Proceed as directed in 436.213 of this
chapter, using both the titration procedures described in paragraphs (e)
(1) and (2) of that section. Calculate the percent ampicillin content
as follows:
(i) Acid titration.
Percent ampicillin content=((A^B) (normality of lithium methoxide
reagent) (349.4) (100) (100))/((Weight of sample in milligrams)
(100^m)),
where:
A=Milliliters of lithium methoxide reagent used in titrating the
sample;
B=Milliliters of lithium methoxide reagent used in titrating the
blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=(Potency in micrograms per milligram/10)^percent
ampicillin content.
(ii) Base titration.
Percent ampicillin content=((A^B) (normality of perchloric acid
reagent) (349.4) (100) (100))/((Weight of sample in milligrams)
(100^m)),
where:
A=Milliliters of perchloric acid reagent used in titrating the
samples;
B=Milliliters of perchloric acid reagent used in titrating the blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=(Potency in micrograms per milligram/10)^percent
ampicillin content.
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
an 0.5 percent potassium bromide disc, prepared as described in
paragraph (b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 46 FR 16683, Mar. 13, 1981;
49 FR 3458, Jan. 27, 1984; 50 FR 19918, May 13, 1985)
21 CFR 440.7a Sterile ampicillin trihydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Ampicillin trihydrate is the trihydrate
form of D(-) -aminobenzyl penicillin. It is so purified and dried that:
(i) It contains not less than 900 micrograms and not more than 1,050
micrograms of ampicillin per milligram on an anhydrous basis.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) (Reserved)
(v) Its loss on drying is not less than 12 percent and not more than
15 percent.
(vi) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 3.5 and not more than 6.0.
(vii) Its ampicillin content is not less than 90 percent on an
anhydrous basis.
(viii) The acid-base titration concordance is such that the
difference between the percent ampicillin content when determined by
nonaqueous acid titration and by nonaqueous base titration is not more
than 6. The potency-acid titration concordance is such that the
difference between the potency value divided by 10 and the percent
ampicillin content of the sample determined by the nonaqueous acid
titration is not more than 6. The potency-base titration concordance is
such that the difference between the potency value divided by 10 and the
percent ampicillin content of the sample determined by the nonaqueous
base titration is not more than 6.
(ix) It is crystalline.
(x) It gives a positive identity test for ampicillin trihydrate.
(2) Labeling. In addition to the labeling requirements prescribed by
432.5(b) of this chapter, this drug shall be labeled ''ampicillin.''
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, loss on drying, pH, ampicillin content, concordance,
crystallinity, and identity.
(ii) Samples required:
(a) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams.
(b) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive:
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient
sterile distilled water to give a stock solution containing 0.1
milligram of ampicillin per milliliter. Further dilute an aliquot of
the stock solution with 0.1M potassium phosphate buffer, pH 8.0
(solution 3) to the reference concentration of 0.1 microgram of
ampicillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except in paragraph (d) of that section, add 3 drops of 1.2N
hydrochloric acid to both the sample and working standard solutions
after the addition of 0.01N iodine solution.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section, except in lieu
of paragraph (e)(1)(i)(a), prepare the sample for test as follows: From
each of 10 immediate containers, aseptically transfer approximately 300
milligrams of sample into a sterile 500-milliliter Erlenmeyer flask
containing approximately 400 milliliters of diluting fluid D. Add at
least 200,000 Levy units1020 of penicillinase. Repeat the process using
10 additional containers. Swirl both of the stoppered flasks to
completely solubilize the suspension prior to filtration and proceed as
directed in paragraph (e)(1)(ii) of that section.
(3) Pyrogens. Proceed as directed in 436.32(f) of this chapter,
using a solution containing 20 milligrams of ampicillin per milliliter.
(4) (Reserved)
(5) Loss on drying. Proceed as directed in 436.200(a) of this
chapter.
(6) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(7) Ampicillin content. Proceed as directed in 436.213 of this
chapter, using both the titration procedures described in paragraph
(e)(1) and (2) of that section. Calculate the ampicillin content as
follows:
(i) Acid titration.
Percent ampicillin content=((A^B) (normality of lithium methoxide
reagent) (349.4) (100) (100))/((Weight of sample in milligrams)
(100^m)).
where:
A=Milliliters of lithium methoxide reagent used in titrating the
sample;
B=Milliliters of lithium methoxide reagent used in titrating the
blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=(Potency in micrograms per milligram/10)^percent
ampicillin content.
(ii) Base titration.
Percent ampicillin content=((A^B) (normality of perchloric acid
reagent) (349.4) (100) (100))/((Weight of sample in milligrams)
(100^m)).
where:
A=Milliliters of perchloric acid reagent used in titrating the
samples;
B=Milliliters of perchloric acid reagent used in titrating the blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference=(Potency in micrograms per milligram/10)^percent
ampicillin content.
(8) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(9) Identity. Proceed as directed in 436.211 of this chapter, using
a 0.5 percent potassium bromide disc, prepared as described in paragraph
(b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 46 FR 16683, Mar. 13, 1981;
49 FR 3458, Jan. 27, 1984; 50 FR 19918, May 13, 1985)
0201One Levy unit of penicillinase inactivates 59.3 units of
penicillin G in 1 hour at 25 C. and at a pH of 7.0 in a phosphate
buffered solution of a pure alkali salt of penicillin G when the
substrate is in sufficient concentration to maintain a zero order
reaction.
21 CFR 440.8 Bacampicillin hydrochloride.
(a) Requirements for certification--(1) Standards of identity,
strength, quality, and purity. Bacampicillin hydrochloride is the
hydrochloride salt of the 1-ethoxycarbonyloxyethyl ester of ampicillin.
It is a white powder. It is so purified and dried that:
(i) Its potency is not less than 623 micrograms and not more than 727
micrograms of ampicillin per milligram on an ''as is'' basis.
(ii) (Reserved)
(iii) Its moisture content is not more than 1.0 percent.
(iv) Its pH in an aqueous solution containing 20 milligrams per
milliliter is not less than 3.0 and not more than 4.5.
(v) It passes the identity test.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, and identity.
(ii) Samples required: 10 packages, each containing approximately
300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Use either of the
following methods; however, the results obtained from the iodometric
assay shall be conclusive.
(i) Hydroxylamine colorimetric assay. Proceed as directed in
442.40(b)(1)(ii) of this chapter, except:
(a) Buffer. In lieu of the buffer described in 442.40(b)(1)(ii)
(b)(2) of this chapter, use the buffer prepared as follows: Dissolve
200 grams of primary standard tris (hydroxymethyl) aminomethane in
sufficient distilled water to make 1 liter. Filter before use.
(b) Preparation of working standard solution. Use the ampicillin
working standard. Dissolve and dilute an accurately weighed portion of
the ampicillin working standard in sufficient distilled water to obtain
a concentration of 1.25 milligrams of ampicillin per milliliter.
(c) Preparation of sample solution. Dissolve and dilute an
accurately weighed portion of the sample with sufficient distilled water
to obtain a concentration of 1.25 milligrams of ampicillin per
milliliter (estimated).
(d) Calculations. Calculate the ampicillin content in micrograms per
milligram as follows:
Ampicillin content in micrograms per milligram=
where:
Au=Absorbance of sample solution;
Pa=Potency of working standard in micrograms per milliliter;
As=Absorbance of working standard solution;
Wu=Milligrams of sample per milliliter of sample solution.
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except use the ampicillin working standard.
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 20 milligrams per milliliter.
(5) Identity. Proceed as directed in 436.330 of this chapter.
(46 FR 25603, May 8, 1981, as amended at 50 FR 19918, May 13, 1985)
21 CFR 440.9a Sterile ampicillin sodium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Sterile ampicillin sodium is the sodium
salt of D(-)a-aminobenzyl penicillin. It is so purified and dried that:
(i) Its potency is not less than 845 micrograms and not more than 988
micrograms of ampicillin per milligram on an anhydrous basis. If it is
packaged for dispensing, it contains not less than 90 percent and not
more than 115 percent of the number of milligrams of ampicillin that it
is represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) (Reserved)
(v) Its moisture content is not more than 2 percent.
(vi) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 8.0 and not more than 10.0.
(vii) Its ampicillin content is not less than 84.5 percent, except if
the high-performance liquid chromatographic (HPLC) assay method is used,
then the ampicillin content standard is not applicable.
(viii) The potency-base titration concordance is such that the
difference between the potency value divided by 10 and the percent
ampicillin content of the sample determined by the nonaqueous base
titration is not more than 6, except if the HPLC assay method is used,
then the concordance standard is not applicable.
(ix) It is crystalline.
(x) It passes the identity test for ampicillin sodium.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, moisture, pH, ampicillin content, concordance, crystallinity,
and identity.
(ii) Samples required:
(a) If the batch is packaged for repacking or for use in
manufacturing another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams.
(2) For sterility testing: 20 packages each containing approximately
300 milligrams.
(b) If the batch is packaged for dispensing:
(1) For all tests except sterility: A minimum of 15 immediate
containers or if each vial contains 250 milligrams or less of ampicillin
a minimum of 24 vials.
(2) For sterility testing: 20 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Potency -- (i) Sample
preparation. Dissolve an accurately weighed sample in sufficient
sterile distilled water to give a stock solution containing 0.1
milligram of ampicillin per milliliter (estimated), for the
microbiological agar diffusion assay and in 1.0 percent potassium
phosphate buffer, pH 6.0 (solution 1), for the iodometric assay or for
the hydroxylamine colorimetric assay to give a stock solution of
convenient concentration. For the high-performance liquid
chromatographic assay (HPLC), transfer an accurately weighed portion of
ampicillin, equivalent to about 100 milligrams of anhydrous ampicillin,
to a 100-milliliter volumetric flask. Add about 75 milliliters of
diluent (prepared as described in paragraph (b)(1)(ii)(d)(1)(ii) of this
section), shake and sonicate, if necessary, to achieve complete
dissolution. Also, if it is packaged for dispensing, reconstitute as
directed in the labeling. Then using a suitable hypodermic needle and
syringe, remove all of the withdrawable contents if it is represented as
a single-dose container, or if the labeling specifies the amount of
potency in a given volume of the resultant preparation, remove an
accurately measured representative portion from each container. Dilute
with either sterile distilled water, solution 1, or HPLC diluent to give
a stock solution as specified above.
(ii) Assay procedure. Use any of the following methods; however,
the results obtained from the microbiological agar diffusion assay shall
be conclusive.
(a) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, diluting an aliquot of the stock solution with
0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference
concentration of 0.1 microgram of ampicillin per milliliter (estimated).
(b) Iodometric assay. Proceed as directed in 436.204 of this
chapter, except in paragraph (d) of that section, add 3 drops of 1.2N
hydrochloric acid to both the sample and working standard solutions
after the addition of 0.01N iodine solution.
(c) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(d) HPLC assay. Proceed as directed in 436.216 of this chapter,
using ambient temperature, an ultraviolet detection system operating at
a wavelength of 254 nanometers, a 4-millimeter X 5-centimeter guard
column containing 40- to 60-micrometer diameter packing material as
described for the analytical column, a 4-millimeter X 30-centimeter
analytical column packed with microparticulate (3 to 10 micrometers in
diameter) reversed phase packing material such as octadecyl hydrocarbon
bonded silica, and a flow rate of about 2.0 milliliters per minute.
Separately inject equal volumes (about 20 microliters) of the working
standard preparation and the sample solution into the chromatograph,
record the chromatogram, and measure the responses for the major peaks.
Reagents, working standard and resolution test solution, system
suitability requirements, and calculations are as follows:
(1) Reagents -- (i) Mobile phase. Prepare a suitably filtered and
degassed mixture of water, acetonitrile, 1.0M monobasic potassium
phosphate, and 1.0N acetic acid (909:80:10:1).
(ii) Diluent. Mix 10 milliliters of 1.0M monobasic potassium and 1
milliliter of 1.0N acetic acid, dilute with water to make 1,000
milliliters, and mix.
(2) Preparation of working and internal standard solutions -- (i)
Working standard solution. Dissolve a portion of ampicillin working
standard, accurately weighed, in the diluent to obtain a solution having
a known concentration of about 1 milligram per milliliter. Shake and
sonicate, if necessary, to achieve complete dissolution. Use this
solution promptly after preparation.
(ii) Resolution test solution. Dissolve caffeine in working standard
solution to obtain a solution containing about 1 milligram per
milliliter.
(3) System suitability requirements -- (i) Tailing factor. The
tailing factor (T) is satisfactory if it is not more than 1.4 at 5
percent of peak height.
(ii) Resolution. The resolution (R) between the caffeine and the
ampicillin peaks is satisfactory if it is not less than 2.0. The
relative retention times are about 2.0 for caffeine and 1.0 for
ampicillin.
(iii) Coefficient of variation (relative standard deviation). The
coefficient of variation (SR in percent) of 5 replicate injections is
satisfactory if it is not more than 2.0 percent.
If the system suitability requirements have been met, then proceed as
described in 436.216(b) of this chapter. Alternate chromatographic
conditions are acceptable provided reproducibility and resolution are
comparable to the system. However, the sample preparation described in
paragraph (b)(1)(i) of this section should not be changed.
(4) Calculations. Calculate the micrograms of ampicillin per
milligram of sample as follows:
where:
Au=Area of the ampicillin peak in the chromatogram of the sample (at
a retention time equal to that observed for the standard);
As=Area of the ampicillin peak in the chromatogram of the ampicillin
working standard;
Ps=Ampicillin activity in the ampicillin working standard solution in
micrograms per milliliter;
Cu=Milligrams of sample per milliliter of sample solution; and
m=Percent moisture content of the sample.
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(b) of this chapter,
using a solution containing 20 milligrams of ampicillin per milliliter.
(4) (Reserved)
(5) Moisture. Proceed as directed in 436.201 of this chapter.
(6) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams of ampicillin per milliliter.
(7) Ampicillin content. Proceed as directed in 436.213 of this
chapter, using the titration procedure described in paragraph (e)(2) of
that section. Calculate the ampicillin content as follow
Percent ampicillin content=
where:
A=Milliliters of perchloric acid reagent used in titrating the
sample;
B=Milliliters of perchloric acid reagent used in titrating the blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the ampicillin
content as follows:
Difference =
(8) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(9) Identity. Proceed as directed in 436.211 of this chapter, using
the method described in paragraph (b)(2) of that section.
(39 FR 18976, May 30, 1974, as amended at 41 FR 10886, Mar. 15, 1976;
41 FR 42649, Sept. 28, 1976; 42 FR 59857, Nov. 22, 1977; 46 FR 16683,
Mar. 13, 1981; 49 FR 3458, Jan. 27, 1984; 50 FR 19918, May 13, 1985;
52 FR 42288, Nov. 4, 1987; 52 FR 45281, Nov. 25, 1987; 54 FR 47204,
Nov. 13, 1989)
21 CFR 440.10 Benzylpenicilloyl-polylysine concentrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Benzylpenicilloyl-polylysine concentrate
is a pale yellow to dark yellow aqueous solution of benzylpenicilloyl e
substituted poly-L-lysine. It contains one or more suitable and
harmless buffers. It is so purified that:
(i) It contains not less than 50 percent and not more than 70 percent
benzylpenicilloyl substitution on the polylysine.
(ii) The benzylpenicilloyl concentration is not less than 1.25 10^2M
and not more than 2.0 10^2M.
(iii) The penamaldate concentration is not more than 6.0 10^4M.
(iv) The penicillenate concentration is not more than 2.0 10^4M.
(v) Its pH is not less than 6.5 and not more than 8.5.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for percent
benzylpenicilloyl substitution, benzylpenicilloyl content, penamaldate
content, penicillenate content, and pH.
(ii) Samples required: 2 vials, each containing not less than 5
milliliters.
(b) Tests and methods of assay -- (1) Percent benzylpenicilloyl
substitution -- (i) Lysine content -- (a) Equipment. Amino acid
analyzer capable of:
(1) Separating the hydrolysis products of benzylpenicilloyl
polylysine into discrete components by means of an ion-exchange column.
(2) Mixing the separated amino acid components with a ninhydrin
reagent and promoting the reaction in a coil at elevated temperatures.
(3) Quantitating the ninhydrin positive materials by means of a
suitable colorimeter and recorder.
(b) Reagents -- (1) Citrate buffer: Dissolve and dilute 19.69 grams
of sodium citrate dihydrate, 16.5 milliliters of hydrochloric acid, 0.1
milliliter of pentachlorophenol, 5 milliliters of thiodiglycol in 900
milliliters of distilled water; adjust to a pH of 2.2 and dilute to 1
liter with distilled water.
(2) Calibration mixture: Dissolve and dilute equal molar amounts of
ammonia, and the L form of lysine in the citrate buffer to result in
final concentrations of 2.5 10^4 M for each.
(c) Preparation of standard and sample solutions -- (1) Standard
solution (standard lysine solution (2.5 10^4 M)). Transfer an
accurately weighed portion of 54.8 milligrams of lysine dihydrochloride
to a 100-milliliter volumetric flask. Dissolve and dilute to mark with
citrate buffer. Make an accurate tenfold dilution of this solution with
citrate buffer. The resulting standard solution is 2.5 10^4 M with
respect to lysine.
(2) Sample solution. Dilute 1 milliliter of the
benzylpenicilloyl-polylysine concentrate to 10 milliliters with
distilled water. Mix 1 milliliter of the diluted solution with 1.5
milliliters of 6.0N hydrochloric acid and seal in an ampule under
nitrogen. Hydrolyze the solution for 22 hours at 110 C. Transfer the
contents of the ampule quantitatively into a 50-milliliter round bottom
flask and dry by rotary evaporation. Wash the contents and evaporate to
dryness three times using 5-milliliter portions of distilled water.
Dissolve the hydrolysate in 10 milliliters of citrate buffer.
(d) Procedure. Standardize the procedure for use of the amino acid
analyzer with the calibration mixture. Apply 0.5 milliliter of the
lysine standard solution to the amino acid analyzer and determine the
area of the lysine peak. Apply 0.5 milliliter of the sample solution to
the amino acid analyzer and determine the area of the lysine peak.
(e) Calculations. Calculate the lysine content by the following
formula:
Molar concentration of lysine in the benzylpenicilloyl-polylysine
concentrate=
where:
A=The area of the lysine peak of the sample solution.
B=The area of the lysine peak of the standard solution.
C=The percent purity of the lysine dihydrochloride.
(ii) Benzylpenicilloyl content -- (a) Reagents. (1) Mercuric
chloride solution: Dissolve 35 milligrams of mercuric chloride in 500
milliliters of distilled water.
(2) Saline phosphate buffer, pH 7.6: Dissolve 9 grams of sodium
chloride and 1.38 grams monobasic sodium phosphate in 900 milliliters of
distilled water, adjust to pH 7.6 and dilute to 1 liter with distilled
water.
(b) Preparation of sample solution. Transfer 1 milliliter of the
benzylpenicilloyl-polylysine concentrate into a 500-milliliter
volumetric flask and dilute to volume with saline phosphate buffer, pH
7.6.
(c) Procedure. Transfer 3 milliliters of the sample solution into a
spectrophotometric cell. Using a suitable spectrophotometer and the
saline phosphate buffer, pH 7.6, as a blank, determine the initial
absorbance at 282 nanometers. Thereafter, react the diluted
benzylpenicilloyl-polylysine solution with 0.02-milliliter portions of
the mercuric chloride solution. Determine the absorbance at 282
nanometers at 1 and 3 minutes after each addition of mercuric chloride
solution. The increased absorbance at 282 nanometers is used in
calculating the benzylpenicilloyl content. Calculate the
benzylpenicilloyl content by means of the following formula:
Molar benzylpenicilloyl content=
where:
A1=The highest absorbance at 282 nanometers
A2=The initial absorbance at 282 nanometers
22,325=The molar absorptivity of the penamaldate formed by the
reaction of the benzylpenicilloyl moiety with the mercuric chloride at a
pH of 7.6.
Percent benzylpenicilloyl substitution=(Molar benzylpenicilloyl
content 100)/Molar lysine content
(2) Penicillenate and penamaldate content. Dilute 1 milliliter of
the benzylpenicilloyl-polylysine concentrate to 50 milliliters with
saline phosphate buffer, pH 7.6. Using a suitable spectrophotometer and
the saline phosphate buffer, pH 7.6, as a blank, determine the
absorbance at 322 and 282 nanometers. Calculate the penicillenate
content by the following formula:
Molar penicillenate content=
where:
26,600=Molar absorptivity of the penicillenate moiety at 322
nanometers at a pH of 7.6
Calculate the penamaldate content by the following formula:
Molar penamaldate content=
where:
22,325=Molar absorptivity of the penamaldate moiety at 282 nanometers
at a pH of 7.6.
(3) pH. Proceed as directed in 436.202 of this chapter, using the
undiluted sample.
(39 FR 35346, Oct. 1, 1974; 39 FR 38370, Oct. 31, 1974; 39 FR
39871, Nov. 12, 1974; 39 FR 40946, Nov. 22, 1974)
21 CFR 440.11 Carbenicillin indanyl sodium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Carbenicillin indanyl sodium is the
monosodium salt of N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo
(3.2.0) hept-6-yl)-2-phenyl-malonamic acid, 1-(5-indanyl) ester. It is
so purified and dried that:
(i) Its potency is not less than 659 micrograms and not more than 769
micrograms of carbenicillin per milligram on an anhydrous basis at the
time of certification, and not less than 630 micrograms of carbenicillin
per milligram on an anhydrous basis at any time during the expiration
period.
(ii) (Reserved)
(iii) Its moisture content is not more than 2.0 percent.
(iv) Its pH in an aqueous solution containing 100 milligrams per
milliliter is not less than 5.0 nor more than 8.0.
(v) It gives a positive result to the identity test for carbenicillin
indanyl sodium.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, and identity.
(ii) Samples required: Five packages, each containing approximately
1.0 gram and one package containing approximately 2.5 grams.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
in 436.300 of this chapter.
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 100 milligrams per milliliter.
(5) Identity. Proceed as directed in 436.211 of this chapter, using
the 0.5-percent potassium bromide disc prepared as described in
paragraph (b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 50 FR 19918, May 13, 1985)
21 CFR 440.13a Sterile carbenicillin disodium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Carbenicillin disodium is the disodium
salt of -carboxy-benzylpenicillin. It is so purified and dried that:
(i) It contains not less than 770 micrograms of carbenicillin per
milligram on an anhydrous basis. If it is packaged for dispensing, its
carbenicillin content is not less than 90 percent and not more than 120
percent of the number of milligrams of carbenicillin that it is
represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) (Reserved)
(v) Its moisture content is not more than 6 percent.
(vi) Its pH in an aqueous solution containing 10 milligrams of
carbenicillin per milliliter (or if packaged for dispensing, after
reconstitution as directed in the labeling) is not less than 6.0 and not
more than 8.0.
(vii) It gives a positive identity test for carbenicillin disodium.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to the
requirements of 431.1 of this chapter, each such request shall contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, moisture, pH, and identity.
(ii) Samples required:
(a) If the batch is packaged for repacking or for use in the
manufacture of another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams; and 5 packages, each containing
approximately 1 gram.
(2) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) If the batch is packaged for dispensing:
(1) For all tests except sterility: A minimum of 15 immediate
containers.
(2) For sterility testing: 20 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
in 436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed sample in sufficient 1.0 percent
potassium phosphate buffer, pH 6.0 (solution 1), to give a stock
solution of convenient concentration; and also if it is packaged for
dispensing, reconstitute as directed in the labeling. Then, using a
suitable hypodermic needle and syringe, remove all of the withdrawable
contents if it is represented as a single-dose container; or if the
labeling specifies the amount of potency in a given volume of the
resultant preparation, remove an accurately measured representative
portion from each container. If it is a single dose container, use a
separate needle and syringe for each container. Dilute with sufficient
solution 1 to give a stock solution of convenient concentration.
Further dilute the stock solution with solution 1 to the reference
concentration of 20.0 micrograms of carbenicillin per milliliter
(estimated).
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(b) of this chapter,
using a solution containing 200 milligrams of carbenicillin per
milliliter.
(4) (Reserved)
(5) Moisture. Proceed as directed in 436.201 of this chapter.
(6) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams of carbenicillin per
milliliter (or if packaged for dispensing, use a solution prepared as
directed for reconstitution in the labeling).
(7) Identity. Proceed as directed in 436.211 of this chapter, using
a 0.5 percent potassium bromide disc prepared as directed in paragraph
(b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
45 FR 22921, Apr. 4, 1980; 50 FR 19918, May 13, 1985; 51 FR 27532,
Aug. 1, 1986)
21 CFR 440.15 Cloxacillin sodium monohydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Cloxacillin sodium is the monohydrate
sodium salt of 5-methyl-3-(o-chlorophenyl)-4-isoxazolyl penicillin. It
is so purified and dried that:
(i) Its potency is not less than 825 micrograms of cloxacillin per
milligram.
(ii) (Reserved)
(iii) Its moisture content is not less than 3 percent and not more
than 5 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 4.5 nor more than 7.5.
(v) Its cloxacillin content is not less than 82.5 percent.
(vi) It passes the identity test.
(vii) It is crystalline.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this subchapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this subchapter, each such request
shall contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, cloxacillin content, identity, and crystallinity.
(ii) Samples required: 10 packages, each containing approximately
300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive.
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient 1
percent potassium phosphate buffer, pH 6.0 (solution 1), to give a stock
solution of convenient concentration. Further dilute an aliquot of the
stock solution with solution 1 to the reference concentration of 5
micrograms of cloxacillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
subchapter.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this subchapter.
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this subchapter.
(4) pH. Proceed as directed in 436.202 of this subchapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Cloxacillin content. Accurately weigh approximately 100
milligrams of the sample and dissolve in sufficient 5N sodium hydroxide
to give a total volume of 25 milliliters. Place in a boiling water bath
for 30 minutes. Cool, acidify 1 milliliter with 1 milliliter of dilute
sulfuric acid (1 in 2), add 8 milliliters of water, and extract with two
25-milliliter portions of ethyl ether. Combine the ether extractives
and extract with 25-milliliter portions of 0.1N sodium hydroxide.
Combine the alkaline extractives and dilute to 100 milliliters with
carbon dioxide-free water. Treat a portion of the cloxacillin working
standard in the same manner. Using a suitable spectrophotometer,
determine the absorbance of the solution in a 1-centimeter cell at the
absorption peaks at 257 3 nanometers and at 282 3 nanometers compared
with a reagent blank. Determine the percent cloxacillin in the sample
by means of the following calculation:
Percent cloxacillin=
where:
A1=Difference in absorbance for the sample between 257 nanometers and
282 nanometers:
A2=Difference in absorbance for the cloxacillin working standard,
similarly treated.
(6) Identity. Proceed as directed in 436.211 of this subchapter,
using the 0.5 percent potassium bromide disc described in paragraph
(b)(1) of that section.
(7) Crystallinity. Proceed as directed in 436.203 of this
subchapter.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
50 FR 19918, May 13, 1985)
21 CFR 440.17 Cyclacillin.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Cyclacillin is
6-(1-aminocyclohexanecarboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicycl
o(3.2.0) heptane-2-carboxylic acid. It is a white to off-white powder.
It is so purified and dried that:
(i) It contains not less than 900 micrograms and not more than 1,050
micrograms of cyclacillin per milligram.
(ii) (Reserved)
(iii) Its moisture content is not more than 1.0 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 4.0 and not more than 6.5.
(v) Its cyclacillin content is not less than 90 percent on an
anhydrous basis.
(vi) The acid-base titration concordance is such that the difference
between the percent cyclacillin content when determined by nonaqueous
acid titration and nonaqueous base titration is not more than six. The
potency-acid titration concordance is such that the difference between
the potency value divided by 10 and the percent cyclacillin content of
the sample determined by the nonaqueous acid titration is not more than
six. The potency base titration concordance is such that the difference
between the potency value divided by 10 and the percent cyclacillin
content of the sample determined by the nonaqueous base titration is not
more than six.
(vii) It is crystalline.
(viii) It gives a positive identity test for cyclacillin.
(2) Labeling. In addition to the labeling requirements of 432.5 of
this chapter, each package shall bear on its outside wrapper or
container and the immediate container the following statement, ''For use
in the manufacture of nonparenteral drugs only.''
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, cyclacillin content, concordance, crystallinity, and identity.
(ii) Samples required: 10 packages, each containing approximately
500 milligrams.
(b) Tests and methods of assay -- (1) Potency. Assay for potency by
any of the following methods; however, the results obtained from the
iodometric assay shall be conclusive.
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay as follows:
Dissolve an accurately weighed portion of the sample in sufficient
sterile distilled water to give a stock solution containing 1 milligram
of cyclacillin per milliliter (estimated). Further dilute an aliquot of
the stock solution with 0.1M potassium phosphate buffer, pH 8.0
(solution 3), to the reference concentration of 1.0 microgram of
cyclacillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Cyclacillin content. Proceed as directed in 436.213 of this
chapter, using both the titration procedures described in paragraph
(e)(1) and (2) of that section. Calculate the percent cyclacillin
content as follows:
(i) Acid titration.
Percent cyclacillin content=
where:
A=Milliliters of lithium methoxide reagent used in titrating the
sample;
B=Milliliters of lithium methoxide reagent used in titrating the
blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the cyclacillin
content as follows:
Difference=
(ii) Base titration.
Percent cyclacillin content=
where:
A=Milliliters of perchloric acid reagent used in titrating the
sample;
B=Milliliters of perchloric acid reagent used in titrating the blank;
m=Percent moisture content of the sample.
Calculate the difference between the potency and the cyclacillin
content as follows:
Difference=
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
a 1-percent potassium bromide disc prepared as described in paragraph
(b)(1) of that section.
(46 FR 2981, Jan. 13, 1981; 46 FR 15880, Mar. 10, 1981, as amended
at 50 FR 19918, May 13, 1985)
21 CFR 440.19 Dicloxacillin sodium monohydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Dicloxacillin sodium monohydrate is the
monohydrated sodium salt of 5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl
penicillin. It is so purified and dried that:
(i) Its potency is not less than 850 micrograms of dicloxacillin per
milligram.
(ii) (Reserved)
(iii) Its moisture content is not less than 3 percent nor more than 5
percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 4.5 nor more than 7.5.
(v) Its organic chlorine content is not less than 13.0 percent nor
more than 14.2 percent.
(vi) Its free chloride content is not more than 0.5 percent.
(vii) It is crystalline.
(viii) It gives a positive identity test for dicloxacillin sodium
monohydrate.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, organic chlorine content, free chloride content, crystallinity, and
identity.
(ii) Samples required: 10 containers, each containing not less than
500 milligrams.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive.
(i) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, preparing the sample for assay, as follows:
Dissolve an accurately weighed portion of the sample in sufficient 1
percent potassium phosphate buffer, pH 6.0 (solution 1), to give a stock
solution of convenient concentration. Further dilute an aliquot of the
stock solution with solution 1 to the reference concentration of 5
micrograms of dicloxacillin per milliliter (estimated).
(ii) Iodometric assay. Proceed as directed in 436.204 of this
chapter.
(iii) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this chapter.
(2) (Reserved)
(3) Moisture content. Proceed as directed in 436.201 of this
chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Organic chlorine content -- (i) Reagents. (a) o-Chlorobenzoic
acid of known purity.
(b) 0.01N Silver nitrate solution. Store in brown glass reagent
bottle. Standardize against an accurately weighed sample of 20 to 25
milligrams of o-chlorobenzoic acid using the procedure described in
paragraph (b)(5)(ii) of this section.
Normality (N)=
(c) 0.1N Sodium hydroxide solution.
(d) 1:1 Nitric acid solution: Mix 1 volume of concentrated nitric
acid with 1 volume of distilled water.
(ii) Total chlorine. (Caution -- The analyst should wear safety
glasses and use a suitable shield between himself and the apparatus.
The glassware must be scrupulously clean.) Accurately weigh 20 to 25
milligrams of the sample and place it on the center of a piece of
halide-free filter paper measuring about 4 centimeters square (this is
specially cut paper with a fuse strip attached to the area that holds
the sample), and fold the paper to enclose it. Place 10 milliliters of
0.1N sodium hydroxide into an oxygen combustion flask (Schoniger flask),
and flush the air from the flask with a stream of rapidly flowing
oxygen. Place the sample into the platinum sample holder and ignite the
fuse strip by suitable means. If the strip is ignited outside the
flask, immediately plunge the stopper into the flask, invert so that the
sodium hydroxide solution makes a seal around the stopper, and hold the
stopper firmly in place. If the ignition is carried out in a closed
system, the inversion of the flask may be omitted. After combustion is
completed, shake the flask vigorously, add a small amount of distilled
water to the collar to insure an air tight seal, and allow to stand for
not less than 10 minutes with intermittent shaking. Transfer to a
suitable titration vessel, heat on a steam bath for 20 to 30 minutes,
cool to room temperature, add 5 milliliters of nitric acid solution, and
titrate potentiometrically with 0.01N silver nitrate, using one silver
electrode and one silver/silver chloride electrode.
Percent total chlorine=
(iii) Free chloride. Accurately weigh 100 to 150 milligrams of
sample directly into a titration flask, dissolve in 10 milliliters of
0.1N sodium hydroxide, and add about 20 milliliters of distilled water,
heat this solution on the steam bath 20 to 30 minutes. Cool to room
temperature, add 5 milliliters of 1:1 nitric acid solution and titrate
potentiometrically with 0.01N silver nitrate using one silver electrode
and one silver/silver chloride electrode.
Percent free chloride=
(iv) Organic chlorine. Percent organic chlorine=Percent total
chlorine^percent free chloride.
(6) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(7) Identity. Proceed as directed in 436.211 of this chapter, using
the 1 percent potassium bromide disc described in paragraph (b)(1) of
that section.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
44 FR 10378, Feb. 20, 1979; 50 FR 19918, May 13, 1985)
21 CFR 440.19a Sterile dicloxacillin sodium monohydrate.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Sterile dicloxacillin sodium monohydrate
is the monohydrated sodium salt of
5-methyl-3-(2,6-dichloro-phenyl)-4-isoxazolyl penicillin. It is so
purified and dried that:
(i) Its potency is not less than 850 micrograms of dicloxacillin per
milligram. If it is packaged for dispensing, its potency is
satisfactory if it contains not less than 90 percent and not more than
120 percent of the number of milligrams of dicloxacillin that it is
represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) (Reserved)
(v) Its moisture content is not less than 3 percent and not more than
5 percent.
(vi) Its pH in an aqueous solution containing 10 milligrams per
milliliter or when reconstituted as directed in the labeling, if it is
packaged for dispensing is not less than 4.5 nor more than 7.5.
(vii) Its organic chlorine content is not less than 13.0 percent and
not more than 14.2 percent.
(viii) Its free chloride content is not more than 0.5 percent.
(ix) It is crystalline.
(x) It gives a positive identity test for dicloxacillin sodium
monohydrate.
(2) Labeling. If this drug is packaged for dispensing, in addition
to the labeling requirements of 432.5 of this chapter, this drug shall
be labeled ''sterile dicloxacillin sodium''.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, moisture, pH, organic chlorine content, free chloride content,
crystallinity, and identity.
(ii) Samples required:
(a) If the batch is packaged for repacking or for use in the
manufacture of another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 500 milligrams.
(2) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) If the batch is packaged for dispensing:
(1) For all tests except sterility: A minimum of 15 immediate
containers.
(2) For sterility testing: 20 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Potency. Use any of the
following methods; however, the results obtained from the
microbiological agar diffusion assay shall be conclusive.
(i) Sample preparation. Dissolve an accurately weighed sample in
sufficient 1 percent potassium phosphate buffer, pH 6.0 (solution 1),
for the microbiological agar diffusion assay and the hydroxylamine
colorimetric assay or in distilled water for the iodometric assay, to
give a stock solution of convenient concentration; and also if it is
packaged for dispensing, reconstitute as directed in the labeling.
Then, using a suitable hypodermic needle and syringe, remove all of the
withdrawable contents if it is represented as a single-dose container,
or if the labeling specifies the amount of potency in a given volume of
the resultant preparation, remove an accurately measured representative
portion from each container. Dilute with either solution 1 or distilled
water, as specified above, to give a stock solution of convenient
concentration.
(ii) Assay procedures. Use any of the following methods; however,
the results obtained from the microbiological agar diffusion assay shall
be conclusive.
(a) Microbiological agar diffusion assay. Proceed as directed in
436.105 of this chapter, diluting an aliquot of the stock solution with
solution 1 to the reference concentration of 5 micrograms of
dicloxacillin per milliliter (estimated).
(b) Iodometric assay. Proceed as directed in 436.204 of this
subchapter.
(c) Hydroxylamine colorimetric assay. Proceed as directed in
436.205 of this subchapter.
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(a) of this chapter,
using a solution containing 20 milligrams of dicloxacillin per
milliliter.
(4) (Reserved)
(5) Moisture. Proceed as directed in 436.201 of this chapter.
(6) pH. Proceed as directed in 436.202 of this subchapter, using an
aqueous solution containing 10 milligrams per milliliter (or using a
solution reconstituted as directed in the labeling if it is packaged for
dispensing).
(7) Organic chlorine content. Proceed as directed in 440.19(b)(5).
(8) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(9) Identity. Proceed as directed in 436.211 of this chapter, using
a 1 percent potassium bromide disc prepared as directed in paragraph
(b)(1) of that section.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
50 FR 19918, May 13, 1985)
21 CFR 440.25 Hetacillin.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Hetacillin is
6-(2,2-Dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-3,3-dimethyl-7-oxo-4-t
hia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid. It occurs as a fine,
white to off-white powder. It is so purified and dried that:
(i) Its potency is not less than 810 micrograms of ampicillin per
milligram.
(ii) (Reserved)
(iii) Its moisture content is not more than 1.0 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 2.5 nor more than 5.5.
(v) Its hetacillin content is not less than 90 and not more than 105
percent.
(vi) It gives a positive identity test for hetacillin.
(vii) It is crystalline.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5(b) of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, hetacillin content, identity, and crystallinity.
(ii) Samples required: 10 packages, each containing approximately
300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
for ampicillin in 436.105 of this chapter, using the ampicillin working
standard as the standard of comparison and preparing the sample for
assay as follows: Dissolve an accurately weighed sample in sufficient
0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock
solution of convenient concentration. Further dilute the stock solution
with solution 3 to the reference concentration of 0.1 microgram of
ampicillin per milliliter (estimated).
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Hetacillin content -- (i) Reagents -- (a) Hydrochloric
acid-acetone solution. Dilute 8.5 milliliters of concentrated
hydrochloric acid to 1 liter with acetone and mix well. Use for 1 day
only.
(b) p-Dimethylaminocinnamalde- hyde solution. Dissolve 0.5 gram of
p-dimethylaminocinnamaldehyde in sufficient hydrochloric acid-acetone
solution to a final volume of 100 milliliters and shake well, filtering
if necessary. Prepare immediately before use.
(ii) Preparation of standard solutions. Transfer about 100
milligrams of the hetacillin working standard, accurately weighed, to a
200-milliliter volumetric flask. Add 150 milliliters of refrigerated
distilled water and 20 milliliters of 1N hydrochloric acid, shake,
dilute to volume with distilled water, and mix well. Transfer 0.5, 1.0,
and 2.0 milliliters into three respective 25-milliliter volumetric
flasks. Add 1.5 and 1.0 milliliters of 0.1N hydrochloric acid
respectively to the first and second flasks to bring the volume in each
to 2.0 milliliters.
(iii) Blank. Use 2.0 milliliters of 0.1N hydrochloric acid in a
25-milliliter volumetric flask.
(iv) Preparation of sample solutions. Using a mortar and pestle,
grind the sample to a fine powder. Transfer an accurately weighed
portion of about 100 milligrams to a 200-milliliter volumetric flask.
Add 150 milliliters of refrigerated distilled water and 20 milliliters
of 1N hydrochloric acid, shake, dilute to volume with distilled water,
and mix well. Transfer 1.0 milliliter to a 25-milliliter volumetric
flask, add 1.0 milliliter of 0.1N hydrochloric acid, and mix.
(v) Procedure. To each of the flasks containing standards, blank,
and sample, add 15 milliliters of hydrochloric acid-acetone solution and
mix. Then add 3 milliliters of p-dimeth- ylaminocinnamaldehyde solution
to each and mix. Add 3 milliliters of 0.1N hydrochloric acid to each,
dilute to volume with hydrochloric acid-acetone solution, mix well, and
allow to stand at 25 C. for exactly 30 minutes. (Filter the sample
solutions, if necessary, to remove any turbidity.) Using a suitable
spectrophotometer, read the absorbance values of standard and sample
solutions at a wavelength of 515 nanometers against the blank. Plot the
absorbance values of the standards versus their concentrations and read
the sample concentration from this standard response line.
(vi) Calculations.
Percent hetacillin=
where:
C=Concentration in milligrams of hetacillin per milliliter of the
final solution of the sample obtained from the standard response line.
P=Hetacillin content of the hetacillin working standard in percent.
(6) Identity. Proceed as directed in 436.211 of this chapter, using
a 1 percent potassium bromide disc prepared as directed in paragraph
(b)(1) of that section.
(7) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
44 FR 10379, Feb. 20, 1979; 50 FR 19918, May 13, 1985)
21 CFR 440.29 Hetacillin potassium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality and purity. Hetacillin potassium is the potassium
salt of hetacillin. It occurs as a fine, white to light buff powder.
It is so purified and dried that:
(i) Its potency is not less than 735 micrograms of ampicillin per
milligram.
(ii) (Reserved)
(iii) Its moisture content is not more than 1.0 percent.
(iv) Its pH in an aqueous solution containing 10 milligrams per
milliliter is not less than 7.0 and not more than 9.0.
(v) Its hetacillin content is not less than 82 percent and not more
than 95.5 percent.
(vi) It gives a positive identity test for hetacillin potassium.
(vii) It is crystalline.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5(b) of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, moisture,
pH, hetacillin content, identity, and crystallinity.
(ii) Samples required: 10 packages, each containing approximately
300 milligrams.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
for ampicillin in 436.105 of this chapter, using the ampicillin working
standard as the standard of comparison and preparing the sample for
assay as follows: Dissolve an accurately weighed sample in sufficient
0.1M potassium phosphate buffer pH 8.0 (solution 3), to give a stock
solution of convenient concentration. Further dilute the stock solution
with solution 3 to the reference concentration of 0.1 microgram of
ampicillin per milliliter (estimated).
(2) (Reserved)
(3) Moisture. Proceed as directed in 436.201 of this chapter.
(4) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter.
(5) Hetacillin content. Proceed as directed in 440.25(b)(5), except
use about 110 milligrams of sample and calculate the hetacillin content
as follows:
Percent hetacillin=
where:
C=Concentration in milligrams of hetacillin per milliliter of the
final solution of the sample obtained from the standard response line.
P=Hetacillin content of the hetacillin working standard in percent.
(6) Identity. Proceed as directed in 436.211 of this chapter, using
a 1 percent potassium bromide disc prepared as directed in paragraph
(b)(1) of that section.
(7) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(39 FR 18976, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
44 FR 10379, Feb. 20, 1979; 50 FR 19918, May 13, 1985)
21 CFR 440.29a Sterile hetacillin potassium.
(a) Requirements for certification -- (1) Standards of identity,
strength, quality, and purity. Hetacillin potassium is the potassium
salt of hetacillin. It occurs as a fine, white to light buff powder.
It is so purified and dried that:
(i) Its potency is not less than 735 micrograms of ampicillin per
milligram. If it is packaged for dispensing, its potency is
satisfactory if it contains not less than 90 percent and not more than
120 percent of the number of milligrams of ampicillin that it is
represented to contain.
(ii) It is sterile.
(iii) It is nonpyrogenic.
(iv) (Reserved)
(v) Its moisture content is not more than 1.0 percent.
(vi) Its pH in an aqueous solution containing 10 milligrams per
milliliter (or when reconstituted as directed in the labeling, if it is
packaged for dispensing) is not less than 7.0 and not more than 9.0.
(vii) Its hetacillin content is not less than 82 percent and not more
than 95.5 percent.
(viii) It gives a positive identity test for hetacillin potassium.
(ix) It is crystalline.
(2) Labeling. It shall be labeled in accordance with the
requirements of 432.5 of this chapter.
(3) Requests for certification; samples. In addition to complying
with the requirements of 431.1 of this chapter, each such request shall
contain:
(i) Results of tests and assays on the batch for potency, sterility,
pyrogens, moisture, pH, hetacillin content, identity, and crystallinity.
(ii) Samples required:
(a) If the batch is packaged for repacking or for use in the
manufacture of another drug:
(1) For all tests except sterility: 10 packages, each containing
approximately 300 milligrams.
(2) For sterility testing: 20 packages, each containing
approximately 300 milligrams.
(b) If the batch is packaged for dispensing:
(1) For all tests except sterility: A minimum of 10 immediate
containers, except if each contains less than 450 milligrams, a minimum
of 16 immediate containers.
(2) For sterility testing: 20 immediate containers, collected at
regular intervals throughout each filling operation.
(b) Tests and methods of assay -- (1) Potency. Proceed as directed
for ampicillin in 436.105 of this chapter, using the ampicillin working
standard as the standard of comparison and preparing the sample for
assay as follows: Dissolve an accurately weighed sample in sufficient
0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock
solution of convenient concentration; and also if it is packaged for
dispensing, reconstitute as directed in the labeling. Then, using a
suitable hypodermic needle and syringe, remove the withdrawable contents
from each container represented as a single-dose container; or if the
labeling specifies the amount of potency in a given volume of the
resultant preparation, withdraw an accurately measured representative
portion from each container. Dilute the sample thus obtained with
sufficient solution 3 to give a stock solution of convenient
concentration. Further dilute the stock solution with solution 3 to the
reference concentration of 0.1 microgram of ampicillin per milliliter
(estimated).
(2) Sterility. Proceed as directed in 436.20 of this chapter, using
the method described in paragraph (e)(1) of that section.
(3) Pyrogens. Proceed as directed in 436.32(a) of this chapter
using a solution containing the equivalent of 18 milligrams of
ampicillin per milliliter.
(4) (Reserved)
(5) Moisture. Proceed as directed in 436.201 of this chapter.
(6) pH. Proceed as directed in 436.202 of this chapter, using an
aqueous solution containing 10 milligrams per milliliter (or using a
solution reconstituted as directed in the labeling, if it is packaged
for dispensing).
(7) Hetacillin content. Proceed as directed in 440.25(b)(5), except
use about 110 milligrams of sample and calculate the potassium
hetacillin content as follows:
Percent hetacillin=
where:
C=Concentration in milligrams of hetacillin per milliliter of the
final solution of the sample obtained from the standard response line.
P=Hetacillin content of the hetacillin working standard in percent.
(8) Identity. Proceed as directed in 436.211 of this chapter, using
a 1 percent potassium bromide disc prepared as directed in paragraph
(b)(1) of that section.
(9) Crystallinity. Proceed as directed in 436.203(a) of this
chapter.
(39 FR 19876, May 30, 1974, as amended at 42 FR 59857, Nov. 22, 1977;
43 FR 2393, Jan. 17, 1978; 44 FR 10379, Feb. 20, 1979; 50 FR 19918,
May 13, 1985)