Professional Documents
Culture Documents
I (4–1–21 Edition)
in section 201(g) of the act. The manu- on which more than one item of label-
facture of medicated premixes is sub- ing is printed.
ject to the requirements of part 226 of
[43 FR 45076, Sept. 29, 1978, as amended at 51
this chapter. FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993;
(15) Quality control unit means any 73 FR 51931, Sept. 8, 2008; 74 FR 65431, Dec. 10,
person or organizational element des- 2009]
ignated by the firm to be responsible
for the duties relating to quality con- PART 211—CURRENT GOOD MAN-
trol.
(16) Strength means:
UFACTURING PRACTICE FOR FIN-
(i) The concentration of the drug sub- ISHED PHARMACEUTICALS
stance (for example, weight/weight,
weight/volume, or unit dose/volume Subpart A—General Provisions
basis), and/or Sec.
(ii) The potency, that is, the thera- 211.1 Scope.
peutic activity of the drug product as 211.3 Definitions.
indicated by appropriate laboratory
tests or by adequately developed and Subpart B—Organization and Personnel
controlled clinical data (expressed, for
211.22 Responsibilities of quality control
example, in terms of units by reference
unit.
to a standard). 211.25 Personnel qualifications.
(17) Theoretical yield means the quan- 211.28 Personnel responsibilities.
tity that would be produced at any ap- 211.34 Consultants.
propriate phase of manufacture, proc-
essing, or packing of a particular drug Subpart C—Buildings and Facilities
product, based upon the quantity of
components to be used, in the absence 211.42 Design and construction features.
211.44 Lighting.
of any loss or error in actual produc-
211.46 Ventilation, air filtration, air heating
tion. and cooling.
(18) Actual yield means the quantity 211.48 Plumbing.
that is actually produced at any appro- 211.50 Sewage and refuse.
priate phase of manufacture, proc- 211.52 Washing and toilet facilities.
essing, or packing of a particular drug 211.56 Sanitation.
product. 211.58 Maintenance.
(19) Percentage of theoretical yield
means the ratio of the actual yield (at Subpart D—Equipment
any appropriate phase of manufacture, 211.63 Equipment design, size, and location.
processing, or packing of a particular 211.65 Equipment construction.
drug product) to the theoretical yield 211.67 Equipment cleaning and mainte-
(at the same phase), stated as a per- nance.
centage. 211.68 Automatic, mechanical, and elec-
(20) Acceptance criteria means the tronic equipment.
product specifications and acceptance/ 211.72 Filters.
rejection criteria, such as acceptable
quality level and unacceptable quality Subpart E—Control of Components and
level, with an associated sampling Drug Product Containers and Closures
plan, that are necessary for making a 211.80 General requirements.
decision to accept or reject a lot or 211.82 Receipt and storage of untested com-
batch (or any other convenient sub- ponents, drug product containers, and
groups of manufactured units). closures.
(21) Representative sample means a 211.84 Testing and approval or rejection of
sample that consists of a number of components, drug product containers,
units that are drawn based on rational and closures.
211.86 Use of approved components, drug
criteria such as random sampling and
product containers, and closures.
intended to assure that the sample ac- 211.87 Retesting of approved components,
curately portrays the material being drug product containers, and closures.
sampled. 211.89 Rejected components, drug product
(22) Gang-printed labeling means la- containers, and closures.
beling derived from a sheet of material 211.94 Drug product containers and closures.
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Food and Drug Administration, HHS § 211.1
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§ 211.3 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS § 211.46
of drug products shall have sufficient (7) Quarantine storage before release
education, training, and experience, or of drug products;
any combination thereof, to advise on (8) Storage of drug products after re-
the subject for which they are retained. lease;
Records shall be maintained stating (9) Control and laboratory oper-
the name, address, and qualifications ations;
of any consultants and the type of (10) Aseptic processing, which in-
service they provide. cludes as appropriate:
(i) Floors, walls, and ceilings of
Subpart C—Buildings and Facilities smooth, hard surfaces that are easily
cleanable;
§ 211.42 Design and construction fea- (ii) Temperature and humidity con-
tures. trols;
(iii) An air supply filtered through
(a) Any building or buildings used in high-efficiency particulate air filters
the manufacture, processing, packing, under positive pressure, regardless of
or holding of a drug product shall be of whether flow is laminar or nonlaminar;
suitable size, construction and location (iv) A system for monitoring environ-
to facilitate cleaning, maintenance, mental conditions;
and proper operations. (v) A system for cleaning and dis-
(b) Any such building shall have ade- infecting the room and equipment to
quate space for the orderly placement produce aseptic conditions;
of equipment and materials to prevent (vi) A system for maintaining any
mixups between different components, equipment used to control the aseptic
drug product containers, closures, la- conditions.
beling, in-process materials, or drug (d) Operations relating to the manu-
products, and to prevent contamina- facture, processing, and packing of pen-
tion. The flow of components, drug icillin shall be performed in facilities
product containers, closures, labeling, separate from those used for other drug
in-process materials, and drug products products for human use.
through the building or buildings shall
[43 FR 45077, Sept. 29, 1978, as amended at 60
be designed to prevent contamination.
FR 4091, Jan. 20, 1995]
(c) Operations shall be performed
within specifically defined areas of ade- § 211.44 Lighting.
quate size. There shall be separate or
Adequate lighting shall be provided
defined areas or such other control sys-
in all areas.
tems for the firm’s operations as are
necessary to prevent contamination or § 211.46 Ventilation, air filtration, air
mixups during the course of the fol- heating and cooling.
lowing procedures: (a) Adequate ventilation shall be pro-
(1) Receipt, identification, storage, vided.
and withholding from use of compo- (b) Equipment for adequate control
nents, drug product containers, clo- over air pressure, micro-organisms,
sures, and labeling, pending the appro- dust, humidity, and temperature shall
priate sampling, testing, or examina- be provided when appropriate for the
tion by the quality control unit before manufacture, processing, packing, or
release for manufacturing or pack- holding of a drug product.
aging; (c) Air filtration systems, including
(2) Holding rejected components, prefilters and particulate matter air
drug product containers, closures, and filters, shall be used when appropriate
labeling before disposition; on air supplies to production areas. If
(3) Storage of released components, air is recirculated to production areas,
drug product containers, closures, and measures shall be taken to control re-
labeling; circulation of dust from production. In
(4) Storage of in-process materials; areas where air contamination occurs
(5) Manufacturing and processing op- during production, there shall be ade-
erations; quate exhaust systems or other sys-
(6) Packaging and labeling oper- tems adequate to control contami-
ations; nants.
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§ 211.48 21 CFR Ch. I (4–1–21 Edition)
(d) Air-handling systems for the man- (c) There shall be written procedures
ufacture, processing, and packing of for use of suitable rodenticides, insecti-
penicillin shall be completely separate cides, fungicides, fumigating agents,
from those for other drug products for and cleaning and sanitizing agents.
human use. Such written procedures shall be de-
signed to prevent the contamination of
§ 211.48 Plumbing. equipment, components, drug product
(a) Potable water shall be supplied containers, closures, packaging, label-
under continuous positive pressure in a ing materials, or drug products and
plumbing system free of defects that shall be followed. Rodenticides, insecti-
could contribute contamination to any cides, and fungicides shall not be used
drug product. Potable water shall meet unless registered and used in accord-
the standards prescribed in the Envi- ance with the Federal Insecticide, Fun-
ronmental Protection Agency’s Pri- gicide, and Rodenticide Act (7 U.S.C.
mary Drinking Water Regulations set 135).
forth in 40 CFR part 141. Water not (d) Sanitation procedures shall apply
meeting such standards shall not be to work performed by contractors or
permitted in the potable water system. temporary employees as well as work
(b) Drains shall be of adequate size performed by full-time employees dur-
and, where connected directly to a ing the ordinary course of operations.
sewer, shall be provided with an air
break or other mechanical device to § 211.58 Maintenance.
prevent back-siphonage.
Any building used in the manufac-
[43 FR 45077, Sept. 29, 1978, as amended at 48 ture, processing, packing, or holding of
FR 11426, Mar. 18, 1983] a drug product shall be maintained in a
good state of repair.
§ 211.50 Sewage and refuse.
Sewage, trash, and other refuse in
and from the building and immediate
Subpart D—Equipment
premises shall be disposed of in a safe § 211.63 Equipment design, size, and
and sanitary manner. location.
§ 211.52 Washing and toilet facilities. Equipment used in the manufacture,
processing, packing, or holding of a
Adequate washing facilities shall be
drug product shall be of appropriate de-
provided, including hot and cold water,
soap or detergent, air driers or single- sign, adequate size, and suitably lo-
service towels, and clean toilet facili- cated to facilitate operations for its in-
ties easily accesible to working areas. tended use and for its cleaning and
maintenance.
§ 211.56 Sanitation.
§ 211.65 Equipment construction.
(a) Any building used in the manufac-
ture, processing, packing, or holding of (a) Equipment shall be constructed so
a drug product shall be maintained in a that surfaces that contact components,
clean and sanitary condition, Any such in-process materials, or drug products
building shall be free of infestation by shall not be reactive, additive, or ab-
rodents, birds, insects, and other sorptive so as to alter the safety, iden-
vermin (other than laboratory ani- tity, strength, quality, or purity of the
mals). Trash and organic waste matter drug product beyond the official or
shall be held and disposed of in a time- other established requirements.
ly and sanitary manner. (b) Any substances required for oper-
(b) There shall be written procedures ation, such as lubricants or coolants,
assigning responsibility for sanitation shall not come into contact with com-
and describing in sufficient detail the ponents, drug product containers, clo-
cleaning schedules, methods, equip- sures, in-process materials, or drug
ment, and materials to be used in products so as to alter the safety, iden-
cleaning the buildings and facilities; tity, strength, quality, or purity of the
such written procedures shall be fol- drug product beyond the official or
lowed. other established requirements.
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Food and Drug Administration, HHS § 211.72
§ 211.67 Equipment cleaning and main- checks and inspections shall be main-
tenance. tained.
(a) Equipment and utensils shall be (b) Appropriate controls shall be ex-
cleaned, maintained, and, as appro- ercised over computer or related sys-
priate for the nature of the drug, sani- tems to assure that changes in master
tized and/or sterilized at appropriate production and control records or other
records are instituted only by author-
intervals to prevent malfunctions or
ized personnel. Input to and output
contamination that would alter the
from the computer or related system of
safety, identity, strength, quality, or
formulas or other records or data shall
purity of the drug product beyond the
be checked for accuracy. The degree
official or other established require-
and frequency of input/output
ments.
verification shall be based on the com-
(b) Written procedures shall be estab- plexity and reliability of the computer
lished and followed for cleaning and or related system. A backup file of data
maintenance of equipment, including entered into the computer or related
utensils, used in the manufacture, system shall be maintained except
processing, packing, or holding of a where certain data, such as calcula-
drug product. These procedures shall tions performed in connection with lab-
include, but are not necessarily limited oratory analysis, are eliminated by
to, the following: computerization or other automated
(1) Assignment of responsibility for processes. In such instances a written
cleaning and maintaining equipment; record of the program shall be main-
(2) Maintenance and cleaning sched- tained along with appropriate valida-
ules, including, where appropriate, tion data. Hard copy or alternative sys-
sanitizing schedules; tems, such as duplicates, tapes, or
(3) A description in sufficient detail microfilm, designed to assure that
of the methods, equipment, and mate- backup data are exact and complete
rials used in cleaning and maintenance and that it is secure from alteration,
operations, and the methods of dis- inadvertent erasures, or loss shall be
assembling and reassembling equip- maintained.
ment as necessary to assure proper (c) Such automated equipment used
cleaning and maintenance; for performance of operations ad-
(4) Removal or obliteration of pre- dressed by §§ 211.101(c) or (d), 211.103,
vious batch identification; 211.182, or 211.188(b)(11) can satisfy the
(5) Protection of clean equipment requirements included in those sec-
from contamination prior to use; tions relating to the performance of an
(6) Inspection of equipment for clean- operation by one person and checking
liness immediately before use. by another person if such equipment is
(c) Records shall be kept of mainte- used in conformity with this section,
nance, cleaning, sanitizing, and inspec- and one person checks that the equip-
tion as specified in §§ 211.180 and 211.182. ment properly performed the oper-
[43 FR 45077, Sept. 29, 1978, as amended at 73 ation.
FR 51931, Sept. 8, 2008] [43 FR 45077, Sept. 29, 1978, as amended at 60
FR 4091, Jan. 20, 1995; 73 FR 51932, Sept. 8,
§ 211.68 Automatic, mechanical, and 2008]
electronic equipment.
(a) Automatic, mechanical, or elec- § 211.72 Filters.
tronic equipment or other types of Filters for liquid filtration used in
equipment, including computers, or re- the manufacture, processing, or pack-
lated systems that will perform a func- ing of injectable drug products in-
tion satisfactorily, may be used in the tended for human use shall not release
manufacture, processing, packing, and fibers into such products. Fiber-releas-
holding of a drug product. If such ing filters may be used when it is not
equipment is so used, it shall be rou- possible to manufacture such products
tinely calibrated, inspected, or checked without the use of these filters. If use
according to a written program de- of a fiber-releasing filter is necessary,
signed to assure proper performance. an additional nonfiber-releasing filter
Written records of those calibration having a maximum nominal pore size
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§ 211.80 21 CFR Ch. I (4–1–21 Edition)
rating of 0.2 micron (0.45 micron if the the area shall conform to the require-
manufacturing conditions so dictate) ments of § 211.80.
shall subsequently be used to reduce
[43 FR 45077, Sept. 29, 1978, as amended at 73
the content of particles in the FR 51932, Sept. 8, 2008]
injectable drug product. The use of an
asbestos-containing filter is prohibited. § 211.84 Testing and approval or rejec-
tion of components, drug product
[73 FR 51932, Sept. 8, 2008] containers, and closures.
(a) Each lot of components, drug
Subpart E—Control of Compo- product containers, and closures shall
nents and Drug Product Con- be withheld from use until the lot has
tainers and Closures been sampled, tested, or examined, as
appropriate, and released for use by the
§ 211.80 General requirements. quality control unit.
(a) There shall be written procedures (b) Representative samples of each
describing in sufficient detail the re- shipment of each lot shall be collected
ceipt, identification, storage, handling, for testing or examination. The num-
sampling, testing, and approval or re- ber of containers to be sampled, and
jection of components and drug prod- the amount of material to be taken
uct containers and closures; such writ- from each container, shall be based
ten procedures shall be followed. upon appropriate criteria such as sta-
(b) Components and drug product tistical criteria for component varia-
containers and closures shall at all bility, confidence levels, and degree of
times be handled and stored in a man- precision desired, the past quality his-
tory of the supplier, and the quantity
ner to prevent contamination.
needed for analysis and reserve where
(c) Bagged or boxed components of
required by § 211.170.
drug product containers, or closures
(c) Samples shall be collected in ac-
shall be stored off the floor and suit-
cordance with the following proce-
ably spaced to permit cleaning and in- dures:
spection.
(1) The containers of components se-
(d) Each container or grouping of lected shall be cleaned when necessary
containers for components or drug in a manner to prevent introduction of
product containers, or closures shall be contaminants into the component.
identified with a distinctive code for (2) The containers shall be opened,
each lot in each shipment received. sampled, and resealed in a manner de-
This code shall be used in recording the signed to prevent contamination of
disposition of each lot. Each lot shall their contents and contamination of
be appropriately identified as to its other components, drug product con-
status (i.e., quarantined, approved, or tainers, or closures.
rejected). (3) Sterile equipment and aseptic
sampling techniques shall be used when
§ 211.82 Receipt and storage of untest- necessary.
ed components, drug product con-
tainers, and closures. (4) If it is necessary to sample a com-
ponent from the top, middle, and bot-
(a) Upon receipt and before accept- tom of its container, such sample sub-
ance, each container or grouping of divisions shall not be composited for
containers of components, drug prod- testing.
uct containers, and closures shall be (5) Sample containers shall be identi-
examined visually for appropriate la- fied so that the following information
beling as to contents, container dam- can be determined: name of the mate-
age or broken seals, and contamina- rial sampled, the lot number, the con-
tion. tainer from which the sample was
(b) Components, drug product con- taken, the date on which the sample
tainers, and closures shall be stored was taken, and the name of the person
under quarantine until they have been who collected the sample.
tested or examined, whichever is appro- (6) Containers from which samples
priate, and released. Storage within have been taken shall be marked to
164
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Food and Drug Administration, HHS § 211.94
show that samples have been removed released for use. Any lot of such mate-
from them. rial that does not meet such specifica-
(d) Samples shall be examined and tions shall be rejected.
tested as follows:
(1) At least one test shall be con- [43 FR 45077, Sept. 29, 1978, as amended at 63
FR 14356, Mar. 25, 1998; 73 FR 51932, Sept. 8,
ducted to verify the identity of each
2008]
component of a drug product. Specific
identity tests, if they exist, shall be § 211.86 Use of approved components,
used. drug product containers, and clo-
(2) Each component shall be tested sures.
for conformity with all appropriate
written specifications for purity, Components, drug product con-
strength, and quality. In lieu of such tainers, and closures approved for use
testing by the manufacturer, a report shall be rotated so that the oldest ap-
of analysis may be accepted from the proved stock is used first. Deviation
supplier of a component, provided that from this requirement is permitted if
at least one specific identity test is such deviation is temporary and appro-
conducted on such component by the priate.
manufacturer, and provided that the
manufacturer establishes the reli- § 211.87 Retesting of approved compo-
ability of the supplier’s analyses nents, drug product containers, and
through appropriate validation of the closures.
supplier’s test results at appropriate Components, drug product con-
intervals. tainers, and closures shall be retested
(3) Containers and closures shall be or reexamined, as appropriate, for iden-
tested for conformity with all appro- tity, strength, quality, and purity and
priate written specifications. In lieu of approved or rejected by the quality
such testing by the manufacturer, a control unit in accordance with § 211.84
certificate of testing may be accepted as necessary, e.g., after storage for
from the supplier, provided that at long periods or after exposure to air,
least a visual identification is con- heat or other conditions that might ad-
ducted on such containers/closures by
versely affect the component, drug
the manufacturer and provided that
product container, or closure.
the manufacturer establishes the reli-
ability of the supplier’s test results § 211.89 Rejected components, drug
through appropriate validation of the product containers, and closures.
supplier’s test results at appropriate
intervals. Rejected components, drug product
(4) When appropriate, components containers, and closures shall be iden-
shall be microscopically examined. tified and controlled under a quar-
(5) Each lot of a component, drug antine system designed to prevent
product container, or closure that is their use in manufacturing or proc-
liable to contamination with filth, in- essing operations for which they are
sect infestation, or other extraneous unsuitable.
adulterant shall be examined against
established specifications for such con- § 211.94 Drug product containers and
tamination. closures.
(6) Each lot of a component, drug (a) Drug product containers and clo-
product container, or closure with po- sures shall not be reactive, additive, or
tential for microbiological contamina- absorptive so as to alter the safety,
tion that is objectionable in view of its identity, strength, quality, or purity of
intended use shall be subjected to the drug beyond the official or estab-
microbiological tests before use. lished requirements.
(e) Any lot of components, drug prod-
(b) Container closure systems shall
uct containers, or closures that meets
the appropriate written specifications provide adequate protection against
of identity, strength, quality, and pu- foreseeable external factors in storage
rity and related tests under paragraph and use that can cause deterioration or
(d) of this section may be approved and contamination of the drug product.
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§ 211.100 21 CFR Ch. I (4–1–21 Edition)
(c) Drug product containers and clo- containers must be reasonably resist-
sures shall be clean and, where indi- ant to fading, durable when exposed to
cated by the nature of the drug, steri- atmospheric conditions, and not read-
lized and processed to remove ily soluble in water.
pyrogenic properties to assure that
[43 FR 45077, Sept. 29, 1978, as amended at 73
they are suitable for their intended
FR 51932, Sept. 8, 2008; 81 FR 81697, Nov. 18,
use. Such depyrogenation processes 2016]
shall be validated.
(d) Standards or specifications, meth-
ods of testing, and, where indicated, Subpart F—Production and
methods of cleaning, sterilizing, and Process Controls
processing to remove pyrogenic prop-
erties shall be written and followed for § 211.100 Written procedures; devi-
drug product containers and closures. ations.
(e) Medical gas containers and closures (a) There shall be written procedures
must meet the following requirements—(1) for production and process control de-
Gas-specific use outlet connections. Port- signed to assure that the drug products
able cryogenic medical gas containers have the identity, strength, quality,
that are not manufactured with perma- and purity they purport or are rep-
nent gas use outlet connections (e.g., resented to possess. Such procedures
those that have been silver-brazed) shall include all requirements in this
must have gas-specific use outlet con- subpart. These written procedures, in-
nections that are attached to the valve cluding any changes, shall be drafted,
body so that they cannot be readily re- reviewed, and approved by the appro-
moved or replaced (without making the priate organizational units and re-
valve inoperable and preventing the viewed and approved by the quality
containers’ use) except by the manu- control unit.
facturer. For the purposes of this para- (b) Written production and process
graph, the term ‘‘manufacturer’’ in- control procedures shall be followed in
cludes any individual or firm that fills the execution of the various production
high-pressure medical gas cylinders or and process control functions and shall
cryogenic medical gas containers. For be documented at the time of perform-
the purposes of this section, a ‘‘port- ance. Any deviation from the written
able cryogenic medical gas container’’ procedures shall be recorded and justi-
is one that is capable of being trans- fied.
ported and is intended to be attached
to a medical gas supply system within § 211.101 Charge-in of components.
a hospital, health care entity, nursing
Written production and control pro-
home, other facility, or home health
cedures shall include the following,
care setting, or is a base unit used to
which are designed to assure that the
fill small cryogenic gas containers for
drug products produced have the iden-
use by individual patients. The term
tity, strength, quality, and purity they
does not include cryogenic containers
purport or are represented to possess:
that are not designed to be connected
to a medical gas supply system, e.g., (a) The batch shall be formulated
tank trucks, trailers, rail cars, or with the intent to provide not less than
small cryogenic gas containers for use 100 percent of the labeled or established
by individual patients (including port- amount of active ingredient.
able liquid oxygen units as defined at (b) Components for drug product
§ 868.5655 of this chapter). manufacturing shall be weighed, meas-
(2) Label and coloring requirements. ured, or subdivided as appropriate. If a
The labeling specified at § 201.328(a) of component is removed from the origi-
this chapter must be affixed to the con- nal container to another, the new con-
tainer in a manner that does not inter- tainer shall be identified with the fol-
fere with other labeling and such that lowing information:
it is not susceptible to becoming worn (1) Component name or item code;
or inadvertently detached during nor- (2) Receiving or control number;
mal use. Each such label as well as ma- (3) Weight or measure in new con-
terials used for coloring medical gas tainer;
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Food and Drug Administration, HHS § 211.110
(4) Batch for which component was manufacture of each batch of a drug
dispensed, including its product name, product. In cases where only one of a
strength, and lot number. particular type of equipment exists in
(c) Weighing, measuring, or subdi- a manufacturing facility, the name of
viding operations for components shall the equipment may be used in lieu of a
be adequately supervised. Each con- distinctive identification number or
tainer of component dispensed to man- code.
ufacturing shall be examined by a sec-
ond person to assure that: § 211.110 Sampling and testing of in-
(1) The component was released by process materials and drug prod-
the quality control unit; ucts.
(2) The weight or measure is correct (a) To assure batch uniformity and
as stated in the batch production integrity of drug products, written pro-
records; cedures shall be established and fol-
(3) The containers are properly iden- lowed that describe the in-process con-
tified. If the weighing, measuring, or trols, and tests, or examinations to be
subdividing operations are performed conducted on appropriate samples of
by automated equipment under § 211.68, in-process materials of each batch.
only one person is needed to assure Such control procedures shall be estab-
paragraphs (c)(1), (c)(2), and (c)(3) of lished to monitor the output and to
this section. validate the performance of those man-
(d) Each component shall either be ufacturing processes that may be re-
added to the batch by one person and sponsible for causing variability in the
verified by a second person or, if the characteristics of in-process material
components are added by automated and the drug product. Such control
equipment under § 211.68, only verified procedures shall include, but are not
by one person. limited to, the following, where appro-
priate:
[43 FR 45077, Sept. 29, 1978, as amended at 73
FR 51932, Sept. 8, 2008]
(1) Tablet or capsule weight vari-
ation;
§ 211.103 Calculation of yield. (2) Disintegration time;
(3) Adequacy of mixing to assure uni-
Actual yields and percentages of the-
formity and homogeneity;
oretical yield shall be determined at
(4) Dissolution time and rate;
the conclusion of each appropriate
(5) Clarity, completeness, or pH of so-
phase of manufacturing, processing,
lutions.
packaging, or holding of the drug prod-
(6) Bioburden testing.
uct. Such calculations shall either be
(b) Valid in-process specifications for
performed by one person and independ-
such characteristics shall be consistent
ently verified by a second person, or, if
with drug product final specifications
the yield is calculated by automated
and shall be derived from previous ac-
equipment under § 211.68, be independ-
ceptable process average and process
ently verified by one person.
variability estimates where possible
[73 FR 51932, Sept. 8, 2008] and determined by the application of
suitable statistical procedures where
§ 211.105 Equipment identification. appropriate. Examination and testing
(a) All compounding and storage con- of samples shall assure that the drug
tainers, processing lines, and major product and in-process material con-
equipment used during the production form to specifications.
of a batch of a drug product shall be (c) In-process materials shall be test-
properly identified at all times to indi- ed for identity, strength, quality, and
cate their contents and, when nec- purity as appropriate, and approved or
essary, the phase of processing of the rejected by the quality control unit,
batch. during the production process, e.g., at
(b) Major equipment shall be identi- commencement or completion of sig-
fied by a distinctive identification nificant phases or after storage for
number or code that shall be recorded long periods.
in the batch production record to show (d) Rejected in-process materials
the specific equipment used in the shall be identified and controlled under
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§ 211.111 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS § 211.132
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§ 211.132 21 CFR Ch. I (4–1–21 Edition)
the Federal Food, Drug, and Cosmetic this section must be sealed using an ac-
Act (the act) to establish a uniform na- ceptable tamper-evident technology.
tional requirement for tamper-evident (c) Labeling. (1) In order to alert con-
packaging of OTC drug products that sumers to the specific tamper-evident
will improve the security of OTC drug feature(s) used, each retail package of
packaging and help assure the safety an OTC drug product covered by this
and effectiveness of OTC drug products. section (except ammonia inhalant in
An OTC drug product (except a der- crushable glass ampules, containers of
matological, dentifrice, insulin, or loz- compressed medical oxygen, or aerosol
enge product) for retail sale that is not products that depend upon the power of
packaged in a tamper-resistant pack- a liquefied or compressed gas to expel
age or that is not properly labeled the contents from the container) is re-
under this section is adulterated under quired to bear a statement that:
section 501 of the act or misbranded (i) Identifies all tamper-evident fea-
under section 502 of the act, or both. ture(s) and any capsule sealing tech-
(b) Requirements for tamper-evident nologies used to comply with para-
package. (1) Each manufacturer and graph (b) of this section;
packer who packages an OTC drug (ii) Is prominently placed on the
product (except a dermatological, den- package; and
tifrice, insulin, or lozenge product) for
(iii) Is so placed that it will be unaf-
retail sale shall package the product in
fected if the tamper-evident feature of
a tamper-evident package, if this prod-
the package is breached or missing.
uct is accessible to the public while
held for sale. A tamper-evident pack- (2) If the tamper-evident feature cho-
age is one having one or more indica- sen to meet the requirements in para-
tors or barriers to entry which, if graph (b) of this section uses an identi-
breached or missing, can reasonably be fying characteristic, that char-
expected to provide visible evidence to acteristic is required to be referred to
consumers that tampering has oc- in the labeling statement. For exam-
curred. To reduce the likelihood of suc- ple, the labeling statement on a bottle
cessful tampering and to increase the with a shrink band could say ‘‘For your
likelihood that consumers will discover protection, this bottle has an im-
if a product has been tampered with, printed seal around the neck.’’
the package is required to be distinc- (d) Request for exemptions from pack-
tive by design or by the use of one or aging and labeling requirements. A man-
more indicators or barriers to entry ufacturer or packer may request an ex-
that employ an identifying char- emption from the packaging and label-
acteristic (e.g., a pattern, name, reg- ing requirements of this section. A re-
istered trademark, logo, or picture). quest for an exemption is required to
For purposes of this section, the term be submitted in the form of a citizen
‘‘distinctive by design’’ means the petition under § 10.30 of this chapter
packaging cannot be duplicated with and should be clearly identified on the
commonly available materials or envelope as a ‘‘Request for Exemption
through commonly available processes. from the Tamper-Evident Packaging
A tamper-evident package may involve Rule.’’ The petition is required to con-
an immediate-container and closure tain the following:
system or secondary-container or car- (1) The name of the drug product or,
ton system or any combination of sys- if the petition seeks an exemption for a
tems intended to provide a visual indi- drug class, the name of the drug class,
cation of package integrity. The tam- and a list of products within that class.
per-evident feature shall be designed to (2) The reasons that the drug prod-
and shall remain intact when handled uct’s compliance with the tamper-evi-
in a reasonable manner during manu- dent packaging or labeling require-
facture, distribution, and retail dis- ments of this section is unnecessary or
play. cannot be achieved.
(2) In addition to the tamper-evident (3) A description of alternative steps
packaging feature described in para- that are available, or that the peti-
graph (b)(1) of this section, any two- tioner has already taken, to reduce the
piece, hard gelatin capsule covered by likelihood that the product or drug
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Food and Drug Administration, HHS § 211.142
class will be the subject of malicious tion for both the reconstituted and
adulteration. unreconstituted drug products.
(4) Other information justifying an (d) Expiration dates shall appear on
exemption. labeling in accordance with the re-
(e) OTC drug products subject to ap- quirements of § 201.17 of this chapter.
proved new drug applications. Holders of (e) Homeopathic drug products shall
approved new drug applications for be exempt from the requirements of
OTC drug products are required under this section.
§ 314.70 of this chapter to provide the (f) Allergenic extracts that are la-
agency with notification of changes in
beled ‘‘No U.S. Standard of Potency’’
packaging and labeling to comply with
are exempt from the requirements of
the requirements of this section.
Changes in packaging and labeling re- this section.
quired by this regulation may be made (g) New drug products for investiga-
before FDA approval, as provided under tional use are exempt from the require-
§ 314.70(c) of this chapter. Manufac- ments of this section, provided that
turing changes by which capsules are they meet appropriate standards or
to be sealed require prior FDA approval specifications as demonstrated by sta-
under § 314.70(b) of this chapter. bility studies during their use in clin-
(f) Poison Prevention Packaging Act of ical investigations. Where new drug
1970. This section does not affect any products for investigational use are to
requirements for ‘‘special packaging’’ be reconstituted at the time of dis-
as defined under § 310.3(l) of this chap- pensing, their labeling shall bear expi-
ter and required under the Poison Pre- ration information for the reconsti-
vention Packaging Act of 1970. tuted drug product.
(Approved by the Office of Management and (h) Pending consideration of a pro-
Budget under OMB control number 0910–0149) posed exemption, published in the FED-
ERAL REGISTER of September 29, 1978,
[54 FR 5228, Feb. 2, 1989, as amended at 63 FR
59470, Nov. 4, 1998] the requirements in this section shall
not be enforced for human OTC drug
§ 211.134 Drug product inspection. products if their labeling does not bear
(a) Packaged and labeled products dosage limitations and they are stable
shall be examined during finishing op- for at least 3 years as supported by ap-
erations to provide assurance that con- propriate stability data.
tainers and packages in the lot have [43 FR 45077, Sept. 29, 1978, as amended at 46
the correct label. FR 56412, Nov. 17, 1981; 60 FR 4091, Jan. 20,
(b) A representative sample of units 1995]
shall be collected at the completion of
finishing operations and shall be vis-
ually examined for correct labeling.
Subpart H—Holding and
(c) Results of these examinations Distribution
shall be recorded in the batch produc-
§ 211.142 Warehousing procedures.
tion or control records.
Written procedures describing the
§ 211.137 Expiration dating. warehousing of drug products shall be
(a) To assure that a drug product established and followed. They shall in-
meets applicable standards of identity, clude:
strength, quality, and purity at the (a) Quarantine of drug products be-
time of use, it shall bear an expiration fore release by the quality control
date determined by appropriate sta- unit.
bility testing described in § 211.166. (b) Storage of drug products under
(b) Expiration dates shall be related appropriate conditions of temperature,
to any storage conditions stated on the humidity, and light so that the iden-
labeling, as determined by stability tity, strength, quality, and purity of
studies described in § 211.166. the drug products are not affected.
(c) If the drug product is to be recon-
stituted at the time of dispensing, its
labeling shall bear expiration informa-
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§ 211.150 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS § 211.167
quality control unit shall be adequate available and are being conducted.
to assure that batches of drug products Where data from accelerated studies
meet each appropriate specification are used to project a tentative expira-
and appropriate statistical quality con- tion date that is beyond a date sup-
trol criteria as a condition for their ap- ported by actual shelf life studies,
proval and release. The statistical there must be stability studies con-
quality control criteria shall include ducted, including drug product testing
appropriate acceptance levels and/or at appropriate intervals, until the ten-
appropriate rejection levels. tative expiration date is verified or the
(e) The accuracy, sensitivity, speci- appropriate expiration date deter-
ficity, and reproducibility of test
mined.
methods employed by the firm shall be
(c) For homeopathic drug products,
established and documented. Such vali-
dation and documentation may be ac- the requirements of this section are as
complished in accordance with follows:
§ 211.194(a)(2). (1) There shall be a written assess-
(f) Drug products failing to meet es- ment of stability based at least on test-
tablished standards or specifications ing or examination of the drug product
and any other relevant quality control for compatibility of the ingredients,
criteria shall be rejected. Reprocessing and based on marketing experience
may be performed. Prior to acceptance with the drug product to indicate that
and use, reprocessed material must there is no degradation of the product
meet appropriate standards, specifica- for the normal or expected period of
tions, and any other relevant criteria. use.
(2) Evaluation of stability shall be
§ 211.166 Stability testing.
based on the same container-closure
(a) There shall be a written testing system in which the drug product is
program designed to assess the sta- being marketed.
bility characteristics of drug products. (d) Allergenic extracts that are la-
The results of such stability testing beled ‘‘No U.S. Standard of Potency’’
shall be used in determining appro- are exempt from the requirements of
priate storage conditions and expira- this section.
tion dates. The written program shall
be followed and shall include: [43 FR 45077, Sept. 29, 1978, as amended at 46
(1) Sample size and test intervals FR 56412, Nov. 17, 1981]
based on statistical criteria for each
attribute examined to assure valid esti- § 211.167 Special testing requirements.
mates of stability; (a) For each batch of drug product
(2) Storage conditions for samples re- purporting to be sterile and/or pyrogen-
tained for testing; free, there shall be appropriate labora-
(3) Reliable, meaningful, and specific tory testing to determine conformance
test methods; to such requirements. The test proce-
(4) Testing of the drug product in the dures shall be in writing and shall be
same container-closure system as that followed.
in which the drug product is marketed;
(b) For each batch of ophthalmic
(5) Testing of drug products for re-
ointment, there shall be appropriate
constitution at the time of dispensing
(as directed in the labeling) as well as testing to determine conformance to
after they are reconstituted. specifications regarding the presence of
(b) An adequate number of batches of foreign particles and harsh or abrasive
each drug product shall be tested to de- substances. The test procedures shall
termine an appropriate expiration date be in writing and shall be followed.
and a record of such data shall be (c) For each batch of controlled-re-
maintained. Accelerated studies, com- lease dosage form, there shall be appro-
bined with basic stability information priate laboratory testing to determine
on the components, drug products, and conformance to the specifications for
container-closure system, may be used the rate of release of each active ingre-
to support tentative expiration dates dient. The test procedures shall be in
provided full shelf life studies are not writing and shall be followed.
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§ 211.170 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS § 211.182
found when tested according to proce- tion. Records that can be immediately
dures specified in ‘Procedures for De- retrieved from another location by
tecting and Measuring Penicillin Con- computer or other electronic means
tamination in Drugs,’ which is incor- shall be considered as meeting the re-
porated by reference. Copies are avail- quirements of this paragraph.
able from the Division of Research and (d) Records required under this part
Testing (HFD–470), Center for Drug may be retained either as original
Evaluation and Research, Food and records or as true copies such as photo-
Drug Administration, 5001 Campus Dr., copies, microfilm, microfiche, or other
College Park, MD 20740, or available for accurate reproductions of the original
inspection at the National Archives records. Where reduction techniques,
and Records Administration (NARA). such as microfilming, are used, suit-
For information on the availability of able reader and photocopying equip-
this material at NARA, call 202–741– ment shall be readily available.
6030, or go to: http://www.archives.gov/ (e) Written records required by this
federallregister/ part shall be maintained so that data
codeloflfederallregulations/ therein can be used for evaluating, at
ibrllocations.html. least annually, the quality standards of
[43 FR 45077, Sept. 29, 1978, as amended at 47
each drug product to determine the
FR 9396, Mar. 5, 1982; 50 FR 8996, Mar. 6, 1985; need for changes in drug product speci-
55 FR 11577, Mar. 29, 1990; 66 FR 56035, Nov. 6, fications or manufacturing or control
2001; 69 FR 18803, Apr. 9, 2004; 81 FR 49897, procedures. Written procedures shall be
July 29, 2016] established and followed for such eval-
uations and shall include provisions
Subpart J—Records and Reports for:
(1) A review of a representative num-
§ 211.180 General requirements. ber of batches, whether approved or re-
(a) Any production, control, or dis- jected, and, where applicable, records
tribution record that is required to be associated with the batch.
maintained in compliance with this (2) A review of complaints, recalls,
part and is specifically associated with returned or salvaged drug products,
a batch of a drug product shall be re- and investigations conducted under
tained for at least 1 year after the expi- § 211.192 for each drug product.
ration date of the batch or, in the case (f) Procedures shall be established to
of certain OTC drug products lacking assure that the responsible officials of
expiration dating because they meet the firm, if they are not personally in-
the criteria for exemption under volved in or immediately aware of such
§ 211.137, 3 years after distribution of actions, are notified in writing of any
the batch. investigations conducted under
(b) Records shall be maintained for §§ 211.198, 211.204, or 211.208 of these reg-
all components, drug product con- ulations, any recalls, reports of
tainers, closures, and labeling for at inspectional observations issued by the
least 1 year after the expiration date Food and Drug Administration, or any
or, in the case of certain OTC drug regulatory actions relating to good
products lacking expiration dating be- manufacturing practices brought by
cause they meet the criteria for exemp- the Food and Drug Administration.
tion under § 211.137, 3 years after dis- [43 FR 45077, Sept. 29, 1978, as amended at 60
tribution of the last lot of drug product FR 4091, Jan. 20, 1995]
incorporating the component or using
the container, closure, or labeling. § 211.182 Equipment cleaning and use
(c) All records required under this log.
part, or copies of such records, shall be A written record of major equipment
readily available for authorized inspec- cleaning, maintenance (except routine
tion during the retention period at the maintenance such as lubrication and
establishment where the activities de- adjustments), and use shall be included
scribed in such records occurred. These in individual equipment logs that show
records or copies thereof shall be sub- the date, time, product, and lot number
ject to photocopying or other means of of each batch processed. If equipment
reproduction as part of such inspec- is dedicated to manufacture of one
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§ 211.184 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS § 211.194
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§ 211.196 21 CFR Ch. I (4–1–21 Edition)
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Food and Drug Administration, HHS Pt. 212
whichever is longer. In the case of cer- turn, quantity returned, date of dis-
tain OTC drug products lacking expira- position, and ultimate disposition of
tion dating because they meet the cri- the returned drug product. If the rea-
teria for exemption under § 211.137, such son for a drug product being returned
written records shall be maintained for implicates associated batches, an ap-
3 years after distribution of the drug propriate investigation shall be con-
product. ducted in accordance with the require-
(1) The written record shall include ments of § 211.192. Procedures for the
the following information, where
holding, testing, and reprocessing of re-
known: the name and strength of the
turned drug products shall be in writ-
drug product, lot number, name of
complainant, nature of complaint, and ing and shall be followed.
reply to complainant.
§ 211.208 Drug product salvaging.
(2) Where an investigation under
§ 211.192 is conducted, the written Drug products that have been sub-
record shall include the findings of the jected to improper storage conditions
investigation and followup. The record including extremes in temperature, hu-
or copy of the record of the investiga- midity, smoke, fumes, pressure, age, or
tion shall be maintained at the estab- radiation due to natural disasters,
lishment where the investigation oc- fires, accidents, or equipment failures
curred in accordance with § 211.180(c). shall not be salvaged and returned to
(3) Where an investigation under the marketplace. Whenever there is a
§ 211.192 is not conducted, the written question whether drug products have
record shall include the reason that an been subjected to such conditions, sal-
investigation was found not to be nec-
vaging operations may be conducted
essary and the name of the responsible
only if there is (a) evidence from lab-
person making such a determination.
oratory tests and assays (including ani-
[43 FR 45077, Sept. 29, 1978, as amended at 51 mal feeding studies where applicable)
FR 24479, July 3, 1986; 68 FR 15364, Mar. 31, that the drug products meet all appli-
2003]
cable standards of identity, strength,
quality, and purity and (b) evidence
Subpart K—Returned and from inspection of the premises that
Salvaged Drug Products the drug products and their associated
§ 211.204 Returned drug products. packaging were not subjected to im-
proper storage conditions as a result of
Returned drug products shall be iden- the disaster or accident. Organoleptic
tified as such and held. If the condi- examinations shall be acceptable only
tions under which returned drug prod-
as supplemental evidence that the drug
ucts have been held, stored, or shipped
products meet appropriate standards of
before or during their return, or if the
identity, strength, quality, and purity.
condition of the drug product, its con-
tainer, carton, or labeling, as a result Records including name, lot number,
of storage or shipping, casts doubt on and disposition shall be maintained for
the safety, identity, strength, quality drug products subject to this section.
or purity of the drug product, the re-
turned drug product shall be destroyed PART 212—CURRENT GOOD MAN-
unless examination, testing, or other UFACTURING PRACTICE FOR
investigations prove the drug product POSITRON EMISSION TOMOG-
meets appropriate standards of safety,
identity, strength, quality, or purity. A
RAPHY DRUGS
drug product may be reprocessed pro-
vided the subsequent drug product Subpart A—General Provisions
meets appropriate standards, specifica- Sec.
tions, and characteristics. Records of 212.1 What are the meanings of the tech-
returned drug products shall be main- nical terms used in these regulations?
tained and shall include the name and 212.2 What is current good manufacturing
label potency of the drug product dos- practice for PET drugs?
age form, lot number (or control num- 212.5 To what drugs do the regulations in
ber or batch number), reason for the re- this part apply?
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