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About 21CFR

[Code of Federal Regulations]

[Title 21, Volume 4]

[Revised as of April 1, 2007]

[CITE: 21CFR211]

TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG
ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUBCHAPTER C--DRUGS: GENERAL

PART 211

CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS

Subpart
A--General Provisions

Sec. 211.1 Scope.

(a) The regulations in this part contain the minimum
current good manufacturing practice for preparation of drug
products for administration to humans or animals.

(b) The current good manufacturing practice regulations in
this chapter as they pertain to drug products; in parts 600
through 680 of this chapter, as they pertain to drugs that are
also biological products for human use; and in part 1271 of
this chapter, as they are applicable to drugs that are also
human cells, tissues, and cellular and tissue-based products
(HCT/Ps) and that are drugs (subject to review under an
application submitted under section 505 of the act or under a
biological product license application under section 351 of
the Public Health Service Act); supplement and do not
supersede the regulations in this part unless the regulations
explicitly provide otherwise. In the event of a conflict
between applicable regulations in this part and in other parts
of this chapter, or in parts 600 through 680 of this chapter,
or in part 1271 of this chapter, the regulation specifically
applicable to the drug product in question shall supersede the
more general.

(c) Pending consideration of a proposed exemption,
published in the Federal Register of September 29, 1978, the
requirements in this part shall not be enforced for OTC drug
products if the products and all their ingredients are
ordinarily marketed and consumed as human foods, and which
products may also fall within the legal definition of drugs by
virtue of their intended use. Therefore, until further notice,
regulations under part 110 of this chapter, and where
applicable, parts 113 to 129 of this chapter, shall be applied
in determining whether these OTC drug products that are also
foods are manufactured, processed, packed, or held under
current good manufacturing practice.

[43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522,
Dec. 19, 1997; 69 FR 29828, May 25, 2004]

Sec. 211.3 Definitions.

The definitions set forth in 210.3 of this chapter apply in
this part.

Subpart
B--Organization and Personnel

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Subpart
C--Buildings and Facilities

Sec. 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 or such other control systems for the firm's
operations as are necessary to prevent contamination or mixups
during the course of the following procedures:

(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.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091,
Jan. 20, 1995]

Sec. 211.44 Lighting.

Adequate lighting shall be provided in all
areas.

Sec. 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.

Sec. 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]

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Subpart
D--Equipment

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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. The degree and frequency of input/output
verification shall be based on the complexity and reliability
of the computer or related system. 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.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091,
Jan. 20, 1995]

Sec. 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.

Subpart
E--Control of Components and Drug Product Containers and Closures

Sec. 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).

Sec. 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.

Sec. 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 date 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.

[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356,
Mar. 25, 1998]

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Subpart
F--Production and Process Controls

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Subpart
G--Packaging and Labeling Control

Sec. 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) Use of gang-printed labeling for different drug
products, or different strengths or net contents of the same
drug product, is prohibited unless the labeling from
gang-printed sheets is adequately differentiated by size,
shape, or color.

(g) If cut labeling is used, packaging and labeling
operations shall include one of the following special control
procedures:

(1) Dedication of labeling and packaging lines to each
different strength of each different drug product;

(2) Use of appropriate electronic or electromechanical
equipment to conduct a 100-percent examination for correct
labeling during or after completion of finishing operations;
or

(3) Use of visual inspection to conduct a 100-percent
examination for correct labeling during or after completion of
finishing operations for hand-applied labeling. Such
examination shall be performed by one person and independently
verified by a second person.

(h) 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.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353,
Aug. 3, 1993]

Sec. 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 used 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. Labeling
reconciliation is waived for cut or roll labeling if a
100-percent examination for correct labeling is performed in
accordance with 211.122(g)(2).

(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.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354,
Aug. 3, 1993]

Sec. 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 and handling of filled drug product
containers that are set aside and held in unlabeled condition
for future labeling operations to preclude mislabeling of
individual containers, lots, or portions of lots.
Identification need not be applied to each individual
container but shall be sufficient to determine name, strength,
quantity of contents, and lot or control number of each
container.

(c) 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.

(d) Examination of packaging and labeling materials for
suitability and correctness before packaging operations, and
documentation of such examination in the batch production
record.

(e) 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.

[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354,
Aug. 3, 1993]

Sec. 211.132 Tamper-evident 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-evident 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
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) Requirements for tamper-evident package. (1)
Each manufacturer and packer who packages an OTC drug product
(except a dermatological, dentifrice, insulin, or lozenge
product) for retail sale shall package the product in a
tamper-evident package, if this product is accessible to the
public while held for sale. A tamper-evident 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 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. A
tamper-evident 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-evident feature shall be
designed to and shall remain intact when handled in a
reasonable manner during manufacture, distribution, and retail
display.

(2) In addition to the tamper-evident packaging feature
described in paragraph (b)(1) of this section, any two-piece,
hard gelatin capsule covered by this section must be sealed
using an acceptable tamper-evident technology.

(c) Labeling. (1) In order to alert consumers to the
specific tamper-evident feature(s) used, each retail package
of an OTC drug product covered by this section (except ammonia
inhalant in crushable glass ampules, containers of compressed
medical oxygen, or aerosol products that depend upon the power
of a liquefied or compressed gas to expel the contents from
the container) is required to bear a statement that:

(i) Identifies all tamper-evident feature(s) and any
capsule sealing technologies used to comply with paragraph (b)
of this section;

(ii) Is prominently placed on the package; and

(iii) Is so placed that it will be unaffected if the
tamper-evident feature of the package is breached or
missing.

(2) If the tamper-evident feature chosen to meet the
requirements in paragraph (b) of this section 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 the Tamper-Evident Packaging
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-evident 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.

[54 FR 5228, Feb. 2, 1989, as amended at 63 FR 59470, Nov.
4, 1998]

Sec. 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.

Sec. 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) New drug products for investigational use are exempt
from the requirements of this section, provided that they meet
appropriate standards or specifications as demonstrated by
stability studies during their use in clinical investigations.
Where new drug products for investigational use are to be
reconstituted at the time of dispensing, their labeling shall
bear expiration information for the reconstituted drug
product.

(h) 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; 60 FR 4091, Jan. 20, 1995]

Subpart
H--Holding and Distribution

Sec. 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.

Sec. 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.

Subpart
I--Laboratory Controls

Sec. 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.

Sec. 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.

Sec. 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]

Sec. 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.

Sec. 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. Except for those for
drug products described in paragraph (b)(2) of this section,
reserve samples from representative sample lots or batches
selected by acceptable statistical procedures shall be
examined visually at least once a year for evidence of
deterioration unless visual examination would affect the
integrity of the reserve sample. 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, as amended at 60 FR 4091, Jan.
20, 1995]

Sec. 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.

Sec. 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, 5100
Paint Branch Pkwy., College Park, MD 20740, or available for
inspection at the National Archives and Records Administration
(NARA). For information on the availability of this material
at NARA, call 202-741-6030, or go to:
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

[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; 66 FR 56035, Nov. 6, 2001; 69 FR 18803, Apr. 9, 2004]

Subpart
J--Records and Reports

Sec. 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 a representative number of batches, 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.

[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091,
Jan. 20, 1995]

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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, AOAC INTERNATIONAL, Book of Methods,1or
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.

1Copies may be obtained from: AOAC
INTERNATIONAL, 481 North Frederick Ave., suite 500,
Gaithersburg, MD 20877.

[43 FR 45077, Sept. 29, 1978, as amended at 55 FR 11577,
Mar. 29, 1990; 65 FR 18889, Apr. 10, 2000; 70 FR 40880, July
15, 2005; 70 FR 67651, Nov. 8, 2005]

Sec. 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.

[49 FR 9865, Mar. 16, 1984]

Sec. 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 and 514.80 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; 68 FR 15364, Mar. 31, 2003]

Subpart
K--Returned and Salvaged Drug Products

Sec. 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.

Sec. 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.

Authority:
21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262,
263a, 264.
Source: 43 FR 45077, Sept. 29, 1978,
unless otherwise noted.

Database Updated April 1, 2007

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