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FDA GMP regulation
PART
211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS
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, and in parts 600 through 680 of this
chapter, as they pertain to biological products for human use, shall be
considered to supplement, not supersede, the regulations in this part
unless the regulations explicitly provide otherwise. In the event it
is impossible to comply with applicable regulations both in this part
and in other parts of this chapter or in parts 600 through 680 of this
chapter, the regulation specifically applicable to the drug product
in question shall supersede the regulation in this part. (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] ------------------------------------------------------------------------ Subpart
A--General Provisions Sec.
211.3 Definitions. The definitions set forth
in Sec. 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. ------------------------------------------------------------------------ Subpart
B--Organization and Personnel 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. ------------------------------------------------------------------------ Subpart
B--Organization and Personnel 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. ------------------------------------------------------------------------ Subpart
B--Organization and Personnel 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] ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities Sec.
211.44 Lighting. Adequate lighting shall be
provided in all areas. ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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. ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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] ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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. ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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. ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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. ------------------------------------------------------------------------ Subpart
C--Buildings and Facilities 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. ------------------------------------------------------------------------ Subpart
D--Equipment 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. ------------------------------------------------------------------------ Subpart
D--Equipment 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 Secs. 211.180 and 211.182. ------------------------------------------------------------------------ Subpart
D--Equipment 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] ------------------------------------------------------------------------ Subpart
D--Equipment 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). ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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 Sec. 211.80. ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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 Sec. 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] ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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. ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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 Sec. 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. ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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. ------------------------------------------------------------------------ Subpart
E--Control of Components and Drug Product Containers and Closures 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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. ------------------------------------------------------------------------ Subpart
F--Production and Process Controls 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] ------------------------------------------------------------------------ Subpart
G--Packaging and Labeling Control 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 Sec. 211.192. Labeling
reconciliation is waived for cut or roll labeling if a 100- percent
examination for correct labeling is performed in accordance with Sec.
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] ------------------------------------------------------------------------ Subpart
G--Packaging and Labeling Control 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] ------------------------------------------------------------------------ Subpart
G--Packaging and Labeling Control 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 Sec.
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 Sec. 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 Sec.
314.70(c) of this chapter. Manufacturing changes by which capsules are to be
sealed require prior FDA approval under Sec. 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 Sec.
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, as amended at 63 FR 59470, Nov. 4, 1998] ------------------------------------------------------------------------ Subpart
G--Packaging and Labeling Control 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. ------------------------------------------------------------------------ Subpart
G--Packaging and Labeling Control 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 Sec. 211.166. (b) Expiration dates shall
be related to any storage conditions stated on
the labeling, as determined by stability studies described in Sec.
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 Sec. 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. ------------------------------------------------------------------------ Subpart
H--Holding and Distribution 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. ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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 Sec.
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. ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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] ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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. ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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 Sec. 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 Sec. 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 Sec. 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] ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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. ------------------------------------------------------------------------ Subpart
I--Laboratory Controls 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 Office of the Federal Register,
800 North Capitol Street, NW., suite 700, 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; 66 FR 56035, Nov. 6, 2001] ------------------------------------------------------------------------ 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 Sec. 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 Sec. 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 Sec. 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 Secs. 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] ------------------------------------------------------------------------ Subpart
J--Records and Reports 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. ------------------------------------------------------------------------ Subpart
J--Records and Reports 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 Sec. 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 Sec. 211.82(a), Sec. 211.84(d), or Sec.
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 Secs. 211.122(c)
and 211.130(c). (e) The disposition of
rejected components, drug product containers, closure,
and labeling. ------------------------------------------------------------------------ Subpart
J--Records and Reports 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 Sec. 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. ------------------------------------------------------------------------ Subpart
J--Records and Reports 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 Sec. 211.192. (13) Results of
examinations made in accordance with Sec. 211.134. ------------------------------------------------------------------------ Subpart
J--Records and Reports 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. ------------------------------------------------------------------------ Subpart
J--Records and Reports 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, Association of Official Analytical Chemists,
Book of Methods,\1\ 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. --------------------------------------------------------------------------- \1\ Copies may be obtained
from: Association of Official Analytical Chemists,
2200 Wilson Blvd., Suite 400, Arlington, VA 22201-3301. --------------------------------------------------------------------------- (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 Sec. 211.160(b)(4). (e) Complete records shall
be maintained of all stability testing performed
in accordance with Sec. 211.166. [43 FR
45077, Sept. 29, 1978, as amended at 55 FR 11577, Mar. 29, 1990; 65 FR
18889, Apr. 10, 2000] ------------------------------------------------------------------------ Subpart
J--Records and Reports 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. (Approved
by the Office of Management and Budget under control number 0910-0139) [49 FR
9865, Mar. 16, 1984] ------------------------------------------------------------------------ Subpart
J--Records and Reports 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec.
211.180(c). (3) Where an investigation
under Sec. 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] Effective Date Note: At 68
FR 15364, Mar. 31, 2003, Sec. 211.198 was amended
in paragraph (a) in the last sentence by removing ``in accordance
with Sec. 310.305 of this chapter`` and adding in its place ``in
accordance with Secs. 310.305 and 514.80 of this chapter.``, effective
June 30, 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 Sec. 211.192. Procedures
for the holding, testing, and reprocessing of returned drug products
shall be in writing and shall be followed. ------------------------------------------------------------------------ Subpart
K--Returned and Salvaged Drug Products 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. |
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