Page 1 of 84

GMP COMPARISON
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
PART 111--CURRENT GOOD
MANUFACTURING PRACTICE
IN MANUFACTURING,
PACKING, OR HOLDING
DIETARY INGREDIENTS AND
DIETARY SUPPLEMENTS
Subpart A--General Provisions
111.1 Who is subject to these
regulations? You are subject to
the regulations in this part if you
manufacture, package, or hold a
dietary ingredient or dietary
supplement.
111.2 What are these
regulations intended to
accomplish?
The regulations in this part establish
the minimum current good
manufacturing practices that you
must use to the extent that you
manufacture, package, or hold a
dietary ingredient or dietary
supplement.
210.3 Definitions.
(a) The definitions and interpretations
contained in section 201 of the act shall be
applicable to such terms when used in this
part and in parts 211 through 226 of this
chapter.
(b) The following definitions of terms apply
to this part and to parts 211 through 226 of
this chapter.
110.3 Definitions
The definitions and interpretations of
terms in section 201 of the Federal
Food, Drug, and Cosmetic Act (the
act) are applicable to such terms
when used in this part. The following
definitions shall also apply:
Definitions
The definitions and interpretations of
terms in section 201 of the Federal
Food, Drug, and Cosmetic Act (the
act) are applicable to such terms when
used in this part. The following
definitions shall also apply:
111.3 What definitions apply to
this Part?
The definitions and interpretations of
terms in section 201 of the Federal
Food, Drug, and Cosmetic Act (the
act) apply to such terms when used
in these regulations. For the
purpose of these regulations, the
following definitions also apply:
(20) Acceptance criteria means the
product specifications and
acceptance/rejection criteria, such as
acceptable quality level and unacceptable
quality level, with an associated sampling
plan, that are necessary for making a
decision to accept or reject a lot or batch
(or any other convenient subgroups of
manufactured units).
(a) Acid foods or acidified foods
means foods that have an
equilibrium pH of 4.6 or below.
(1) Act means the Federal Food, Drug, and
Cosmetic Act, as amended (21 U.S.C. 301
et seq.).
(7) Active ingredient means any
component that is intended to furnish
pharmacological activity or other direct
effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease, or to
affect the structure or any function of the
body of man or other animals. The term
includes those components that may
undergo chemical change in the
manufacture of the drug product and be
present in the drug product in a modified
form intended to furnish the specified
activity or effect.
Page 2 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(18) Actual yield means the quantity that is
actually produced at any appropriate phase
of manufacture, processing, or packing of a
particular drug product.
Actual yield means the quantity that
is actually produced at any
appropriate step of manufacture or
packaging of a particular dietary
ingredient or dietary supplement.
(b) Adequate means that which is
needed to accomplish the intended
purpose in keeping with good public
health practice.
(a) "Adequate" means that which is
needed to accomplish the intended
purpose in keeping with good public
health practice.
(2) Batch means a specific quantity of a
drug or other material that is intended to
have uniform character and quality, within
specified limits, and is produced according
to a single manufacturing order during the
same cycle of manufacture.
(b) "Batch or Lot" means a specific
quantity of a finished product or other
material that is intended to have
uniform character and quality, within
specified limits, and is produced
according to a single manufacturing
order during the same cycle of
manufacture.
Batch means a specific quantity of a
dietary ingredient or dietary
supplement that is intended to meet
specifications for identity, purity,
quality, strength, and composition,
and is produced during a specified
time period according to a single
manufacturing record during the
same cycle of manufacture.
(11) Lot number, control number, or batch
number means any distinctive combination
of letters, numbers, or symbols, or any
combination of them, from which the
complete history of the manufacture,
processing, packing, holding, and
distribution of a batch or lot of drug product
or other material can be determined.
(j) "Lot number" means any
distinctive combination of letters,
numbers, or symbols, or any
combination of them from which the
complete history of the manufacture,
processing, packing, holding, and
distribution of a batch or lot of a
finished dietary ingredient, dietary
supplement or other material can be
determined.
Batch number, lot number, or
control number means any
distinctive group of letters,
numbers, or symbols, or any
combination of them, from which
the complete history of the
manufacturing, packaging, or
holding of a batch or lot of dietary
ingredients or dietary supplements
can be determined.
(c) Batter means a semifluid
substance, usually composed of
flour and other ingredients, into
which principal components of food
are dipped or with which they are
coated, or which may be used
directly to form bakery foods.
(d) Blanching, except for tree nuts
and peanuts, means a prepackaging
heat treatment of foodstuffs for a
sufficient time and at a sufficient
temperature to partially or
completely inactivate the naturally
occurring enzymes and to effect
other physical or bio-chemical
changes in the food.
(c) "Blanching" means a
prepackaging heat treatment of a
dietary product for a sufficient time
and at a sufficient temperature to
partially or completely inactivate the
naturally occurring enzymes and to
effect other physical or bio-chemical
changes in the product.
(3) Component means any ingredient
intended for use in the manufacture of a
drug product, including those that may not
appear in such drug product.
(q) "Raw material" means any
ingredient intended for use in the
manufacture of a dietary ingredient or
dietary supplement, including those
that may not appear in such finished
product.
Component means any substance
intended for use in the manufacture
of a dietary ingredient or dietary
supplement including those that
may not appear in the finished
dietary ingredient or dietary
supplement. Component includes
ingredients and dietary ingredients
as, described in section 20l(ff) of the
act.
(d) "Composition" means, as
appropriate:
(1) the identity of a dietary
ingredient or dietary supplement, and
(2) the concentration of a dietary
ingredient (e.g., weight or other unit of
use/weight or volume), or the potency
or activity of one or more dietary
ingredients, as indicated by
appropriate procedures.
Page 3 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
Consumer complaint means
communication that contains any
allegation, written or oral,
expressing dissatisfaction with the
quality of a dietary ingredient or a
dietary supplement related to good
manufacturing practices. Examples
of product quality related to good
manufacturing practices are: Foul
odor, off taste, super-potent,
subpotent, wrong ingredient, drug
contaminant, other contaminant
(e.g., bacteria, pesticide, mycotoxin,
glass, lead), disintegration time,
color variation, mycotoxin, glass,
lead), disintegration time, color
variation, tablet size or size
variation, under-filled container,
foreign material in a dietary
supplement container, improper
packaging, or mislabeling. For the
purposes of the regulations in this
part, a consumer complaint about
product quality may or may not
include concerns about a possible
hazard to health. However, a
consumer complaint does not
include an adverse event, illness, or
injury related to the safety of a
particular dietary ingredient
independent of whether the product
is produced under good
manufacturing practices.
(e) Critical control point means a
point in a food process where there
is a high probability that improper
control may cause, allow, or
contribute to a hazard or to filth in the
final food or decomposition of the
final food.
(e) "Dietary ingredient" means an
ingredient intended for use or used in
a dietary supplement that is:
(1) a vitamin,
(2) a mineral,
(3) an herb or other botanical,
(4) an amino acid,
(5) a dietary substance for use by
man to supplement the diet by
increasing the total dietary intake, or
(6) a concentrate, metabolite,
constituent, extract, or combination of
any of the foregoing ingredients.
(f) "Dietary product" means either a
dietary ingredient or dietary
supplement as defined in this part.
(g) "Dietary supplement" means
dietary supplement as defined in
section 201 (ff) of the act.
(4) Drug product means a finished dosage
form, for example, tablet, capsule, solution,
etc., that contains an active drug ingredient
generally, but not necessarily, in
association with inactive ingredients. The
term also includes a finished dosage form
that does not contain an active ingredient
but is intended to be used as a placebo.
Page 4 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(5) Fiber means any particulate
contaminant with a length at least three
times greater than its width.
(f) Food means food as defined in
section 201(f) of the act and includes
raw materials and ingredients.
(g) Food-contact surfaces are
those surfaces that contact human
food and those surfaces from which
drainage onto the food or onto
surfaces that contact the food
ordinarily occurs during the normal
course of operations. "Food-contact
surfaces" includes utensils and food-
contact surfaces of equipment.
Contact surface means any surface
that contacts a component, dietary
ingredient, dietary supplement, and
those surfaces from which drainage
onto the component, dietary
ingredient, dietary supplement, or
onto surfaces that contact the
component, dietary ingredient, or
dietary supplement ordinarily
occurs during the normal course of
operations. Examples of contact
surfaces include, but are not limited
to, containers, utensils, tables,
contact surfaces of equipment, and
packaging.
(22) Gang-printed labeling means labeling
derived from a sheet of material on which
more than one item of labeling is printed.
(8) Inactive ingredient means any
component other than an active ingredient.
Ingredient means any substance
that is used in the manufacture of a
dietary ingredient or dietary
supplement that is intended to be
present in the finished dietary
ingredient or
dietary supplement. An ingredient
includes, but is not necessarily
limited to, a dietary ingredient as
described in section 201(ff) of the
act.
(9) In-process material means any
material fabricated, compounded, blended,
or derived by chemical reaction that is
produced for, and used in, the preparation
of the drug product.
(h) "In-process material" means any
material fabricated, compounded,
blended, ground, extracted, sifted,
sterilized, derived by chemical
reaction or processed in any other
way that is produced for, and used in,
the preparation of a dietary product.
Inprocess material means any
material that is fabricated,
compounded, blended, ground,
extracted; sifted, sterilized, derived
by chemical reaction, or processed
in any other way for use in the
manufacture of a dietary ingredient
or dietary supplement.
(10) Lot means a batch, or a specific
identified portion of a batch, having uniform
character and quality within specified
limits; or, in the case of a drug product
produced by continuous process, it is a
specific identified amount produced in a
unit of time or quantity in a manner that
assures its having uniform character and
quality within specified limits.
(h) Lot means the food produced
during a period of time indicated by a
specific code.
(i) "Lot" means "batch" as defined in
this part.
Lot means a batch, or a specific
identified portion of a batch intended
to have uniform identity, purity,
quality, strength, and composition;
or, in the case of a dietary ingredient
or dietary supplement produced by
continuous process, a specific
identified amount produced in a
specified unit of time or quantity in a
manner that is intended to have
uniform identity, purity, quality,
strength, and composition.
(12) Manufacture, processing, packing, or
holding of a drug product includes
packaging and labeling operations, testing,
and quality control of drug products.
(k) "Manufacture" or "manufacturing"
includes all operations associated
with the production of dietary
products, including packaging and
labeling operations, testing, and
quality control of a dietary ingredient
or dietary supplement.
Page 5 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(13) The term medicated feed means any
Type B or Type C medicated feed as
defined in 558.3 of this chapter. The feed
contains one or more drugs as defined in
section 201(g) of the act. The manufacture
of medicated feeds is subject to the
requirements of part 225 of this chapter.
(14) The term medicated premix means a
Type A medicated article as defined in
558.3 of this chapter. The article contains
one or more drugs as defined in section
201(g) of the act. The manufacture of
medicated premixes is subject to the
requirements of part 226 of this chapter.
(i) Microorganisms means yeasts,
molds, bacteria, and viruses and
includes, but is not limited to,
species having public health
significance. The term "undesirable
microorganisms" includes those
microorganisms that are of public
health significance, that subject food
to decomposition, that indicate that
food is contaminated with filth, or
that otherwise may cause food to be
adulterated within the meaning of the
act. Occasionally in these
regulations, FDA used the adjective
"microbial" instead of using an
adjectival phrase containing the
word microorganism.
(l) "Microorganisms" means yeasts,
molds, bacteria, and viruses and
includes, but is not limited to, species
having public health significance. The
term "undesirable microorganisms"
includes those microorganisms that
are of public health significance, that
subject a dietary product to
decomposition, that indicate that a
dietary ingredient or dietary
supplement is contaminated with filth,
or that otherwise may cause a dietary
product to be adulterated within the
meaning of the act. Occasionally in
these regulations, the adjective
"microbial" is used instead of an
adjectival phrase containing the word
microorganism.
Microorganisms means yeasts,
molds, bacteria, viruses, and other
similar microscopic organisms
having public health or sanitary
concern. This definition includes,
but is not limited to, species that:
(1) Have public health significance;
(2) Could cause a component,
dietary ingredient, or dietary
supplement to decompose;
(3) Indicate that the component,
dietary ingredient, or dietary
supplement is contaminated with
filth; or
(4) Otherwise may cause the
component, dietary ingredient, or
dietary supplement to be
adulterated.
(p) Shall is used to state mandatory
requirements.
(u) "Shall" is used to state mandatory
requirements.
Must is used to state mandatory
requirements.
(6) Non-fiber-releasing filter means any
filter, which after any appropriate
pretreatment such as washing or flushing,
will not release fibers into the component
or drug product that is being filtered. All
filters composed of asbestos are deemed
to be fiber-releasing filters.
(19) Percentage of theoretical yield means
the ratio of the actual yield (at any
appropriate phase of manufacture,
processing, or packing of a particular drug
product) to the theoretical yield (at the
same phase), stated as a percentage.
(j) Pest refers to any objectionable
animals or insects including, but not
limited to, bird, rodents, flies, and
larvae.
(m) "Pest" refers to any objectionable
animals or insects including, but not
limited to, bird, rodents, flies, and
larvae.
Pest means any objectionable
insects or other animals including,
but not limited to, birds, rodents,
flies, mites, and larvae.
(k) Plant means the building or
facility or parts thereof, used for or in
connection with the manufacturing,
packaging, labeling, or holding of
human food.
(n) "Plant" means the building or
facility or parts thereof, used for or in
connection with the manufacturing,
packaging, labeling, or holding of a
dietary product.
Physical plant means all or parts of
a building or facility used for or in
connection with manufacturing,
packaging, or holding a dietary
ingredient or dietary supplement.
(l) Quality control operation means
a planned and systematic procedure
for taking all actions necessary to
prevent food from being adulterated
within the meaning of the act.
(o) "Quality control operation" means
a planned and systematic procedure
for taking all actions necessary to
prevent a dietary product from being
adulterated within the meaning of the
act.
Quality control means a planned
and systematic operation or
procedure for preventing a dietary
ingredient or dietary supplement
from being adulterated.
Page 6 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(15) Quality control unit means any person
or organizational element designated by
the firm to be responsible for the duties
relating to quality control.
(p) "Quality control unit" means any
person or organizational element
designated by the firm to be
responsible for the duties relating to
quality control operations.
Quality control unit means any
person or group that you designate
to be responsible for quality control
operations.
(21) Representative sample means a
sample that consists of a number of units
that are drawn based on rational criteria
such as random sampling and intended to
assure that the sample accurately portrays
the material being sampled.
(r) "Representative sample" means a
sample that consists of a number of
units that are drawn based on rational
criteria, such as random sampling,
and is intended to assure that the
sample accurately portrays the
material being sampled.
Representative sample means a
sample that consists of a number of
units that are drawn based on
rational criteria, such as random
sampling, and intended to ensure
that the sample accurately portrays
the material being sampled.
(m) Rework means clean,
unadulterated food that has been
removed from processing for
reasons other than insanitary
conditions or that has been
successfully reconditioned by
reprocessing and that is suitable for
use as food.
(s) "Rework" means clean,
unadulterated material that has been
removed from processing for reasons
other than insanitary conditions or that
has been successfully reconditioned
by reprocessing and that is suitable
for use in the manufacture of a dietary
product.
Reprocessing means using, in the
manufacture of a dietary ingredient
or a dietary supplement, clean,
unadulterated components, dietary
ingredients, or dietary supplements
that have been previously removed
from manufacturing for reasons
other than insanitary conditions and
that have been made suitable for
use in the manufacture of a diet any
ingredient or dietary supplement.
(n) Safe moisture level is a level of
moisture low enough to prevent the
growth of undesirable
microorganisms in the finished
product under the intended
conditions of manufacturing, storage,
and distribution. The maximum safe
moisture level for a food is based on
its water activity (aw). An aw will be
considered safe for food if adequate
data are available that demonstrate
that the food at or below the given aw
will not support growth of
undesirable microorganisms.
(o) Sanitize means to adequately
treat food-contact surfaces by a
process that is effective in
destroying vegetative cells of
microorganisms of public health
significance, and in substantially
reducing numbers of other
undesirable microorganisms, but
without adversely affecting the
product or its safety for the
consumer.
(t) "Sanitize" means to adequately
treat equipment, containers or
utensils by a process that is effective
in destroying vegetative cells of
microorganisms of public health
significance, and in substantially
reducing numbers of other
undesirable microorganisms, but
without adversely affecting the
product or its safety for the consumer.
Sanitize means to adequately treat
equipment, containers, utensils, or
any other dietary product contact
surface by applying cumulative heat
or chemicals on cleaned food
contact surfaces that when
evaluated for efficacy, yield a
reduction of 5 logs, which is equal to
99.999 percent reduction, of
representative disease
microorganisms of public health
significance and substantially
reduce the numbers of other
undesirable microorganisms, but
without adversely affecting the
product or its safety for the
consumer.
(q) Should is used to state
recommended or advisory
procedures or identify
recommended equipment.
(v) "Should" is used to state
recommended or advisory
procedures or identify recommended
equipment.
Page 7 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(16) Strength means:
(i) The concentration of the drug substance
(for example, weight/weight,
weight/volume, or unit dose/volume basis),
and/or
(ii) The potency, that is, the therapeutic
activity of the drug product as indicated by
appropriate laboratory tests or by
adequately developed and controlled
clinical data (expressed, for example, in
terms of units by reference to a standard).
(17) Theoretical yield means the quantity
that would be produced at any appropriate
phase of manufacture, processing, or
packing of a particular drug product, based
upon the quantity of components to be
used, in the absence of any loss or error in
actual production.
Theoretical yield means the quantity
that would be produced at any
appropriate step of manufacture or
packaging of a particular dietary
ingredient or dietary supplement,
based upon the quantity of
components or packaging to be
used; in the absence of any loss or
error in actual production.
(r) Water activity (aw) is a
measure of the free moisture in a
food and is the quotient of the water
vapor pressure of the substance
divided by the vapor pressure of
pure water at the same temperature.
(w) "Water activity (aw)" is a
measure of the free moisture in a
dietary ingredient or dietary
supplement and is the quotient of the
water vapor pressure of the
substance divided by the vapor
pressure of pure water at the same
temperature.
Water activity (a w ) is a measure of
the free moisture in a component,
dietary ingredient, or dietary
supplement and is the quotient of the
water vapor pressure of the
substance divided by the vapor
pressure of pure water at the same
temperature.
We means the United States Food
and Drug Administration (FDA).
You means a person who
manufactures, packages, or holds
dietary ingredients or dietary
supplements.
111.5 Do other statutory
provisions and regulations
apply?
In addition to the regulations in this
part, you must comply with other
applicable statutory provisions and
regulations under the act related to
the manufacturing, packaging, or
holding of dietary ingredients or
dietary supplements.
110.19 Exclusions
(a) The following operations are not
subject to this part: Establishments
engaged solely in the harvesting,
storage, or distribution of one or
more "raw agricultural
commodities," as defined in section
201(r) of the act, which are
ordinarily cleaned, prepared, treated,
or otherwise processed before being
marketed to the consuming public.
(b) FDA, however, will issue
special regulations if it is necessary
to cover these excluded operations.
Exclusions
The following operations are not
subject to this part: Establishments
engaged solely in the harvesting,
storage, or distribution of one or more
"raw agricultural commodities," as
defined in section 201(r) of the act,
which are ordinarily cleaned,
prepared, treated, or otherwise
processed before being marketed to
the consuming public.
111.6 Exclusions. The
regulations in this part do not apply
to a person engaged solely in
activities related to the harvesting,
storage, or distribution of raw
agricultural commodities that will
be incorporated into a dietary
ingredient or dietary supplement by
other persons.
Page 8 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.28 Personnel responsibilities.
(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.
110.10 Personnel
The plant management shall take all
reasonable measures and
precautions to ensure the following:
(a) Disease control. Any person
who, by medical examination or
supervisory observation, is shown to
have, or appears to have, an illness,
open lesion, including boils, sores,
or infected wounds, or any other
abnormal source of microbial
contamination by which there is a
reasonable possibility of food, food-
contact surfaces, or food-packaging
materials becoming contaminated,
shall be excluded from any
operations which may be expected
to result in such contamination until
the condition is corrected.
Personnel shall be instructed to
report such health conditions to their
supervisors.
Personnel

The plant management shall take all
reasonable measures and
precautions to assure the following:
(a) Disease control. Any person
who, by medical examination or
supervisory observation, is shown to
have, or appears to have, an illness,
open lesion, including boils, sores, or
infected wounds, or any other
abnormal source of microbial
contamination by which there is a
reasonable possibility of an in-
process or finished dietary product
becoming adulterated, or processing
equipment, utensils or packaging
materials becoming contaminated,
shall be excluded from any operations
which may be expected to result in
such adulteration or contamination
until the condition is corrected.
Personnel shall be instructed to report
such health conditions to their
supervisors.
Subpart B--Personnel
111.10 What microbial
contamination and hygiene
requirements apply?
(a) Microbial contamination. You
must take measures to exclude
from any operations any person
who might be a source of microbial
contamination of any material
including components, dietary
ingredients, dietary supplements,
and contact surfaces used in the
manufacture, packaging, or holding
of a dietary ingredient or a dietary
supplement. Such measures
include, but are not limited to, the
following:
(1) Excluding any person who, by
medical examination or supervisory
observation, is shown to have, or
appears to have an illness, open
lesion, or any other abnormal
source of microbial contamination,
which may be expected to result in
microbial contamination of
components, dietary ingredients,
dietary supplements, or contact,
surfaces, from working in any
operations until the condition is
corrected; and
(2) Instructing your employees to
notify their supervisor(s) if they
have or if there is a reasonable
possibility that they have a health
condition, described in paragraph
(a) (1) of this section that could
contaminate any components,
dietary ingredients, dietary
supplements, or any contact
surface.
(b) Cleanliness. All persons
working in direct contact with food,
food-contact surfaces, and food-
packaging materials shall conform
to hygienic practices while on duty to
the extent necessary to protect
against contamination of food. The
methods for maintaining cleanliness
include, but are not limited to:
(b) Cleanliness. All persons working
in direct contact with raw materials,
in-process or finished dietary
products, processing equipment,
utensils or packaging materials shall
conform to hygienic practices while
on duty to the extent necessary to
protect against adulteration or
contamination of such materials. The
methods for maintaining cleanliness
include, but are not limited to:
(b) Hygienic Practices. If you work
in operations during which
adulteration of the component,
dietary ingredients, dietary
supplement, or contact surface may
occur, you must use hygienic
practices to the extent necessary to
protect against contamination of
components, dietary ingredients,
dietary supplements, or contact
surfaces. The hygienic practices
include, but are not limited to:
(a) Personnel engaged in the manufacture,
processing, packing, or holding of a drug
product shall wear clean clothing
appropriate for the duties they perform
(1) Wearing outer garments
suitable to the operation in a manner
that protects against the
contamination of food, food-contact,
surfaces or food-packaging
materials.
(1) Wearing outer garments
suitable to the operation in a manner
that protects against the adulteration
of in-process or finished dietary
products, or contamination of
processing equipment, utensils or
packaging materials.
(1) Wearing outer garments in a
manner that protects against the
contamination of components,
dietary ingredients, dietary
supplements, or any contact
surface;
(b) Personnel shall practice good
sanitation and health habits.
(2) Maintaining adequate personal
cleanliness
(2) Maintaining adequate personal
cleanliness.
(2) Maintaining adequate personal,
cleanliness;
Page 9 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(3) Washing hands thoroughly (and
sanitizing if necessary to protect
against contamination with
undesirable microorganisms) in an
adequate hand-washing facility
before starting work, after each
absence from the work station, and
at any other time when the hands
may have become soiled or
contaminated.
(3) Washing hands thoroughly (and
sanitizing if necessary to protect
against contamination with
undesirable microorganisms) in an
adequate hand-washing facility before
starting work, after each absence
from the work station, and at any
other time when the hands may have
become soiled or contaminated.
(3) Washing hands thoroughly (and,
sanitizing if necessary to protect
against contamination with
microorganisms) in an adequate
hand-washing facility:
(i) Before starting work; and
(ii) At any time when the hands may
have become soiled or
contaminated;
(4) Removing all unsecured
jewelry and other objects that might
fall into food, equipment, or
containers, and removing hand
jewelry that cannot be adequately
sanitized during periods in which
food is manipulated by hand. If such
hand jewelry cannot be removed, it
may be covered by material which
can be maintained in an intact, clean,
and sanitary condition and which
effectively protects against the
contamination by these objects of the
food, food-contact surfaces, or food-
packaging materials.
(4) Removing all unsecured
jewelry and other objects that might
fall into raw materials, in-process or
finished dietary product, equipment,
or containers, and removing hand
jewelry that cannot be adequately
sanitized during periods in which in-
process or finished product is
manipulated by hand. If such hand
jewelry cannot be removed, it may be
covered by material which can be
maintained in an intact, clean, and
sanitary condition and which
effectively protects against the
adulteration of dietary products or
contamination of processing
equipment, utensils or packaging
materials.
(4) Removing all unsecured jewelry
and other objects that might fall into
components, dietary ingredients,
dietary supplements, equipment, or
packaging, and removing hand
jewelry that cannot be adequately
sanitized during periods in which
components, dietary ingredients, or
dietary supplements are
manipulated by hand. If hand
jewelry cannot be removed, it must
be covered by material that is
maintained in an intact, clean, and
sanitary condition and that
effectively protects against
contamination of components,
dietary ingredients, dietary
supplements, or contact surfaces;
(5) Maintaining gloves, if they are
used in food handling, in an intact,
clean, and sanitary condition. The
gloves should be of an impermeable
material.
(5) Maintaining gloves, if they are
used in in-process or finished product
handling, in an intact, clean, and
sanitary condition. The gloves should
be of a material that adequately
protects the product from
contamination.
(5) Maintaining gloves used in
handling components, dietary
ingredients, or dietary supplements
in an intact, clean, and sanitary
condition. The gloves must be of an
impermeable material;
(a)Protective apparel, such as head,
face, hand, and arm coverings, shall be
worn as necessary to protect drug
products from contamination.
(6) Wearing, where appropriate, in
an effective manner, hair nets,
headbands, caps, beard covers, or
other effective hair restraints.
(6) Wearing, where appropriate, in
an effective manner, hair nets, caps,
beard covers, or other effective hair
restraints.
(6) Wearing, where appropriate, in
an effective manner, hairnets, caps,
beard covers, or other effective hair
restraints;
(7) Storing clothing or other
personal belongings in areas other
than where food is exposed or where
equipment or utensils are washed.
(7) Storing clothing or other
personal belongings in areas other
than where in-process or finished
product is exposed or where
processing equipment or utensils are
washed.
(7) Not storing clothing or other
personal belongings in areas where
components, dietary ingredients, or
dietary supplements or any contact
surfaces are exposed or where
contact surfaces are washed;
(8) Confining the following to areas
other than where food may be
exposed or where equipment or
utensils are washed: eating food,
chewing gum, drinking beverages,
or using tobacco.
(8) Confining the following to areas
other than where in-process or
finished product may be stored or
exposed, or where processing
equipment or utensils are washed:
eating food, chewing gum, drinking
beverages, or using tobacco.
(8) Not eating food, chewing gum,
drinking beverages and using
tobacco products in areas, where
components, dietary ingredients,
dietary supplements, or any contact
surfaces are exposed, or where
contact surfaces are washed; and
(9) Taking any other necessary
precautions to protect against
contamination of food, food-contact,
surfaces, or food-packaging
materials with micro-organisms or
foreign substances including, but not
limited to, perspiration, hair,
cosmetics, tobacco, chemicals, and
medicines applied to the skin.
(9) Taking any other necessary
precautions to protect against
adulteration of raw materials, in-
process or finished product, or
contamination of processing
equipment, utensils or packaging
materials with micro-organisms or
foreign substances including, but not
limited to, perspiration, hair,
cosmetics, tobacco, chemicals, and
medicines applied to the skin.
(9) Taking any other precautions
necessary to protect against the
contamination of components,
dietary ingredients, dietary
supplements, or contact surfaces
with microorganisms, filth, or any
other extraneous materials,
including, but not limited to,
perspiration, hair, cosmetics,
tobacco, chemicals, and medicines
applied to the skin.
Page 10 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(c) Only personnel authorized by
supervisory personnel shall enter those
areas of the buildings and facilities
designated as limited-access areas.
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.
(c) Education and training.
Personnel responsible for identifying
sanitation failures or food
contamination should have a
background of education or
experience, or a combination
thereof, to provide a level of
competency necessary for
production of clean and safe food.
Food handlers and supervisors
should receive appropriate training
in proper food handling techniques
and food-protection principles and
should be informed of the danger of
poor personal hygiene and insanitary
practices.
(c) Education and training. Each
person engaged in the manufacture of
a dietary product should have the
proper education, training, and
experience (or any combination
thereof) needed to perform the
assigned functions. Training should
be in the particular operation(s) that
the employee performs as they relate
to the employee's functions.
Appropriate documentation of training
shall be retained by the manufacturer.
111.12 What personnel
qualification requirements
apply?
(a) You must have qualified
employees to manufacture,
package, or hold dietary ingredients
or dietary supplements; and
(b) Each person engaged in
manufacturing, packaging, or
holding must have the training and
experience to perform the person's
duties.
(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.
(d) Supervision. Responsibility for
assuring compliance by all
personnel with all requirements of
this part shall be clearly assigned to
competent supervisory personnel.
d) Supervision. Responsibility for
assuring compliance by all personnel
with all requirements of this part shall
be clearly assigned to qualified
personnel with proper education,
training and experience (or any
combination thereof).
111.13 What supervisor
requirements apply?
(a) You must assign qualified
personnel to supervise the
manufacturing, packaging, or
holding of dietary ingredients and
dietary supplements.
(b) You and the supervisors you use
must be qualified by training and
experience to supervise.
(c) There shall be an adequate number of
qualified personnel to perform and
supervise the manufacture, processing,
packing, or holding of each drug product.
Page 11 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
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.
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.
110.35 Sanitary operations.
(a) General maintenance. Buildings,
fixtures, and other physical facilities
of the plant shall be maintained in a
sanitary condition and shall be kept
in repair sufficient to prevent food
from becoming adulterated within
the meaning of the act....
Sanitation of Buildings and
Facilities
(a) General maintenance. Buildings,
fixtures, and other physical facilities
of the plant shall be maintained in a
sanitary condition and shall be kept in
repair sufficient to prevent raw
materials, in-process or finished
dietary products from becoming
adulterated within the meaning of the
act.
Subpart C--Physical Plant
111.15 What sanitation
requirements apply to your
physical plant?
(a) Physical plant facilities.
(1) You must maintain your
physical plant in a clean and
sanitary condition; and
(2) You must keep your physical
plant in repair sufficient to prevent
components, dietary ingredients,
dietary supplements or contact
surfaces from becoming
contaminated.
211.56 Sanitation.
(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.
(b) Substances used in cleaning and
sanitizing; storage of toxic materials.
(1) Cleaning compounds and
sanitizing agents used in cleaning
and sanitizing procedures shall be
free from undesirable
microorganisms and shall be safe
and adequate under the conditions of
use.
(b) Cleaning and sanitizing
materials.
(1) Cleaning compounds and
sanitizing agents used in cleaning and
sanitizing procedures shall be free
from undesirable microorganisms
and shall be safe and adequate under
the conditions of use.
(b) Cleaning compounds. sanitizing
agents. and pesticides.
(1) You must use cleaning
compounds and sanitizing agents
that are free from microorganisms
of public health significance and
safe and adequate under the
conditions of use.
Compliance with this requirement
may be verified by any effective
means including purchase of these
substances under a supplier's
guarantee or certification, or
examination of these substances for
contamination.
Compliance with this requirement
may be verified by any effective
means including purchase of these
substances under a supplier's
guarantee or certification, or
examination of these substances for
contamination.
Page 12 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
Only the following toxic materials
may be used or stored in a plant
where food is processed or exposed:
(i) Those required to maintain
clean and sanitary conditions;
(ii) Those necessary for use in
laboratory testing procedures;
(iii) Those necessary for plant and
equipment maintenance and
operation; and
(iv) Those necessary for use in the
plant's operations.
Only the following toxic materials
may be used or stored in a plant
where product is processed or
exposed:
(i) Those required to maintain
clean and sanitary conditions;
(ii) Those necessary for use in
laboratory testing procedures;
(iii) Those necessary for plant and
equipment maintenance and
operation; and
(iv) Those necessary for use in the
plant's operations.
(2) You must not use or hold toxic
materials in a physical plant in
which contact surfaces,
components, dietary ingredients, or
dietary supplements are
manufactured or exposed, unless
those materials are necessary:
(i) To maintain clean and sanitary
conditions;
(ii) For use in, laboratory testing
procedures;
(iii) For maintaining or operating the
physical plant or equipment; or
(iv) For use in the plant's
operations.
211.56 Sanitation.
(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.
(2) Toxic cleaning compounds,
sanitizing agents, and pesticide
chemicals shall be identified, held,
and stored in a manner that protects
against contamination of food, food-
contact surfaces, or food-packaging
materials.
(2) Toxic cleaning compounds,
sanitizing agents, and pesticide
chemicals shall be identified, used,
held, and stored in a manner that
protects against adulteration of raw
materials, in-process or finished
product, or contamination of
processing equipment or packaging
materials.
(3) You must identify and hold toxic
cleaning compounds, sanitizing
agents, pesticides, and pesticide
chemicals in a manner that protects
against contamination of
components, dietary ingredients,
dietary supplements, or contact
surfaces.
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).
All relevant regulations promulgated
by other Federal, State, and local
government agencies for the
application, use or holding of these
products should be followed.
All relevant regulations promulgated
by other Federal, State, and local
government agencies for the
application, use or holding of these
products should be followed.
Rodenticides, insecticides, and
fungicides should be registered and
used in accordance with the Federal
Insecticide, Fungicide, and
Rodenticide Act.
(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.
Page 13 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(c) Pest control. No pests shall be
allowed in any area of a food plant.
Guard or guide dogs may be allowed
in some areas of a plant if the
presence of the dogs is unlikely to
result in contamination of food, food-
contact surfaces, or food-packaging
materials. Effective measures shall
be taken to exclude pests from the
processing areas and to protect
against the contamination of food on
the premises by pests. The use of
insecticides or rodenticides is
permitted only under precautions
and restrictions that will protect
against the contamination of food,
food-contact surfaces, and food-
packaging materials.
(c) Pest control. No pests shall be
allowed in any area of a dietary
product manufacturing plant.
Effective measures shall be taken to
exclude pests from the processing
areas and to protect against the
adulteration of product on the
premises by pests. The use of
insecticides or rodenticides is
permitted only under precautions and
restrictions that will protect against
the adulteration of raw materials, in-
process or finished product, or
contamination of processing
equipment, utensils or packaging
materials.
(c) Pest control.
(1) You must not allow animals or
pests in any area of your physical
plant. Guard or guide dogs are
allowed in some areas of your
physical plant if the presence of the
dogs will not result in contamination
of components, dietary ingredients,
dietary supplements, or contact
surfaces;
(2) You must take effective
measures to exclude pests from the
physical plant and to protect against
contamination of components,
dietary ingredients, dietary
supplements, and contact surfaces
on the premises by pests; and
(3) You must not use insecticides,
fumigants, fungicides or
rodenticides, unless you take
precautions to protect against the
contamination of components,
dietary ingredients, dietary
supplements, or contact surfaces.
Page 14 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
110.37 Sanitary facilities and
controls.
Each plant shall be equipped with
adequate sanitary facilities and
accommodations including, but not
limited to:
(a) Water supply. The water supply
shall be sufficient for the operations
intended and shall be derived from
an adequate source. Any water that
contacts food or food-contact
surfaces shall be safe and of
adequate sanitary quality. Running
water at a suitable temperature, and
under pressure as needed, shall be
provided in all areas where required
for the processing of food, for the
cleaning of equipment, utensils, and
food-packaging materials, or for
employee sanitary facilities.
(d) Water supply. Potable water at a
suitable temperature, and under
pressure as needed, shall be provided
in all areas where required for the
processing of dietary products, for the
cleaning of processing equipment,
utensils, and packaging materials, or
for employee sanitary facilities. Any
water that contacts in-process or
finished dietary products, utensils or
processing equipment shall meet the
standards prescribed in the
Environmental Protection Agency's
Primary Drinking Water Regulations
(40 CFR Part 141).
(d) Water supply.
(1) You must provide water that is
safe and of adequate sanitary
quality, at suitable temperatures,
and under pressure as needed, in all
areas where water is necessary for:
(i) Manufacturing dietary
ingredients or dietary supplements;
(ii) Making ice that comes in
contact with components, dietary
ingredients, dietary supplements or
contact surfaces;
(iii) Cleaning any surface; and
(iv) Employee bathrooms and hand-
washing facilities.
(2) Water that contacts
components, dietary ingredients,
dietary supplements, or any contact
surface must at a minimum comply
with the National Primary Drinking
Water regulations prescribed by the
Environmental Protection Agency
under 40 CFR part 141 and any
state and local government
requirements;
(3) You must have documentation
or otherwise be able to show that
water that contacts components,
dietary ingredients, dietary
supplements, or any contact surface
meets the requirements in
paragraph (d) (2) of this section.
Page 15 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(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.
(b) Plumbing. Plumbing shall be of
adequate size and design and
adequately installed and maintained
to:
(1) Carry sufficient quantities of
water to required locations
throughout the plant.
(2) Properly convey sewage and
liquid disposable waste from the
plant.
(3) Avoid constituting a source of
contamination to food, water
supplies, equipment, or utensils or
creating an unsanitary condition.
(4) Provide adequate floor drainage
in all areas where floors are subject
to flooding-type cleaning or where
normal operations release or
discharge water or other liquid
waste on the floor.
(5) Provide that there is not
backflow from, or cross-connection
between, piping systems that
discharge waste water or sewage
and piping systems that carry water
for food or food manufacturing.
(e) Plumbing. Plumbing shall be of
adequate size and design and
adequately installed and maintained
to:
(1) Carry sufficient quantities of
water to required locations throughout
the plant.
(2) Properly convey sewage and
liquid disposable waste from the
plant.
(3) Avoid constituting a source of
adulteration to product, or
contamination of water supplies,
processing equipment, or utensils or
creating an unsanitary condition.
(4) Provide adequate floor drainage
or other appropriate means of water
removal in all areas where floors are
subject to flooding-type cleaning or
where normal operations release or
discharge water or other liquid waste
on the floor.
(5) Provide that there is not
backflow from, or cross-connection
between, piping systems that
discharge waste water or sewage and
piping systems that carry water used
for the manufacture of dietary
products.
(e) Plumbing. The plumbing in your
physical plant must be of an
adequate size and design and be
adequately installed and maintained
to:
(1) Carry sufficient amounts of
water to required locations
throughout the physical plant;
(2) Properly convey sewage and
liquid disposable waste from your
physical plant;
(3) Avoid being a source of
contamination to components,
dietary ingredients, dietary
supplements, water supplies, or any
contact surface, or creating an
unsanitary condition;
(4) Provide adequate floor drainage
in all areas where floors are subject
to flooding-type cleaning or where
normal operations release or
discharge water or other liquid
waste on the floor; and
(5) Not allow backflow from, or
cross connection between, piping
systems that discharge waste water
or sewage and piping systems that
carry water used for manufacturing
dietary ingredients or dietary
supplements, for cleaning contact
surfaces, or for use in bathrooms or
hand-washing facilities.
Page 16 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(c) Sewage disposal. Sewage
disposal shall be made into an
adequate sewerage system or
disposed of through other adequate
means.
(f) Sewage disposal. Sewage
disposal shall be made into an
adequate sewerage system or
disposed of through other adequate
means.
(f) Sewage disposal. You must
dispose of sewage into an adequate
sewage system or through other
adequate means.
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 accessible to working areas.
(d) Toilet facilities. Each plant
shall provide its employees with
adequate, readily accessible toilet
facilities. Compliance with this
requirement may be accomplished
by:
(1) Maintaining the facilities in a
sanitary condition.
(2) Keeping the facilities in good
repair at all times.
(3) Providing self-closing doors.
(4) Providing doors that do not open
into areas where food is exposed to
airborne contamination, except
where alternate means have been
taken to protect against such
contamination (such as double doors
or positive air-flow systems).
(g) Toilet facilities. Each plant shall
provide its employees with adequate,
readily accessible toilet facilities.
Compliance with this requirement
may be accomplished by:
(1) Maintaining the facilities in a
sanitary condition.
(2) Keeping the facilities in good
repair at all times.
(3) Providing self-closing doors.
(4) Providing doors that do not open
into areas where dietary product is
exposed to airborne contamination,
except where alternate means have
been taken to protect against such
contamination (such as double doors
or positive air-flow systems).
(g) Bathrooms. You must provide
your employees with adequate,
readily accessible bathrooms. The
bathrooms must be kept clean and
must not become a potential source
of
contamination to components,
dietary ingredients, dietary
supplements, or contact surfaces.
You must:
(1) Keep the bathrooms in good
repair at all times;
(2) Provide self-closing doors; and
(3) Provide doors that do not open
into areas where components,
dietary ingredients, dietary
supplements, or contact surfaces
are exposed to airborne
contamination except where
alternate means have been taken to
protect against contamination (such
as double doors or positive airflow
systems).
Page 17 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(e) Hand-washing facilities. Hand-
washing facilities shall be adequate
and convenient and be furnished with
running water at a suitable
temperature. Compliance with this
requirement may be accomplished
by providing:
(1) Hand-washing and, where
appropriate, hand-sanitizing facilities
at each location in the plant where
good sanitary practices require
employees to wash and/or sanitize
their hands.
(2) Effective hand-cleaning and
sanitizing preparations.
(3) Sanitary towel service or
suitable drying devices.
(4) Devices or fixtures, such as
water control valves, so designed
and constructed to protect against
recontamination of clean, sanitized
hands.
(5) Readily understandable signs
directing employees handling
unprotected food, unprotected food-
packaging materials, food-contact
surfaces to wash and, where
appropriate, sanitize their hands
before they start work, after each
absence from post of duty, and when
their hands may have become soiled
or contaminated. These signs may
be posted in the processing room(s)
and in all other areas where
employees may handle such food,
materials, or surfaces.
(6) Refuse receptacles that are
constructed and maintained in a
manner that protects against
contamination of food.
(h) Hand-washing facilities. Hand-
washing facilities shall be adequate
and convenient and be furnished with
running water at a suitable
temperature. Compliance with this
requirement may be accomplished by
providing:
(1) Hand-washing and, where
appropriate, hand-sanitizing facilities
at each location in the plant where
good sanitary practices require
employees to wash and/or sanitize
their hands.
(2) Effective hand-cleaning and
sanitizing preparations.
(3) Air driers, sanitary towel
service or suitable drying devices.
(4) Devices or fixtures, such as
water control valves, so designed and
constructed to protect against
recontamination of clean, sanitized
hands.
(5) Readily understandable signs
directing employees handling
unprotected product, packaging
materials, utensils or processing
equipment to wash and, where
appropriate, sanitize their hands
before they start work, after each
absence from post of duty, and when
their hands may have become soiled
or contaminated. These signs may
be posted in the processing room(s)
and in all other areas where
employees may handle such
products, materials, utensils or
equipment.
(6) Refuse receptacles that are
constructed and maintained in a
manner that protects against
adulteration of dietary products.
(h) Hand-washing facilities. You
must provide hand-washing
facilities that are adequate,
convenient, and furnish running
water at a suitable temperature. You
must do this by providing:
(1) Hand-washing and, where
appropriate, hand-sanitizing
facilities at each location in your
physical plant where good hygienic
practices require employees to
wash or to sanitize or both wash
and sanitize their hands;
(2) Effective hand-cleaning and
sanitizing preparations;
(3) Air driers, sanitary towel
service, such as disposable paper
towels, or other suitable drying
devices;
(4) Devices or fixtures, such as
water control valves, designed and
constructed to protect against
recontamination of clean, sanitized
hands;
(5) Signs that are easy to
understand and are posted
throughout the physical plant that
direct employees handling
components, dietary ingredients,
dietary supplements, or contact
surfaces to wash and, where
appropriate, to sanitize their hands
before they start work, after each
absence from their duty station, and
when their hands may have become
soiled or contaminated; and
(6) Trash bins that are constructed
and maintained in a manner to
protect against recontamination of
hands and contamination of
components, dietary ingredients;
dietary supplements, or any contact
surface.
Page 18 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(f) Rubbish and offal disposal.
Rubbish and any offal shall be so
conveyed, stored, and disposed of as
to minimize the development of
odor, minimize the potential for the
waste becoming an attractant and
harborage or breeding place for
pests, and protect against
contamination of food, food-contact
surfaces, water supplies, and ground
surfaces.
(i) Rubbish disposal. Rubbish shall
be so conveyed, stored, and disposed
of as to minimize the development of
odor, minimize the potential for the
waste becoming an attractant and
harborage or breeding place for pests,
and protect against adulteration of raw
materials, in-process or finished
dietary products, or contamination of
utensils, processing equipment, water
supplies, and ground surfaces.
(i) Trash disposal. You must
convey, store, and dispose of trash
to:
(1) Minimize the development of
odor;
(2) Minimize the potential for the
trash to attract, harbor, or become a
breeding place for pests;
(3) Protect against contamination of
components, dietary ingredients,
dietary supplements, any contact
surface, water supplies, and
grounds surrounding your physical
plant; and
(4) Control hazardous waste to
prevent contamination of
components, dietary ingredients,
dietary supplements, and contact
surfaces.
110.80 Processes and controls.
...Overall sanitation of the plant shall
be under the supervision of one or
more competent individuals
assigned responsibility for this
function...
(j) Supervision. Overall sanitation of
the plant shall be under the
supervision of one or more
individuals qualified by education,
experience and training (or any
combination thereof) assigned
responsibility for assuring that
sanitation procedures are
accomplished.
(j) Sanitation supervisors. You must
assign one or more employees to
supervise overall sanitation. These
supervisors must be qualified by
training and experience to develop
and supervise sanitation
procedures.
Page 19 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
Subpart B--Buildings and
Facilities
110.20 Plant and grounds.
(a) Grounds. The grounds about a
food plant under the control of the
operator shall be kept in a condition
that will protect against the
contamination of food. The methods
for adequate maintenance of grounds
include, but are not limited to:
(1) Properly storing equipment,
removing litter and waste, and
cutting weeds or grass within the
immediate vicinity of the plant
buildings or structures that may
constitute an attractant, breeding
place, or harborage for pests.
(2) Maintaining roads, yards, and
parking lots so that they do not
constitute a source of contamination
in areas where food is exposed.
(3) Adequately draining areas that
may contribute contamination to food
by seepage, foot-borne filth, or
providing a breeding place for pests.
(4) Operating systems for waste
treatment and disposal in an
adequate manner so that they do not
constitute a source of contamination
in areas where food is exposed. If
the plant grounds are bordered by
grounds not under the operator's
control and not maintained in the
manner described in paragraph
(a)(1) through (3) of this section,
care shall be exercised in the plant
by inspection, extermination, or
other means to exclude pests, dirt,
and filth that may be a source of food
contamination.
Plant and Grounds
(a) Grounds. The grounds about a
dietary product manufacturing plant
under the control of the operator shall
be kept in a condition that will protect
against the adulteration of dietary
products. The methods for adequate
maintenance of grounds include, but
are not limited to:
(1) Properly storing equipment,
removing litter and waste, and cutting
weeds or grass within the immediate
vicinity of the plant buildings or
structures that may constitute an
attractant, breeding place, or
harborage for pests.
(2) Maintaining roads, yards, and
parking lots so that they do not
constitute a source of adulteration in
areas where product is exposed.
(3) Adequately draining areas that
may contribute to product adulteration
by seepage, foot-borne filth, or
providing a breeding place for pests.
(4) Operating systems for waste
treatment and disposal in an adequate
manner so that they do not constitute
a source of adulteration in areas
where product is exposed. If the plant
grounds are bordered by grounds not
under the operator's control and not
maintained in the manner described
in paragraph (a)(1) through (3) of this
section, care shall be exercised in the
plant by inspection, extermination, or
other means to exclude pests, dirt,
and filth that may be a source of
product adulteration.
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) Plant construction and design.
Plant buildings and structures shall
be suitable in size, construction, and
design to facilitate maintenance and
sanitary operations for food-
manufacturing purposes. The plant
and facilities shall:
(b) Plant construction and design.
Plant buildings and structures shall be
suitable in size, construction, and
design to facilitate maintenance,
cleaning and sanitary operations for
dietary product manufacturing
purposes and to prevent mixups
between different raw materials and
products. The plant and facilities
shall:
111.20 What design and
construction requirements apply
to your physical plant?
Any physical plant you use in the
manufacture, packaging, or holding
of dietary ingredients or dietary
supplements must:
(a) Be suitable in size, construction,
and design to facilitate maintenance,
cleaning, and sanitizing 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.
(1) Provide sufficient space for
such placement of equipment and
storage of materials as is necessary
for the maintenance of sanitary
operations and the production of safe
food.
(1) Provide sufficient space for
such placement of equipment and
storage of materials as is necessary
for the prevention of mixups,
maintenance of sanitary operations
and the production of safe dietary
products.
(b) Have adequate space for the
orderly placement of equipment and
holding materials as is necessary
for maintenance, cleaning, and
sanitizing operations and to prevent
contamination and mixups of
components, dietary ingredients,
and dietary supplements during
manufacturing, packaging, or
holding;
Page 20 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(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.
(2) Permit the taking of proper
precautions to reduce the potential
for contamination of food, food-
contact surfaces, or food-packaging
materials with microorganisms,
chemicals, filth, or other extraneous
material. ...The potential for
contamination may be reduced by
adequate food safety controls and
operating practices or effective
design, including the separation of
operations in which contamination is
likely to occur, by one or more of the
following means: location, time,
partition, air flow, enclosed systems,
or other effective means.
(2) Permit the taking of proper
precautions to reduce the potential for
mixups or adulteration of in-process
or finished dietary product, or
contamination of processing
equipment, utensils or packaging
materials with microorganisms,
chemicals, filth, or other extraneous
material. The potential for mixups
and product adulteration may be
reduced by adequate product safety
controls and operating practices or
effective design, including the
separation of operations in which
contamination is likely to occur, by
one or more of the following means:
location, time, partition, air flow,
enclosed systems, or other effective
means.
(c) Permit the use of proper
precautions to reduce the potential
for mixups or contamination of
components, dietary ingredients,
dietary supplements, or contact
surfaces, with microorganisms,
chemicals, filth, or other-extraneous
material. Your physical plant must
have and you must use separate or
defined areas of adequate size or
other control systems, such as
computerized inventory controls or
automated systems of separation, to
prevent contamination and mixups
of components, dietary ingredients,
and dietary supplements during the
following operations:
(1) Receiving, identifying, holding,
and withholding from use,
components, dietary ingredients,
dietary supplements, packaging,
and labels that will be used in or
during the manufacturing,
packaging, or holding of dietary
ingredients and dietary
supplements;
(2) Separating, as necessary,
components, dietary ingredients,
dietary supplements, packaging,
and labels, that are to be used from
components, dietary ingredients,
dietary supplements, packaging, or
labels that are awaiting material
review and disposition decision,
reprocessing, or are awaiting
disposal after rejection;
(3) Separating the manufacturing,
packaging, and holding of different
product types including, but not
limited to, different types of dietary
ingredients, dietary supplements
and other foods, cosmetics, and
pharmaceutical products;
(4) Performing laboratory analyses
and holding laboratory supplies and
samples;
(5) Cleaning and sanitizing contact
surfaces;
(6) Packaging and label operations;
and
(7) Holding dietary ingredients or
dietary supplements.
Page 21 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(c) (10) Aseptic processing, which
includes as appropriate:
(i) Floors, walls, and ceilings of smooth,
hard surfaces that are easily cleanable;
(4) Be constructed in such a manner
that floors, walls, and ceilings may
be adequately cleaned and kept
clean and kept in good repair; that
drip or condensate from fixtures,
ducts and pipes does not
contaminate food, food-contact
surfaces, or food-packaging
materials;
(4) Be constructed in such a
manner that floors, walls, and ceilings
may be adequately cleaned and kept
clean and kept in good repair; that drip
or condensate from fixtures, ducts
and pipes does not adulterate raw
materials, in-process or finished
dietary products, or contaminate
product containers, utensils or
packaging materials;
(d) Be designed and constructed in
a manner that prevents
contamination of components,
dietary ingredients, dietary
supplements, or contact surfaces.
The design and construction must
include, but not be limited to:
(1) Floors, Walls, and ceilings that
are of smooth and hard surfaces
that can be adequately cleaned and
kept clean and in good repair;
(2) Fixtures, ducts, and pipes that
do not contaminate components,
dietary ingredients, dietary
supplements, or contact surfaces by
dripping or condensate;
(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.
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.
(6) Provide adequate ventilation or
control equipment to minimize odors
and vapors (including steam and
noxious fumes) in areas where they
may contaminate food; and locate
and operate fans and other air-
blowing equipment in a manner that
minimizes the potential for
contaminating food, food-packaging
materials, and food-contact
surfaces.
(6) Provide adequate ventilation or
control equipment to maintain
adequate control over
microorganisms, dust, humidity, and
temperature, when appropriate, for
the manufacture of dietary products;
to minimize odors and vapors
(including steam and noxious fumes)
in areas where they may adulterate
dietary products; and locate and
operate fans and other air-blowing
equipment in a manner that
minimizes the potential for
adulterating raw materials, in-
process or finished dietary products,
or contaminating processing
equipment, utensils or packaging
materials.
(3) Adequate ventilation or
environmental control equipment
such as air flow systems, including
filters, fans, and other air-blowing
equipment, that minimize odors and
vapors (including steam and
noxious fumes) in areas where they
may contaminate components,
dietary ingredients, dietary
supplements, or contact surfaces;
(4) Fans and other air-blowing
equipment located and operated in a
manner that minimizes the potential
for microorganisms and particulate
matter to contaminate components,
dietary ingredients, dietary
supplements, or contact surfaces;
(5) Equipment that controls
temperature and humidity; and
(4)and that aisles or working
spaces are provided between
equipment and walls and are
adequately unobstructed and of
adequate width to permit employees
to perform their duties and to protect
against contaminating food or food-
contact surfaces with clothing or
personal contact.
(4)and that aisles or working
spaces are provided between
equipment and walls and are
adequately unobstructed and of
adequate width to permit employees
to perform their duties and to protect
against adulterating in-process or
finished product, or contaminating
processing equipment with clothing or
personal contact.
(6) Aisles or working spaces
between equipment and walls that
are adequately unobstructed and of
adequate width to permit all persons
to perform their duties and to protect
against contamination of
components, dietary ingredients,
dietary supplements, or contact
surfaces with clothing or personal
contact.
Page 22 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.44 Lighting.
Adequate lighting shall be provided in all
areas.
(5) Provide adequate lighting in
hand-washing areas, dressing and
locker rooms, and toilet rooms and
in all areas where food is examined,
processed, or stored and where
equipment or utensils are cleaned;
and
(5) Provide adequate lighting in
hand-washing areas, dressing and
locker rooms, and toilet rooms and in
all areas where product is examined,
processed, or stored and where
equipment or utensils are cleaned;
and
(e) Provide adequate light in:
(1) All areas where components,
dietary ingredients, or dietary
supplements are examined,
processed, or held;
(2) All areas where contact
surfaces are cleaned; and
(3) Hand-washing areas, dressing
and locker rooms, and bathrooms.
(5)provide safety-type light bulbs,
fixtures, sky-lights, or other glass
suspended over exposed food in any
step of preparation or otherwise
protect against food contamination in
case of glass breakage.
(5)provide safety-type light bulbs,
fixtures, sky-lights, or other glass
suspended over exposed product in
any step of preparation or otherwise
protect against product adulteration in
case of glass breakage.
(f) Use safety-type light bulbs,
fixtures, skylights, or other glass
that is suspended over exposed
components, dietary ingredients, or
dietary supplements in any step of
preparation, unless otherwise
constructed in a manner that will
protect against contamination of
components, dietary ingredients, or
dietary supplements in case of
glass breakage.
(3) Permit the taking of proper
precautions to protect food in outdoor
bulk fermentation vessels by any
effective means, including:
(i) Using protective
coverings.
(ii) Controlling areas over
and around the vessels
to eliminate harborages
for pests.
(iii) Checking on a regular
basis for pests and pest
infestation.
(iv) Skimming the
fermentation vessels, as
necessary.
(3) Permit the taking of proper
precautions to protect dietary
ingredients or dietary supplements in
outdoor bulk fermentation vessels by
any effective means, including:
(i) Using protective
coverings.
(ii) Controlling areas over
and around the vessels
to eliminate
harborages for pests.
(iii) Checking on a regular
basis for pests and
pest infestation.
(iv) Skimming the
fermentation vessels,
as necessary.
(g) Provide protection by any
effective means against
contamination of components,
dietary ingredients, and dietary
supplements in bulk fermentation
vessels, including consideration of:
(1) Use of protective coverings;
(2) Placement in areas where you
can eliminate harborages for pests
over and around the vessels;
(3) Placement in areas where you
can check regularly for pests, pest
infestation, filth or any other
extraneous materials; and
(4) Use of skimming equipment.
(7) Provide, where necessary,
adequate screening or other
protection against pests.
(7) Provide, where necessary,
adequate screening or other
protection against pests.
(h) Use adequate screening or other
protection against pests, where
necessary.
Page 23 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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 CEquipment
110.40 Equipment and utensils.
(a) All plant equipment and utensils
shall be so designed and of such
material and workmanship as to be
adequately cleanable, and shall be
properly maintained.
(d) Holding, conveying, and
manufacturing systems, including
gravimetric, pneumatic, closed, and
automated systems, shall be of a
design and construction that enables
them to be maintained in an
appropriate sanitary condition.
Equipment and Utensils
(a) Design and construction.
(1) All plant equipment and utensils
shall be so designed and of such
material and workmanship as to be
adequately cleanable, and shall be
properly maintained.
(6) Holding, conveying, and
manufacturing systems, including
gravimetric, pneumatic, closed, and
automated systems, shall be of a
design and construction that enables
them to be maintained in an
appropriate clean condition.
Subpart D--Equipment and
Utensils
111.25 What requirements
apply to the equipment and
utensils you use?
(a) (1) You must use equipment and
utensils that are of appropriate
design, construction, and
workmanship to enable them to be
suitable for their intended use and to
be adequately cleaned and properly
maintained. Equipment and utensils
include, but are not limited to, the
following:
(i) Equipment used to hold or
convey;
(ii) Equipment used to measure;
(iii) Equipment using compressed
air or gas;
iv) Equipment used to carry out
processes in closed pipes and
vessels; and
(v) Equipment used in automatic,
mechanical, or electronic systems.
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.
The design, construction, and use
of equipment and utensils shall
preclude the adulteration of food with
lubricants, fuel, metal fragments,
contaminated water, or any other
contaminants.
(2) The design, construction and
use of equipment and utensils shall
preclude the adulteration of raw
materials, packaging materials, in-
process materials or finished product
with lubricants, fuel, metal fragments,
contaminated water, or any other
contaminants.
(2) You must use equipment and
utensils of appropriate design and
construction so that use will not
result in the contamination of
components, dietary ingredients, or
dietary
supplements with:
(i) Lubricants;
(ii) Fuel;
(iii) Coolants;
(iv) Metal or glass fragments;
(v) Filth or any other extraneous
material;
(vi) Contaminated water; or
(vii) Any other contaminants.
Page 24 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
All equipment should be so
installed and maintained as to
facilitate the cleaning of the
equipment and of all adjacent
spaces. Food-contact surfaces shall
be corrosion-resistant when in
contact with food. They shall be
made of nontoxic materials and
designed to withstand the
environment of their intended use
and the action of food, and, if
applicable, cleaning compounds and
sanitizing agents. Food-contact
surfaces shall be maintained to
protect food from being
contaminated by any source,
including unlawful indirect food
additives.
....(7) Equipment, containers, and
utensils used to convey, hold, or
store raw materials, work-in-
process, rework, or food shall be
constructed, handled, and
maintained during manufacturing or
storage in a manner that protects
against contamination....
(3) All equipment should be so
installed and maintained as to
facilitate the cleaning of the equipment
and of all adjacent spaces.
Processing equipment and utensils
shall be corrosion-resistant when in
contact with raw materials, in-
process or finished dietary product.
They shall be made of nontoxic
materials and designed to withstand
the environment of their intended use
and the action of dietary products,
and, if applicable, cleaning
compounds and sanitizing agents.
Processing equipment and utensils
shall be maintained to protect dietary
products from being adulterated by
any source.
(12) Equipment, containers, and
utensils used to convey, hold, or store
raw materials, in-process material,
rework, or finished product shall be
constructed, handled, and maintained
during manufacturing or storage in a
manner that protects against
contamination.
(3) All equipment and utensils you
use must be:
(i) Installed and maintained to
facilitate cleaning the equipment,
utensils, and all adjacent spaces;
(ii) Corrosion-resistant if the
equipment or utensils contact
components, dietary ingredients, or
dietary supplements;
(iii) Made of nontoxic materials;
(iv) Designed and constructed to
withstand the environment of their
intended use, the action of
components, dietary ingredients, or
dietary supplements, and, if
applicable, cleaning compounds and
sanitizing agents; and
(v) Maintained to protect
components, dietary ingredients,
and dietary supplements from being
contaminated by any source.
(b) Seams on food-contact surfaces
shall be smoothly bonded or
maintained so as to minimize
accumulation of food particles, dirt,
and organic matter and thus
minimize the opportunity for growth
of microorganisms.
(4) Seams on utensils and
processing equipment shall be
smoothly bonded or maintained so as
to minimize accumulation of product,
dirt, and organic matter and thus
minimize the opportunity for growth of
microorganisms.
(4) Equipment and utensils you use
must have seams that are smoothly
bonded or maintained to minimize
accumulation of component, dietary
ingredient, or dietary supplement
particles, dirt, filth, organic material,
or any extraneous materials or
contaminants to minimize the
opportunity for growth of
microorganisms.
(c) Equipment that is in the
manufacturing or food-handling area
and that does not come into contact
with food shall be so constructed that
it can be kept in a clean condition.
(5) Equipment that is in the
manufacturing or product handling
area and that does not come into
contact with a dietary product shall be
so constructed that it can be kept in a
clean condition.
(e) Each freezer and cold storage
compartment used to store and hold
food capable of supporting growth of
microorganisms shall be fitted with
an indicating thermometer,
temperature-measuring device, or
temperature-recording device so
installed as to show the temperature
accurately within the compartment,
and should be fitted with an
automatic control for regulating
temperature or with an automatic
alarm system to indicate a
significant temperature change in a
manual operation.
(7) Each freezer and cold storage
compartment used to store and hold a
dietary product capable of supporting
growth of microorganisms shall be
fitted with an indicating thermometer,
temperature-measuring device, or
temperature-recording device so
installed as to show the temperature
accurately within the compartment,
and should be fitted with an automatic
control for regulating temperature or
with an automatic alarm system to
indicate a significant temperature
change in a manual operation.
(5) Each freezer and cold storage
compartment you use to hold
components, dietary ingredients, or
dietary supplements:
(i) Must be fitted with an indicating
thermometer, temperature-
measuring device, or temperature-
recording device that shows the
temperature accurately within the
compartment; and
(ii) Must have an automatic device
for regulating temperature or an
automatic alarm system to indicate
a significant temperature change in
a manual operation.
Page 25 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(f) Instruments and controls used
for measuring, regulating, or
recording temperatures, pH, acidity,
water activity, or other conditions
that control or prevent the growth of
undesirable microorganisms in food
shall be accurate and adequately
maintained, and adequate in number
for their designated uses.
(8) Instruments and controls used
in the manufacture, processing,
packing or holding dietary products,
including instruments and controls
used for measuring, regulating, or
recording temperatures, pH, acidity,
water activity, or other conditions that
control or prevent the growth of
undesirable microorganisms in such
products shall be accurate and
adequately maintained, and adequate
in number for their designated uses.
(6) Instruments or controls used in
the manufacturing, packaging, or
holding of a dietary ingredient or
dietary supplement, including but
not limited to, instruments or
controls you use to measure,
regulate, or record temperatures,
hydrogen ion concentration (pH),
water activity, or other conditions
that control or prevent the growth of
microorganisms or other
contamination must be:
(i) Accurate and precise;
(ii) Adequately maintained; and
(iii) Adequate in number for their
designated uses.
(g) Compressed air or other gases
mechanically introduced into food or
used to clean food-contact surfaces or
equipment shall be treated in such a
way that food is not contaminated with
unlawful indirect food additives.
(9) Compressed air or other gases
mechanically introduced into a dietary
product or used to clean equipment or
utensils shall be treated in such a way
that dietary ingredients or dietary
supplements are not adulterated.
(7) Compressed air or other gases
you introduce mechanically into or
onto a component, dietary
ingredient, dietary supplement, or
contact surface or that you use to
clean any contact surface must be
treated in such a way that the
component, dietary ingredient,
dietary supplement, or contact
surface is not contaminated.
(b)(l) You must calibrate
instruments and controls you use in
manufacturing or testing a
component, dietary ingredient, or
dietary supplement.
(2) You must calibrate before first
use; and
(i) As specified in writing by the
manufacturer of the instrument and
control, or
(ii) At routine intervals or as
otherwise necessary to ensure the
accuracy and precision of the
instrument and control.
211.160 General requirements.
Laboratory controls shall include:
(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.
(c) You must:
(1) Establish a written procedure for
calibrating instruments and controls
you use in manufacturing or testing
a component, dietary ingredient, or
dietary supplement and document
that the written procedure was
followed each time a calibration is
performed, or
(2) Document, at the time of
performance that the instrument and
control calibration established in
accordance with this section was
performed.
Page 26 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(d) You must identify the following
for calibrating instruments and
controls in any written procedure or
at the time of performance:
(1) The instrument or control
calibrated;
(2) The date of calibration;
(3) The reference standard used
including the certification of
accuracy of the known reference
standard and a history of
recertification of accuracy;
(4) The calibration method used
including appropriate limits for
accuracy and precision of
instruments and controls when
calibrating;
(5) The calibration reading or
readings found; and
(6) The recalibration method used if
accuracy or precision or both
accuracy and precision limits for
instruments and controls were not
met; and
(7) The initials of the person who
performed the calibration.
(d) You must repair or replace
instruments or controls that cannot
be adjusted to agree with the
reference standard.
Page 27 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
110.80(b) Manufacturing
operations.
(1) Equipment and utensils and
finished food containers shall be
maintained in an acceptable
condition through appropriate
cleaning and sanitizing, as
necessary. Insofar as necessary,
equipment shall be taken apart for
thorough cleaning....
110.35 Sanitary operations.
(a) General maintenance.
....Cleaning and sanitizing of utensils
and equipment shall be conducted in
a manner that protects against
contamination of food, food-contact
surfaces, or food-packaging
materials....
(d) Sanitation of food-contact
surfaces. All food-contact surfaces,
including utensils and food-contact
surfaces of equipment, shall be
cleaned as frequently as necessary
to protect against contamination of
food.
(1) Food-contact surfaces used for
manufacturing or holding low-
moisture food shall be in a dry,
sanitary condition at the time of use.
When the surfaces are wet-cleaned,
they shall, when necessary, be
sanitized and thoroughly dried before
subsequent use.
(b) Sanitation of equipment and
utensils.
(9) Equipment and utensils and
finished product containers shall be
maintained in an acceptable condition
through appropriate cleaning and
sanitizing, as necessary. Insofar as
necessary, equipment shall be taken
apart for thorough cleaning.
(1) Cleaning and sanitizing of
utensils and equipment shall be
conducted in a manner that protects
against adulteration of raw materials,
in-process or finished dietary product,
processing equipment, utensils or
packaging materials.
(2) All utensils and processing
equipment shall be cleaned as
frequently as necessary to protect
against product adulteration.
(3) Utensils and processing
equipment used for manufacturing or
holding of dry dietary products shall
be in a dry, sanitary condition at the
time of use. When the surfaces are
wet-cleaned, they shall, when
necessary, be sanitized and
thoroughly dried before subsequent
use.
(e)(1) You must maintain, clean,
and sanitize as necessary, all
equipment, utensils, and any other
contact surfaces that are used to
manufacture, package, or hold
components, dietary ingredients, or
dietary supplements. Equipment
and utensils must be taken apart as
necessary for thorough
maintenance, cleaning, and
sanitizing.
(2) You must ensure that all contact
surfaces used for manufacturing or
holding of low-moisture
components, dietary ingredients, or
dietary supplements are in a dry
and sanitary condition at the time of
use. When the surfaces are wet-
cleaned, they must be sanitized,
when necessary, and thoroughly
dried before subsequent use.
(2) In wet processing, when cleaning
is necessary to protect against the
introduction of microorganisms into
food, all food-contact surfaces shall
be cleaned and sanitized before use
and after any interruption during
which the food-contact surfaces may
have become contaminated. Where
equipment and utensils are used in a
continuous production operation. the
utensils and food-contact surfaces of
the equipment shall be cleaned and
sanitized as necessary.
(4) In wet processing, when cleaning
is necessary to protect against the
introduction of microorganisms into a
dietary product, all utensils and
processing equipment shall be
cleaned and sanitized as appropriate
before use and after any interruption
during which the utensils or
processing equipment may have
become contaminated. Where
equipment and utensils are used in a
continuous production operation or in
back-to-back operations involving
different batches of the same
products, the utensils and product-
contact surfaces of the equipment
shall be cleaned and sanitized as
appropriate.
(3) If you use wet processing during
manufacturing, you must clean and
sanitize all contact surfaces, as
necessary, to protect against the
introduction of microorganisms into
components, dietary ingredients, or
dietary supplements. When
cleaning and sanitizing is
necessary, you must clean and
sanitize all contact surfaces before
use and after any interruption during
which the contact surface may have
become contaminated. If you use
contact surfaces in a continuous
production operation or in back-to-
back operations involving different
batches of the same dietary
ingredient or dietary supplement,
you must clean and sanitize the
contact surfaces as necessary.
(3) Non-food-contact surfaces of
equipment used in the operation of
food plants should be cleaned as
frequently as necessary to protect
against contamination of food.
(5) Non-product-contact surfaces of
equipment should be cleaned as
frequently as necessary to protect
against product adulteration.
(4) You must clean surfaces that do
not touch components, dietary
ingredients, or dietary supplements
as frequently as necessary to
protect against contaminating
components, dietary ingredients, or
dietary supplements.
Page 28 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(4) Single-service articles (such as
utensils intended for one-time use,
paper cups, and paper towels)
should be stored in appropriate
containers and shall be handled,
dispensed, used, and disposed of in
a manner that protects against
contamination of food or food-contact
surfaces.
(6) Single-service articles (such as
utensils intended for one-time use,
paper cups, and paper towels) should
be stored in appropriate containers
and shall be handled, dispensed,
used, and disposed of in a manner
that protects against adulteration of
dietary products, and contamination of
utensils and processing equipment.
(5) Single-service articles (such as
utensils intended for one-time use,
paper cups, and paper towels) must
be:
(i) Stored in appropriate containers;
and
(ii) Handled, dispensed, used, and
disposed of in a manner that
protects against contamination of
components, dietary ingredients,
dietary supplements, or any contact
surface.
(5) Sanitizing agents shall be
adequate and safe under conditions
of use. Any facility, procedure, or
machine is acceptable for cleaning
and sanitizing equipment and
utensils if it is established that the
facility, procedure, or machine will
routinely render equipment and
utensils clean and provide adequate
cleaning and sanitizing treatment.
(7) Sanitizing agents shall be
adequate and safe under conditions of
use. Any facility, procedure, or
machine is acceptable for cleaning
and sanitizing equipment and utensils
if it is established that the facility,
procedure, or machine will routinely
render equipment and utensils clean
and provide adequate cleaning and
sanitizing treatment.
(6) Cleaning compounds and
sanitizing agents must be adequate
for intended use and safe under
condition of use;
(e) Storage and handling of
cleaned portable equipment and
utensils. Cleaned and sanitized
portable equipment with food-contact
surfaces and utensils should be
stored in a location and manner that
protects food-contact surfaces from
contamination.
(8) Cleaned and sanitized portable
equipment with product-contact
surfaces and utensils should be
stored in a location and manner that
protects product-contact surfaces
from contamination.
(7) You must store cleaned and
sanitized portable equipment and
utensils that have contact surfaces
in a location and manner that
protects them from contamination.
(b) Written procedures shall be
established and followed for cleaning and
maintenance of equipment, including
utensils, used in the manufacture,
processing, packing, or holding of a drug
product. These procedures shall include,
but are not necessarily limited to, the
following:
(1) Assignment of responsibility for
cleaning and maintaining equipment;
(2) Maintenance and cleaning schedules,
including, where appropriate, sanitizing
schedules;
(3) A description in sufficient detail of the
methods, equipment, and materials used in
cleaning and maintenance operations, and
the methods of disassembling and
reassembling equipment as necessary to
assure proper cleaning and maintenance;
(4) Removal or obliteration of previous
batch identification;
(5) Protection of clean equipment from
contamination prior to use;
(6) Inspection of equipment for cleanliness
immediately before use.
(c) Records shall be kept of maintenance,
cleaning, sanitizing, and inspection as
specified in 211.180 and211.182.
(10) Written procedures shall be
established and followed for cleaning
and maintaining equipment and
utensils used in the manufacture of
dietary products.
(f) You must keep calibration
records as required by this section
in accordance with 111.125.
Page 29 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
111.30 What requirements
apply to automatic, mechanical,
or electronic equipment?
(a) When you use automatic,
mechanical, or electronic
equipment to manufacture, package,
label, and hold a dietary ingredient
or dietary supplement, you must:
(1) Design or select equipment to
ensure that dietary ingredient or
dietary supplement specifications
are consistently achieved and
(2) Determine the suitability of your
equipment by ensuring that your
equipment is capable of operating
satisfactorily within the operating
limits required by the process.
If such equipment is so used, it shall be
routinely calibrated, inspected, or checked
according to a written program designed to
assure proper performance.
(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.
(b) For any automatic, mechanical,
or electronic equipment you use,
you must:
(1) Routinely calibrate, inspect, or
check to ensure proper
performance. Your quality control
unit must approve these
calibrations, inspections, or checks;
(2) Make and keep written records
of equipment calibrations,
inspections, or checks;
(3) Establish and use appropriate
controls, to ensure that your quality
control unit approves changes in the
master manufacturing record, batch
control records, packaging
operations and label operations, or
changes to other operations related
to the equipment that you use and
that only authorized personnel
institute the changes;
(4) Establish and use appropriate
controls to ensure that the
equipment functions in accordance
with its intended use. These
controls must be approved by your
quality control unit; and
(5) Make and keep backup file(s) of
software programs and of data
entered into your computer system.
Your backup file (e.g., a hard copy
of data you have entered, diskettes,
tapes, microfilm, or compact disks)
must be an exact and complete
record of the data you entered. You
must keep your backup software
programs and data secure from
alterations, inadvertent erasures, or
equipment loss.
(a) ...Written records of those calibration
checks and inspections shall be
maintained.
(c) You must keep automatic,
mechanical, or electronic
equipment records required by this
section in accordance with
111.125.
Page 30 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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--Production and
Process Controls
111.35 What production and
process controls must you use?
(a) You must implement a system
of production and process controls
that covers all stages of
manufacturing, packaging, labeling,
and holding of the dietary
ingredients and dietary
supplements.
(b) Your production and in-process
control system must be designed to
ensure that the dietary ingredient or
dietary supplement is
manufactured, packaged, and held
in a manner that will prevent
adulteration of the dietary ingredient
or dietary supplement. The
production and in-process control
system must include all
requirements of this subpart and
must be reviewed and approved by
the quality control unit.
(c) You must use a quality control
unit in your manufacturing,
packaging, and label operations for
producing the dietary ingredient or
dietary supplement to ensure that
these operations are performed in a
manner that prevents adulteration
and ensures that the dietary
ingredient or dietary supplement
meets specifications for identity,
purity, quality, strength, and
composition.
Page 31 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(d) Any substance, other than a
"dietary ingredient" within the
meaning of section 201(ff) of the
Federal Food, Drug; and Cosmetic
Act (the act), the intended use of
which results or may reasonably be
expected to result, directly or
indirectly, in its becoming a
component or otherwise affecting
the characteristics of the dietary
ingredient or dietary supplement
must be:
(1) Authorized for use as a food
additive under section 409 of the act;
or
(2) Authorized by a prior sanction
consistent with 170.3(l) of this
chapter; or
(3) If used as a color additive,
subject to a listing that, by the terms
of that listing, includes the use in a
dietary supplement; or
(4) Generally recognized as safe
(GRAS) for use in a dietary
ingredient or dietary supplement.
Any claim that a substance is
GRAS, other than a dietary
ingredient within the meaning of
section 201(ff) of the act, must be
supported by a citation to the
agency's regulations or by an
explanation for why there is general
recognition of safety of the use of the
substance in a dietary ingredient or
dietary supplement; and
(5) Must comply with all other
applicable statutory and regulatory
requirements under the act
Page 32 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.160 General requirements.
(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.
(e) You must establish a
specification for any point, step, or
stage in the manufacturing process
where control is necessary to
prevent adulteration. Specifications
must be established for:
(1) The identity, purity, quality,
strength, and composition of
components, dietary ingredients, or
dietary supplements that you
receive;
(2) The in-process controls in the
master manufacturing record where
control is necessary to ensure the
identity, purity, quality, strength, and
composition of dietary ingredients
or dietary supplements;
(3) The identity, purity, quality,
strength, and composition of the
dietary ingredient or dietary
supplement that you manufacture;
and
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.
(4) The dietary ingredient or dietary
supplement labels and the
packaging that may come in contact
with dietary ingredients and dietary
supplements. The packaging must
be safe and suitable for its intended
use and comply with all other
applicable statutory and regulatory
requirements under the act and
must not be reactive or absorptive
so as to affect the safety of the
dietary ingredient and dietary
supplement.
Page 33 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(f) You must monitor the in-process
control points, steps, or stages to
ensure that specifications
established under paragraph (e) of
this section are met and to detect
any unanticipated occurrence that
may result in adulteration;
Page 34 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(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.
(4) When appropriate, components shall
be microscopically examined.
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.
(7) (iv) Each lot of raw material shall
undergo at least one test by the
manufacturer to verify its identity.
Such tests may include any
appropriate test with sufficient
specificity to determine identity,
including chemical and laboratory
tests, gross organoleptic analysis,
microscopic identification, or analysis
of constituent markers.
(11) Written procedures shall be
established and followed that describe
appropriate tests, and/or
examinations to be conducted that
may be necessary to assure the
purity, composition and quality of the
finished product.
(g) You must ensure, through
testing or examination, that each
specification that you established
under paragraph (e) of this section
is met. Specific testing
requirements are as follows:
(1) You must test each finished
batch of the dietary ingredient or
dietary supplement produced before
releasing for distribution to
determine whether established
specifications for identity, purity,
quality, strength, and composition
are met provided that there are
scientifically valid analytical
methods available to conduct such
testing.
(2) For any specification for identity,
purity, quality, strength, or
composition for which you
document cannot be tested on the
finished batch of a dietary ingredient
or dietary supplement, because
there is no scientifically valid
analytical method available for such
testing, then you must:
(i) Perform testing on each
shipment lot of components, dietary
ingredients or dietary supplements
received to determine whether such
specification is met; and
(ii) Perform testing in-process in
accordance with the master
manufacturing record where control
is necessary to ensure the identity,
purity, quality, strength, and
composition of dietary ingredients
or dietary supplements; and
(3) Your quality control unit must
determine when finished batch
testing cannot be completed for any
specification on the identity, purity,
quality, strength, and composition of
dietary ingredients or dietary
supplements.
(e) The accuracy, sensitivity, specificity,
and reproducibility of test methods
employed by the firm shall be established
and documented. Such validation and
documentation may be accomplished in
accordance with 211.194(a)(2).
(h) You must use an appropriate
test or examination to determine
whether your specifications are
met. An appropriate test is one that
is a scientifically valid analytical
method.
Page 35 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(i) You must:
(1) Establish corrective action plans
for use when an established
specification is not met;
(2) Review the results of the
monitoring required by this section
and conduct a material review of
any component, dietary ingredient,
dietary supplement, packaging or
label for which you establish a
specification that is not met, or any
unanticipated occurrence that
adulterates or could result in
adulteration of the component,
dietary ingredient, dietary
supplement, packaging, or label;
and
(3) Make a material disposition
decision for any component, dietary
ingredient, dietary supplement,
packaging, or label:
(i) If a component, dietary
ingredient, dietary supplement,
packaging, or label fails to meet
specifications;
(ii) If any step established in the
master manufacturing record is not
completed;
(iii) If there is any unanticipated
occurrence during the
manufacturing operations that
adulterates or may lead to
adulteration of the component,
dietary ingredient, dietary
supplement, packaging, or label;
(iv) If calibration of an instrument,
or control suggests a problem that
may have caused batches of, a
dietary ingredient or dietary
supplement to become adulterated;
or
(v) If a dietary ingredient or dietary
supplement is returned.
Page 36 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(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.
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(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
110.80 Processes and controls.
All food that has become
contaminated to the extent that it is
adulterated within the meaning of the
act shall be rejected, or if
permissible, treated or processed to
eliminate the contamination.
(3) All product that has become
contaminated to the extent that it is
adulterated within the meaning of the
act shall be rejected, or if
permissible, treated or processed to
eliminate the contamination.
(4) For any deviation, or
unanticipated occurrence which
resulted in or could lead to
adulteration of the component,
dietary ingredient, dietary
supplement, packaging, or label
(i) You must reject the component,
dietary ingredient, dietary
supplement, packaging, or label
unless the quality control unit
determines that in-process
adjustments are possible to correct
the deviation or occurrence;
(ii) You must not reprocess a
rejected component, dietary
ingredient, or dietary supplement
unless approved by the quality
control unit; and
(iii) You must not reprocess any
component, dietary ingredient or
dietary supplement if it is rejected
because of contamination with
microorganisms or other
contaminants, such as heavy
metals;
(5) Have your quality control unit
review and approve any material
review and disposition decision
described in paragraphs (i) (2) and
(i) (3) of this section.
(j) The person who conducts the
material review and makes the
disposition decision must, at the
time of performance, document
every material review and
disposition decision in paragraph (i)
of this section. The documentation
must be included in the appropriate
batch production record and must:
(1) Identify the specific deviation
from the specification or the
unanticipated occurrence;
(2) Describe your investigation into
the cause of the deviation from the
specification or the unanticipated
occurrence;
(3) Evaluate whether or not the
deviation from the specification or
unanticipated occurrence has
resulted in or could lead to
adulteration;
(4) Identify the action(s) taken to
correct and prevent a recurrence of
the deviation or the unanticipated
occurrence; and
(5) Discuss what you did with the
component, dietary ingredient,
dietary supplement, packaging, or
label.
Page 37 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(d) Samples shall be examined and tested
as follows:
(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.
(4) Raw materials, other
ingredients, and rework susceptible
to contamination with pests,
undesirable microorganisms, or
extraneous material shall comply
with applicable Food and Drug
Administration regulations,
guidelines, and defect action levels
for natural or unavoidable defects if a
manufacturer wishes to use the
materials in manufacturing food.
Compliance with this requirement
may be verified by any effective
means, including purchasing the
materials under a supplier's
guarantee or certification, or
examination of these materials for
contamination.
(7) Raw material samples shall be
examined and tested as follows:
(i) Each lot of raw material, in-
process material and rework that is
liable to adulteration with filth, insect
infestation or other visually evident
extraneous material shall be
examined against established
specifications for such adulteration,
and shall comply with any applicable
Food and Drug Administration
regulations, and guidelines. In lieu of
such examination by the
manufacturer, a guarantee or
certification of examination may be
accepted from the supplier of a
component provided that the
manufacturer establishes the
reliability of the supplier's
examination.
(ii) Each lot of a raw material that is
liable to microbiological
contamination that is objectionable in
view of its intended use shall be
subjected to microbiological tests
before use. Raw materials shall
either not contain levels of
microorganisms that may produce
food poisoning or other disease in
humans, or they shall be otherwise
treated during manufacturing
operations so that they no longer
contain levels that would cause the
product to be adulterated within the
meaning of the act. In lieu of such
testing by the manufacturer, a
guarantee or certification of analysis
may be accepted from the supplier of
a component provided that the
manufacturer establishes the
reliability of the supplier's analyses.
(k) You must test or examine
components, dietary ingredients,
and dietary supplements for those
types of contamination that may
adulterate or may lead to
adulteration. You must use an
appropriate scientifically valid
method for the test or examination.
The types of contamination include,
but are not limited to, the following:
(1) Filth, insects, or other
extraneous material;
(2) Microorganisms; and
(3) Toxic substances.
(l) Tests in accordance with this
section must include at least, one of
the following:
(1) Gross organoleptic analysis;
(2) Microscopic analysis;
(3) Chemical analysis; or
(4) Other appropriate test.
(3) Raw materials and other
ingredients susceptible to
contamination with aflatoxin or other
natural toxins shall comply with
current Food and Drug
Administration regulations,
guidelines, and action levels for
poisonous or deleterious substances
before these materials or ingredients
are incorporated into finished food.
Compliance with this requirement
may be accomplished by purchasing
raw materials and other ingredients
under a supplier's guarantee or
certification, or may be verified by
analyzing these materials and
ingredients for aflatoxins and other
natural toxins.
(iii) Raw materials and other
ingredients susceptible to adulteration
with aflatoxin or other natural toxins
shall comply with current Food and
Drug Administration regulations,
guidelines, and action levels for
poisonous or deleterious substances
before these materials or ingredients
are incorporated into a finished
dietary ingredient or dietary
supplement. Compliance with this
requirement may be accomplished by
analyzing these materials and
ingredients for aflatoxins and other
natural toxins or, in lieu of such
testing by the manufacturer, a
guarantee or certification of analysis
may be accepted from the supplier of
a component provided that the
manufacturer establishes the
reliability of the supplier's analyses.
Page 38 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(b) Laboratory records.
Laboratory records shall be
maintained and shall include
complete data derived from all
specified tests.
(m) You must record results of all
testing and examinations performed
in accordance with this section. If a
test or examination is performed on
a batch production you must record
the test or examination result in the
batch production record in
accordance with 111.50(c) (10).
Your records must document
whether the testing and examination
demonstrates that specifications are
met.
Page 39 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(n) For any specification that is not
met, you must conduct a material
review and disposition decision
under paragraph (i) of this section.
211.194 Laboratory records.
(a) Laboratory records shall include
complete data derived from all tests
necessary to assure compliance with
established specifications and standards,
including examinations and assays, as
follows:
(1) A description of the sample received for
testing with identification of source (that is,
location from where sample was obtained),
quantity, lot number or other distinctive
code, date sample was taken, and date
sample was received for testing.
(2) A statement of each method used in the
testing of the sample. The statement shall
indicate the location of data that establish
that the methods used in the testing of the
sample meet proper standards of accuracy
and reliability as applied to the product
tested. (If the method employed is in the
current revision of the United States
Pharmacopeia, National Formulary,
Association of Official Analytical Chemists,
Book of Methods,
2
or in other recognized
standard references, or is detailed in an
approved new drug application and the
referenced method is not modified, a
statement indicating the method and
reference will suffice). The suitability of all
testing methods used shall be verified under
actual conditions of use.
2
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.
(o) You must make and retain
records, in accordance with
111.125, to ensure that you follow
the requirements of this section.
The records must include, but are
not limited to:
(1) The specifications established;
(2) The actual results obtained
during the monitoring operation;
(3) Any deviation from
specifications and any unanticipated
occurrences;
(4) Any corrective actions taken;
(5) The disposition decisions and
follow-up; and
(6) The identity of the individual
qualified by training and experience
who investigated any deviation from
specifications) or unanticipated
occurrence and the identity of the
individual from the quality control
unit who reviewed the results of that
investigation.
Page 40 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(b) Complete records shall be maintained
of any modification of an established
method employed in testing. Such records
shall include the reason for the
modification and data to verify that the
modification produced results that are at
least as accurate and reliable for the
material being tested as the established
method.
(c) Complete records shall be maintained
of any testing and standardization of
laboratory reference standards, reagents,
and standard solutions.
(d) Complete records shall be maintained
of the periodic calibration of laboratory
instruments, apparatus, gauges, and
recording devices required by
211.160(b)(4).
(e) Complete records shall be maintained of
all stability testing performed in accordance
with 211.166.
Subpart E--Production and
Process Controls
110.80 Processes and controls.
...Appropriate quality control
operations shall be employed to
ensure that food is suitable for
human consumption and that food-
packaging materials are safe and
suitable...
Quality Control and Laboratory
Operations
Appropriate quality control
operations shall be employed to
assure that dietary products conform
to appropriate standards of purity,
quality and composition, and that
packaging materials are safe and
suitable for their intended purpose.
111.37 What requirements
apply to quality control?
(a) You must use a quality control
unit to ensure that your
manufacturing, packaging, label,
and holding operations in the
production of dietary ingredients and
dietary supplements are performed
in a manner that prevents
adulteration and misbranding,
including ensuring that dietary
ingredients and dietary supplements
meet specifications for identity,
purity, quality, strength, and
composition.
Page 41 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(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.
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.
(a) Quality control unit.
(1) There shall be a quality control
unit that has the responsibility and
authority to:
(i) Approve or reject all
procedures, specifications,
controls, tests and examinations,
or deviations from them, that
impact the purity, quality and
composition of a dietary
ingredient or dietary supplement;
and
(ii) Approve or reject all raw
materials, packaging materials,
labeling, and finished dietary
products, including products
manufactured, processed,
packed, or held under contract by
another company, based on
adequate determination of
conformance to established
specifications; and
(iii) Assure that completed
production records are reviewed
as appropriate. Quality control
shall be responsible for evaluation
of errors committed in the
manufacture of a product and
shall have the final authority to
determine if the error may be
corrected in such manner that the
product can be approved for
distribution or must be destroyed.
Such evaluations and their
resolution must be documented
and maintained with and/or cross-
referenced in the batch production
record.
(b) Your quality control unit must do
the following:
(1) Approve or reject all processes,
specifications, controls, tests, and
examinations, and deviations from
or modifications to them, that may
affect the identity, purity, quality,
strength, and composition of a
dietary ingredient or dietary
supplement;
(2) Determine whether all
components, dietary ingredients
dietary supplements, packaging,
and labels conform to
specifications;
(3) Approve or reject all
components, dietary ingredients,
dietary supplements, packaging and
labels;
(4) Review and approve all master
manufacturing records and all
modifications to the master
manufacturing records;
(5) Review and approve all batch
production-related records which
include, but are not limited to,
cross-referencing receiving and
batch production records, approval
of a material review and disposition
decision, approval for reprocessing,
and reject all components, dietary
ingredients packaging, and labels;
approve all master manufacturing
records and the master
manufacturing records; approval for
releasing for distribution;
(6) Review and approve all
processes for calibrating
instruments or controls;
(7) Review all records for
calibration of instruments,
apparatus, gauges, and recording
devices;
(8) Review all records for
equipment calibrations, inspections,
and checks;
(9) Review and approve all
laboratory control processes, and
testing results;
(10) Review and approve all
packaging and label records which
include, but are not limited to,
cross-referencing receiving and
batch production records, approval
for repackaging and relabeling, and
approval for releasing for
distribution;
Page 42 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(b) Representative samples of each
shipment of each lot shall be collected for
testing or examination. The number of
containers to be sampled, and the amount
of material to be taken from each
container, shall be based upon appropriate
criteria such as statistical criteria for
component variability, confidence levels,
and degree of precision desired, the past
quality history of the supplier, and the
quantity needed for analysis and reserve
where required by 211.170.
(c) Samples shall be collected in
accordance with the following procedures:
(1) The containers of components selected
shall be cleaned where necessary, by
appropriate means.
(2) The containers shall be opened,
sampled, and resealed in a manner
designed to prevent contamination of their
contents and contamination of other
components, drug product containers, or
closures.
(3) Sterile equipment and aseptic sampling
techniques shall be used when necessary.
(4) If it is necessary to sample a
component from the top, middle, and
bottom of its container, such sample
subdivisions shall not be composited for
testing.
(5) Sample containers shall be identified
so that the following information can be
determined: name of the material sampled,
the lot number, the container from which
the sample was taken, the date on which
the sample was taken, and the name of the
person who collected the sample.
(6) Containers from which samples have
been taken shall be marked to show that
samples have been removed from them.
(11) Collect representative samples
of:
(i) Each shipment lot of
components, dietary ingredients,
dietary supplements, packaging,
and labels received to determine
whether the component, dietary
ingredient, dietary supplement,
packaging, or labels meet
specifications;
Page 43 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(ii) In process materials at points,
steps, or stages, in the
manufacturing process as specified
in the, master manufacturing record
where control is necessary to
ensure the identity, purity, quality,
strength, and composition of dietary
ingredients or dietary supplements;
(iii) Each batch of dietary ingredient
or dietary supplement manufactured
to determine, before releasing for
distribution, whether the dietary
ingredient or dietary supplement
meets its specifications for identity,
purity, quality, strength, and
composition; and
(iv) Each batch of packaged and
labeled dietary ingredients or
dietary supplements to determine
that you used the packaging
specified in the master
manufacturing record and applied
the label specified in the master
manufacturing record.
(12) Keep the reserve samples for 3
years from the date of manufacture
for use in appropriate investigations
including, but not limited to,
consumer complaint investigations
to determine, for example, whether
the dietary ingredient or dietary
supplement associated with a
consumer complaint failed to meet
any of its specifications for identity,
purity, quality, strength, and
composition. The reserve samples
must:
(i) Be identified with the batch or lot
number; and
(ii) Consist of at least twice the
quantity necessary for tests.
Page 44 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(13) Perform appropriate tests and
examinations of:
(i) Components, dietary ingredients,
dietary supplements, packaging,
and labels received to ensure that
they meet specifications;
(ii) Dietary ingredient and dietary
supplement batch production at
points, steps, or stages identified in
the master manufacturing record
where control is necessary to
prevent adulteration;
(iii) Dietary ingredients and dietary
supplements that you manufacture
to ensure that they meet
specifications; and
(iv) Packaged and labeled dietary
ingredients and dietary supplements
to ensure that you used the
packaging specified in the master
manufacturing record and you
applied the label specified in the
master manufacturing record.
(14) Review and approve all
material review and disposition
decisions; and
(15) Approve the reprocessing or
distribution of returned dietary
ingredients or dietary supplements.
(c) Your quality control unit must
establish and maintain
documentation at the time of
performance that it performed the
review, approval, or rejection
requirements of this section by
recording the following:
(1) Date the required review,
approval, or rejection was
performed; and
(2) Signature of the person
performing the requirement.
211.22 Responsibilities of quality
control unit.
(d) The responsibilities and procedures
applicable to the quality control unit shall
be in writing; such written procedures shall
be followed.
(3) The responsibilities and
procedures applicable to the quality
control unit shall be established in
writing and followed.
(d) You must keep quality control
records in accordance with
111.125.
Page 45 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.137 Expiration dating.
(a) To assure that a drug product meets
applicable standards of identity, strength,
quality, and purity at the time of use, it shall
bear an expiration date determined by
appropriate stability testing described in
211.166.
(b) Expiration dates shall be related to any
storage conditions stated on the labeling,
as determined by stability studies
described in 211.166.
(c) If the drug product is to be reconstituted
at the time of dispensing, its labeling shall
bear expiration information for both the
reconstituted and unreconstituted drug
products.
(d) Expiration dates shall appear on
labeling in accordance with the
requirements of 201.17 of this chapter.
(c) Expiration dating.
(1) Whenever a dietary ingredient
or dietary supplement bears an
expiration date, such date shall be
supported by data and rationale to
reasonably assure that the product
meets established specifications at
the expiration date.
(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.
Page 46 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(2) Appropriate accelerated
stability studies or data from similar
product formulations may be used for
an initial determination of shelf life.
Product shelf life shall be confirmed
and may be extended on the basis of
real time studies on product stored
under labeled storage conditions.
(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.
Page 47 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
211.82 Receipt and storage of
untested components, drug product
containers, and closures.
(a) Upon receipt and before acceptance,
each container or grouping of containers of
components, drug product containers, and
closures shall be examined visually for
appropriate labeling as to contents,
container damage or broken seals, and
contamination.
(b) Components, drug product containers,
and closures shall be stored under
quarantine until they have been tested or
examined, as appropriate, and released.
Storage within the area shall conform to
the requirements of 211.80.
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(d) (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.
110.80 (a) Raw materials and
other ingredients.
...Containers and carriers of raw
materials should be inspected on
receipt to ensure that their condition
has not contributed to the
contamination or deterioration of
food.
(c) Handling and storage of raw
materials, in-process materials and
rework.
Containers of raw materials should
be inspected on receipt to assure that
their condition has not contributed to
the adulteration or deterioration of the
contents.
(2) Written procedures shall be
established and followed describing in
sufficient detail the control procedures
employed for the receipt, storage,
handling, sampling, examination,
and/or testing that may be necessary
to assure the identity of labeling and
the appropriate identity, cleanliness
and quality characteristics of
packaging materials for dietary
products.
111.40 What requirements
apply to components, dietary
ingredients. dietary
supplements, packaging, and
labels you receive?
(a) For components, dietary
ingredients, or dietary supplements
you receive, you must:
(1) Visually examine each container
or grouping of containers in a
shipment for appropriate content
label, container, damage, or broken
seals to determine whether the
container condition has resulted in
contamination or deterioration of the
components, dietary ingredients, or
dietary supplement;
(2) Visually examine the suppliers
invoice, guarantee, or certification to
ensure that the components, dietary
ingredients, or dietary supplements
are consistent with your purchase
order and perform testing, as
needed, to determine whether
specifications are met.
Page 48 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(3) Quarantine components, dietary
ingredients, or dietary supplements
until your quality control unit
reviews the suppliers invoice,
guarantee, or certification and
performs testing, as needed, of a
representative sample to determine
that specifications are met. If
specifications are not met, you must
conduct a material review and
make a disposition decision. Your
quality control unit must approve
and release the components, dietary
ingredients, and dietary
supplements from quarantine before
you use them;
211.80 General requirements.
(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).
(6) Each lot of raw material shall
be identified with a distinctive lot
number and shall be appropriately
controlled according to its status (e.g.
quarantined, approved, rejected).
(4) Identify each lot of components,
dietary ingredients, or dietary
supplements in a shipment in a
manner that allows you to trace the
shipment to the supplier, the date
received, the name of the
component or dietary supplement,
and the status (e.g., quarantined,
approved, or rejected) and to trace
the shipment lot to the dietary
ingredient or dietary supplement
manufactured and distributed. You
must use this unique identifier
whenever you record the disposition
of each shipment lot received; and
(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.
110.80 (a) Raw materials and
other ingredients.
(1) Raw materials and other
ingredients shall be inspected and
segregated or otherwise handled as
necessary to ascertain that they are
clean and suitable for processing
into food and shall be stored under
conditions that will protect against
contamination and minimize
deterioration.
(7) Liquid or dry raw materials and
other ingredients received and
stored in bulk form shall be held in a
manner that protects against
contamination.
(5) Raw materials, other
ingredients, and rework shall be held
in bulk, or in containers designed
and constructed so as to protect
against contamination and shall be
held at such temperature and
relative humidity and in such a
manner as to prevent the food from
becoming adulterated within the
meaning of the act. Material
scheduled for rework shall be
identified as such.
(1) Raw materials, in-process
materials and rework shall be
inspected and segregated or
otherwise handled as necessary to
ascertain that they are clean and
suitable for processing into dietary
products and shall be stored under
conditions that will protect against
adulteration and minimize
deterioration.
(1)Liquid or dry raw materials and
other ingredients received and stored
in bulk form shall be held in a manner
that protects against contamination.
(3) Raw materials, in-process
materials, and rework shall be held in
bulk, or in containers designed and
constructed so as to protect against
adulteration and shall be held at such
temperature and relative humidity and
in such a manner as to prevent a
dietary ingredient or dietary
supplement from becoming
adulterated within the meaning of the
act. Material scheduled for rework
shall be identified as such.
(5) Hold components, dietary
ingredients, or dietary supplements
under conditions that will protect
against contamination, deterioration,
and avoid mixups.
(6) Frozen raw materials and other
ingredients shall be kept frozen. If
thawing is required prior to use, it
shall be done in a manner that
prevents the raw materials and other
ingredients from becoming
adulterated within the meaning of the
act.
(4) Frozen raw materials and other
ingredients shall be kept frozen. If
thawing is required prior to use, it
shall be done in a manner that
prevents the raw materials and other
ingredients from becoming
adulterated within the meaning of the
act.
Page 49 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(5) Written procedures shall be
established and followed describing
the receipt, identification,
examination, handling, sampling,
testing and approval or rejection of
raw materials.
211.82 Receipt and storage of
untested components, drug product
containers, and closures.
(a) Upon receipt and before acceptance,
each container or grouping of containers of
components, drug product containers, and
closures shall be examined visually for
appropriate labeling as to contents,
container damage or broken seals, and
contamination.
(b) Components, drug product containers,
and closures shall be stored under
quarantine until they have been tested or
examined, as appropriate, and released.
Storage within the area shall conform to
the requirements of 211.80.
211.84 Testing and approval or
rejection of components, drug
product containers, and closures.
(d) (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.
(b) For packaging and labels you
receive, you must:
(1) Visually examine each container
or grouping of containers in a
shipment for appropriate content
label, container damage, or broken
seals to determine whether the
container condition has resulted in
contamination or deterioration of the
packaging and labels;
(d) (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.
(2) Quarantine packaging and labels
until your quality control unit tests or
examines a representative sample
to determine that specifications are
met. You must conduct at least a
visual identification on the
containers and closures. If
specifications are not met, you must
conduct a material review and
make a disposition decision. Your
quality control unit must approve
and release packaging and labels
from quarantine before you use
them;
211.80 General requirements.
(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).
(3) Identify each shipment lot of
packaging and labels in a manner
that allows you to trace the
shipment lot to the supplier, the date
received, the name of the packaging
and label and the status (e.g.,
quarantined, approved, or rejected)
and to trace the shipment lot to the
dietary ingredient or dietary
supplement manufactured and
distributed. You must use this
unique identifier whenever you
record the disposition of each
shipment lot received; and
Page 50 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(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.
(4) Hold packaging and labels under
conditions that will protect against
contamination, deterioration, and
avoid mixups.
Page 51 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
211.184 Component, drug product
container, closure, and labeling records.
These records shall include the following:
(a) The identity and quantity of each
shipment of each lot of components, drug
product containers, closures, and labeling;
the name of the supplier; the supplier's lot
number(s) if known; the receiving code as
specified in 211.80; and the date of
receipt. The name and location of the
prime manufacturer, if different from the
supplier, shall be listed if known.
(b) The results of any test or examination
performed (including those performed as
required by 211.82(a), 211.84(d), or
211.122(a)) and the conclusions derived
therefrom.
(c) An individual inventory record of each
component, drug product container, and
closure and, for each component, a
reconciliation of the use of each lot of such
component. The inventory record shall
contain sufficient information to allow
determination of any batch or lot of drug
product associated with the use of each
component, drug product container, and
closure.
(d) Documentation of the examination and
review of labels and labeling for conformity
with established specifications in accord
with 211.122(c) and211.130(c).
(e) The disposition of rejected
components, drug product containers,
closure, and labeling.
(c) (1) The person who performs
the component, dietary ingredient,
dietary supplement, packaging, or
label requirements of this section
must document, at the time of
performance, that the requirements
were followed. The documentation
must include, but not be limited to:
(i) The date that the components,
dietary ingredients, dietary
supplements, packaging, or labels
were received;
(ii) The signature of the person
performing the requirement;
(iii) Any test results; and
(iv) Any material review and
disposition decision you conducted
in accordance with 111.35(i) and
disposition of any rejected material
under S 111.74.
(2) You must keep component,
dietary supplement, packaging, and
label receiving records in
accordance with 111.125.
Page 52 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
Production and Process Controls
(a) Master production and control
records.
(1) To assure uniformity from
batch to batch, a master production
and control record shall be prepared
for the manufacture of each dietary
ingredient and dietary supplement,
111.45 What requirements
apply to establishing a master
manufacturing record?
(a) You must prepare and follow a
written master manufacturing
record for each type of dietary
ingredient or dietary supplement
that you manufacture and for each
batch size to ensure uniformity from
batch to batch. The master
manufacturing record must:
(1) Identify specifications for the
points, steps, or stages in the
manufacturing process where
control is necessary to prevent
adulteration; and
(2) Establish controls and
procedures to ensure that each
batch of dietary ingredient or dietary
supplement manufactured meets
those specifications.
(b) Master production and control records
shall include:
(1) The name and strength of the product
and a description of the dosage form;
Master production and control
records shall include, as
appropriate:
(b) The master manufacturing
record must include the following
information:
(1) The name of the dietary
ingredient or dietary supplement to
be manufactured and the strength,
concentration, weight, or measure
of each dietary ingredient for each
batch size;
(3) A complete list of components
designated by names or codes sufficiently
specific to indicate any special quality
characteristic;
(i) A complete list of raw materials
used in the manufacture of a dietary
product, designated by names or
codes sufficiently specific to
indicate any special quality
characteristic(s).
(2) A complete list of components to
be used;
(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;
211.101 Charge-in of components.
(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.
(ii) An accurate statement of the
weight or measure of each raw
material used in the manufacture of
a dietary product. Each batch shall
be formulated with the intent to
provide not less than 100 percent of
each claimed dietary ingredient.
(3) An accurate statement of the
weight or measure of each
component to be used;
Page 53 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.186 Master production and
control records.
(b) (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;
(iii) For dietary supplements, the
name and weight or measure of
each dietary ingredient per unit or
portion or per unit of weight or
measure of the supplement.
(4) The identity and, weight or
measure of each dietary ingredient
that will be declared on the
Supplement Facts label and the
identity of each ingredient that will
be declared on the ingredients list of
the dietary supplement in
compliance with section 403(s) of
the Federal Food, Drug, and
Cosmetic Act;
(5) A statement concerning any calculated
excess of component;
(iv) A statement concerning any
calculated excess of dietary
ingredient contained in a dietary
supplement.
(5) A statement that explains any
intentional excess amount of a
dietary ingredient;
(v) A statement of the total weight
or measure of any dietary
supplement unit.
(6) A statement of theoretical weight or
measure at appropriate phases of
processing;
(7) A statement of theoretical yield,
including the maximum and minimum
percentages of theoretical yield beyond
which investigation according to 211.192
is required;
(vi) A statement of theoretical
weight or measure of a dietary
ingredient or dietary supplement
expected at the conclusion of
manufacture, including the
maximum and minimum
percentages of theoretical yield
beyond which investigation is
required.
(6) A statement of theoretical yield
of a manufactured dietary ingredient
or dietary supplement expected at
each point, step, or stage of the
manufacturing process where
control is needed to prevent
adulteration, and the expected yield
when you finish manufacturing the
dietary ingredient or dietary
supplement, including the
maximum and minimum
percentages of theoretical yield
beyond which a deviation
investigation of a batch is performed
and material review is conducted
and disposition decision is made;
(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;
(vii) A description of the product
container(s), closure(s), and other
packaging materials, including
positive identification of all labeling
used.
(7) A description of packaging and a
copy of the label to be used; and
Page 54 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(9) Complete manufacturing and control
instructions, sampling and testing
procedures, specifications, special
notations, and precautions to be followed.
(viii) Manufacturing and control
instructions, designed to assure that
the dietary product has the purity,
composition and quality it is
represented to possess.
(8) Written instructions including,
but not limited to, the following:
(i) Specifications for each point,
step, or stage in manufacturing the
dietary ingredient or dietary
supplement necessary to prevent
adulteration;
(ii) Sampling and testing
procedures;
(iii) Specific actions necessary to
perform and verify points, steps, or
stages, necessary to meet
specifications and otherwise
prevent adulteration, including, but
not limited to, one person weighing
or measuring a component and
another person verifying the weight
or measure and one person adding
the component and another person
verifying the addition;
(iv) Special notations and
precautions to be followed; and
(v) Corrective action plans for use
when a specification is not met.
(a) (1) and shall be reviewed and
approved by the quality control unit.
(c) You must have the quality
control unit review and approve
each master manufacturing record
and any modifications to a master
manufacturing record.
(d) You must keep master
manufacturing records in
accordance with 111.125.
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.
(b) Batch production and control
records.
(1) Individual batch production and
control records shall be prepared and
followed for each batch of dietary
product produced and shall include
complete information relating to the
production and control of each batch.
111.50 What requirements
apply to establishing a batch
production record?
(a) You must prepare a batch
production record every time you
manufacture a batch of a dietary
ingredient or dietary supplement
and the batch production record
must include complete information
relating to the production and control
of each batch.
211.188 Batch production and control
records. (Cont.)
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:
(2) These records shall be an
accurate reproduction of the
appropriate master production and
control record and shall include
documentation that each significant
step in the manufacture, processing,
packing, or holding of the batch was
accomplished, including:
(b) Your batch production record
must accurately follow the
appropriate master manufacturing
record and you must perform each
step in producing the batch.
(c) The batch production record
must include, but is not limited to,
the following information:
(1) The batch, lot, or control
number,
Page 55 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(1) Dates; (i) Dates;
(2) Documentation at the time of
performance, showing the date on
which each step of the master
manufacturing record was
performed, and the initials of the
persons performing each step,
including but not limited to:
(i) The person responsible for
weighing or measuring each
component used in the batch; and
(ii) The person responsible for
adding the component to the batch.
(2) Identity of individual major equipment
and lines used;
(ii) Identity of individual major
equipment and lines used;
(3) The identity of equipment and
processing lines used in producing
the batch;
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.
Equipment and Utensils
(b) Sanitation of equipment and
utensils.
(11) A written record of major
equipment cleaning and use shall be
maintained in individual equipment
logs that show the date, product and
lot number of each batch processed.
The persons performing the cleaning
shall record in the log that the work
was performed. Entries in the log
should be in chronological order.
4) The date and time of the
maintenance, cleaning, and
sanitizing of the equipment and
processing lines used in producing
the batch;
211.188 Batch production and
control records. (Cont.)
(6) Inspection of the packaging and labeling
area before and after use;
(vi) Inspection of the packaging and
labeling area;
(3) Specific identification of each batch of
component or in-process material used;
(iii) Specific identification, including
lot number, of each raw material or
in-process material used;
(5) The shipment lot unique
identifier of each component, dietary
ingredient, dietary supplement,
packaging, and label used;
(4) Weights and measures of components
used in the course of processing;
(iv) Weight or measure of each raw
material used in the course of
processing;
(6) The identity and weight or
measure of each component used;
(11) Identification of the persons
performing and directly supervising or
checking each significant step in the
operation;
(7) The initials at the time of
performance or at the completion of
the batch of the person responsible
for verifying the weight or measure
of each component used in the
batch;
(11) Identification of the persons
performing and directly supervising or
checking each significant step in the
operation;
(8) The initials at the time of
performance or at the completion of
the batch of the person responsible
for verifying the addition of
components to the batch;
Page 56 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(7) A statement of the actual yield and a
statement of the percentage of theoretical
yield at appropriate phases of processing;
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.
(vii) A statement of the actual yield
at the conclusion of manufacture
and a statement of the percentage of
theoretical yield, as appropriate;
(9) A statement of the actual yield
and a statement of the percentage of
theoretical yield at appropriate
phases of processing;
211.188 Batch production and
control records. (Cont.)
(5) In-process and laboratory control
results;
(v) Quality control results;
(10) The actual test results for any
testing performed during the batch
production;
(11) Documentation that the dietary
ingredient and dietary supplement
meets specifications;
(8) Complete labeling control records,
including specimens or copies of all
labeling used;
(viii) Label control records,
including specimens, copies or
records of all labels used;
(12) Copies of all container labels
used and the results of
examinations conducted during the
label operation to ensure that the
containers have the correct label;
(9) Description of drug product containers
and closures;
(ix) Description of product
containers and closures used;
(12) Any investigation made according to
211.192.
(x) Any special notes of
investigations or deviations from
the described process.
(13) Any documented material
review and disposition decision in
accordance with 111.35(j); and
(14) Signature of the quality control
unit to document batch production
record review and any approval for
reprocessing or repackaging.
(10) Any sampling performed;
(13) Results of examinations made in
accordance with 211.134.
Page 57 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
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.
(3) Any deviation from written,
approved specifications, standards,
test procedures or other laboratory
control mechanisms shall be
recorded and justified.
(d) The quality control unit must
review in accordance with 111.37
(b) (5) the batch production record
established in paragraph (c) of this
section.
(1) If a batch deviates from the
master manufacturing record,
including any deviation from
specifications, the quality control
unit must conduct a material review
and make a disposition decision and
record any decision in the batch
production record.
(2) The quality control unit must not
approve and release for distribution
any batch of dietary ingredient or
dietary supplement that does not
meet all specifications.
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.
(e) The quality control unit must
document in accordance with
111.37(c) the review performed in
accordance with paragraph (d) of
this section and it must be
documented at the time of
performance. The review and
documentation must include, but is
not limited to, the following:
(1) Review of component, dietary
ingredient, and dietary supplement
receiving records including review
of testing and examination results;
(2) Identification of any deviation
from the master manufacturing
record that may have caused a
batch or any of its components to
fail to meet specifications identified
in the master production record;
(3) Records of investigations,
conclusions, and corrective actions
performed in accordance with
paragraph (d) of this section; and
(4) The identity of the person
qualified by training and experience
who performed the investigation in
accordance with paragraph (d) of
this section.
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PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(f) You must not reprocess a batch
that deviates from the master
manufacturing record unless
approved by the quality control unit.
You must not reprocess a dietary
ingredient or dietary supplement if it
is rejected because of
contamination with microorganisms
of public health significance or other
contaminants, such as heavy
metals;
(g) Any batch of dietary ingredient
or dietary supplement that is
reprocessed must meet all
specifications for the batch of
dietary ingredient or dietary
supplement and be evaluated and
approved by the quality control unit
before releasing for distribution.
The results of the reevaluation by
the quality control unit must be
documented in the batch production
record; and
211.170 Reserve samples.
(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
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.
(3) For an OTC drug product that is
exempt for bearing an expiration date
under 211.137, the reserve sample must
be retained for 3 years after the lot or batch
of drug product is distributed.
(h) You must collect representative
reserve samples of each batch of
dietary ingredient or dietary
supplement and keep the reserve
samples for 3 years from the date of
manufacture for use in appropriate
investigations including, but not
limited to, consumer complaint
investigations to determine whether,
for example, the dietary ingredient
or dietary supplement associated
with a consumer complaint failed to
meet any of its specifications for
identity, purity, quality, strength, and
composition.
(i) You must keep batch production
records in accordance with
111.125.
Page 59 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.22 Responsibilities of quality
control unit.
(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.
(2) Adequate laboratory facilities
should be available, as needed, to the
quality control unit.
111.60 What requirements
apply to laboratory operations?
(a) You must use adequate
laboratory facilities to perform
whatever testing and examinations
are necessary to determine that
components, dietary ingredients,
and dietary supplements received
meet specifications; that
specifications are met during in-
process, as specified in the master
manufacturing record; and that
dietary ingredients and dietary
supplements manufactured meet
specifications.
Page 60 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(b)(1) You must establish and
follow laboratory control processes
that are approved by the quality
control unit. Laboratory control
processes must include, but are not
limited to, the following:
(i) Use of criteria for selecting
appropriate examination and testing
methods;
(ii) Use of criteria for establishing
appropriate specifications; and
(iii) Use of sampling plans for
obtaining representative samples of:
(A) Components, dietary
ingredients, and dietary
supplements received to determine
whether specifications are met;
(B) In-process materials during the
batch manufacturing when testing or
examination is required in the
master manufacturing record;
(C) Each batch of dietary ingredient
or dietary supplement manufactured
to determine that the dietary
ingredient or dietary supplement
meets specifications;
(D) Packaging and labels received
to determine that he materials meet
specifications; and
(E) Each batch of packaged and
labeled dietary ingredients or
dietary supplements to ensure that
the label specified in the master
manufacturing record has been
applied.
(iv) Use of criteria for selecting
standard reference materials used
in performing tests and
examinations;
(v) Use of appropriate test method
validations; and
(vi) Use of test methods and,
examinations in accordance with
established criteria,
(2) The person who conducts the
testing and examination at the time
of performance must document that
laboratory examination results.
(3) You must keep laboratory
examination and testing records in
accordance with 111.125.
(c) You must verify that the
laboratory examination and testing
methodologies are appropriate for
their intended use.
(d) You must identify and use the
appropriate validated testing method
for each established specification
for which testing is required to
determine whether the specification
is met.
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PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
111.65 What requirements
apply to manufacturing
operations?
(a) You must design or select
manufacturing processes to ensure
that dietary ingredient or dietary
specifications are consistently
achieved.
110.80 Processes and controls.
All operations in the receiving,
inspecting, transporting, segregating,
preparing, manufacturing,
packaging, and storing of food shall
be conducted in accordance with
adequate sanitation principles...
(d) Manufacturing operations.
(1) All operations in the receiving,
inspecting, transporting, segregating,
preparing, manufacturing, packaging,
and storing of dietary products shall
be conducted in accordance with
adequate sanitation principles.
(b) You must conduct all
manufacturing operations in
accordance with adequate sanitation
principles.
...All reasonable precautions shall be
taken to ensure that production
procedures do not contribute
contamination from any source.
Chemical, microbial, or extraneous-
material testing procedures shall be
used where necessary to identify
sanitation failures or possible food
contamination.
(2) All reasonable precautions shall
be taken to assure that production
procedures do not contribute
adulteration from any source.
Chemical, microbial, or extraneous-
material testing procedures shall be
used where necessary to identify
sanitation failures or possible product
adulteration.
(c) You must take all the necessary
precautions during the manufacture
of a dietary ingredient or dietary
supplement to prevent
contamination of components,
dietary ingredients, or dietary
supplements. These precautions
include, but are not limited to:
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.
110.80(b) Manufacturing
operations.
...(2) All food manufacturing,
including packaging and storage,
shall be conducted under such
conditions and controls as are
necessary to minimize the potential
for the growth of microorganisms, or
for the contamination of food.
(4) All product manufacturing,
including packaging and storage, shall
be conducted under such conditions
and controls as are necessary to
minimize the potential for the growth
of microorganisms, or for the
adulteration of raw materials, in-
process materials and finished
product.
(1) Performing manufacturing
operations under conditions and
controls that protect against the
potential for growth of
microorganisms and the potential
for contamination;
(1)...Raw materials shall be
washed or cleaned as necessary to
remove soil or other contamination.
(2) Raw agricultural materials that
contain soil or other contaminants
shall be washed or cleaned as
necessary.
(2) Washing or cleaning
components that contain soil or
other contaminants;
(1)...Water used for washing,
rinsing, or conveying food shall be
safe and of adequate sanitary quality.
Water may be reused for washing,
rinsing, or conveying food if it does
not increase the level of
contamination of the food.
(2) Water used for washing,
rinsing, or conveying raw agricultural
materials shall be safe and of
adequate sanitary quality.
Notwithstanding the general
requirement for potable water, water
may be reused for washing, rinsing,
or conveying raw agricultural
materials if it does not increase the
level of contamination of the such
materials.
(3) Using water that meets the
National Primary Drinking Water
regulations or, where necessary,
higher sanitary quality and that
complies with all applicable
Federal, State, and local regulations
for water that is used in the
manufacturing operation. If you
reuse water that was used to wash
components to remove soil or
contaminants, the reused water
must be safe and of adequate
sanitary quality so that it does not
become a source of contamination;
(4) Performing chemical,
microbiological, or other testing as
necessary to prevent the use of
contaminated components, dietary
ingredients, and dietary
supplements;
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PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(2) Raw materials and other
ingredients shall either not contain
levels of microorganisms that may
produce food poisoning or other
disease in humans, or they shall be
pasteurized or otherwise treated
during manufacturing operations so
that they no longer contain levels that
would cause the product to be
adulterated within the meaning of the
act. Compliance with this
requirement may be verified by any
effective means, including
purchasing raw materials and other
ingredients under a supplier's
guarantee or certification.
One way to comply with this
requirement is careful monitoring of
physical factors such as time,
temperature, humidity, a
w
, pH,
pressure, flow rate, and manufacturing
operations such as freezing,
dehydration, heat processing,
acidification, and refrigeration to
ensure that mechanical breakdowns,
time delays, temperature fluctuations,
and other factors do not contribute to
the decomposition or contamination
of food.
(4) Measures such as sterilizing,
irradiating, pasteurizing, freezing,
refrigerating, controlling pH or
controlling a
w
that are taken to
destroy or prevent the growth of
undesirable microorganisms,
particularly those of public health
significance, shall be adequate under
the conditions of manufacture,
handling, and distribution to prevent
food from being adulterated within the
meaning of the act.
(14) Food such as, but not limited to,
dry mixes, nuts, intermediate
moisture food, and dehydrated food,
that relies on the control of a
w
for
preventing the growth of undesirable
microorganisms shall be processed
to and maintained at a safe moisture
level. Compliance with this
requirement may be accomplished by
any effective means, including
employment of one or more of the
following practices:
(i) Monitoring the a
w
of food.
(ii) Controlling the soluble
solids-water ratio in
finished food.
(iii) Protecting finished food
from moisture pickup, by
use of a moisture barrier
or by other means, so
that the a
w
of the food
does not increase to an
unsafe level.
(5) Measures such as sterilizing,
irradiating, pasteurizing, freezing,
refrigerating, controlling pH or
controlling water activity (aw) that are
taken to destroy or prevent the growth
of undesirable microorganisms,
particularly those of public health
significance, shall be adequate under
the conditions of manufacture,
handling, and distribution to prevent
dietary products from being
adulterated within the meaning of the
act.
(15) Intermediate or dehydrated
dietary products that rely on the
control of water activity (aw) for
preventing the growth of undesirable
microorganisms shall be processed
to and maintained at a safe moisture
level. Compliance with this
requirement may be accomplished by
any effective means, including
employment of one or more of the
following practices:
(i) Monitoring the water
activity (aw) of the
material.
(ii) Controlling the soluble
solids-water ratio in
finished product.
(iii) Protecting finished
product from moisture
pickup, by use of a
moisture barrier or by
other means, so that the
water activity (aw) of the
product does not
increase to an unsafe
level.
(5) Sterilizing, pasteurizing,
freezing, refrigerating controlling
hydrogen-ion concentration (pH),
controlling humidity, controlling
water activity (Aw), or using any
other effective means to remove,
destroy, or prevent the growth of
microorganisms and prevent
decomposition;
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PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(15) Food such as, but not limited to,
acid and acidified food, that relies
principally on the control of pH for
preventing the growth of undesirable
microorganisms shall be monitored
and maintained at a pH of 4.6 or
below. Compliance with this
requirement may be accomplished
by any effective means, including
employment of one or more of the
following practices:
(i) Monitoring the pH of
raw materials, food in
process, and finished
food.
(ii) Controlling the amount
of acid or acidified
food added to low-acid
food.
(16) Dietary ingredients and dietary
supplements that rely principally on
the control of pH for preventing the
growth of undesirable
microorganisms shall be monitored
and maintained at an appropriate pH.
Compliance with this requirement
may be accomplished by any
effective means, including
employment of one or more of the
following practices:
(i) Monitoring the pH of raw
materials, in process material, and
finished product.
(ii) Controlling the amount of acid
added to the product
(3) Food that can support the rapid
growth of undesirable micro-
organisms, particularly those of
public health significance, shall be
held in a manner that prevents the
food from becoming adulterated
within the meaning of the act.
Compliance with this requirement
may be accomplished by any
effective means, including:
(i) Maintaining refrigerated
foods at 45F (7.2C) or
below as appropriate for
the particular food
involved.
(ii) Maintaining frozen foods
in a frozen state.
(iii) Maintaining hot foods at
140F (60C) or above.
(iv) Heat treating acid or
acidified foods to
destroy mesophilic
micro-organisms when
those foods are to be
held in hermetically
sealed containers at
ambient temperatures.
(6) Holding components, dietary
ingredients, and dietary
supplements that can support the
rapid growth of microorganisms of
public health significance in a
manner that prevents the
components, dietary ingredients,
and dietary supplements from
becoming adulterated;
(7) Identifying and holding any
components, dietary ingredients, or
dietary supplements, for which a
material review and disposition
decision is required, in a manner
that protects the components,
dietary ingredients, or dietary
supplements against contamination
and mixups;
Page 64 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(10) Mechanical manufacturing
steps such as washing, peeling,
trimming, cutting, sorting and
inspecting, mashing, dewatering,
cooling, shredding, extruding, drying,
whipping, defatting, and forming
shall be performed so as to protect
food against contamination.
Compliance with this requirement
may be accomplished by providing
adequate physical protection of food
from contaminants that may drip,
drain, or be drawn into the food.
Protection may be provided by
adequate cleaning and sanitizing of
all food-contact surfaces, and by
using time and temperature controls
at and between each manufacturing
step.
(13) Mechanical manufacturing
steps such as cutting, sorting,
inspecting, shredding, drying,
grinding, blending and sifting shall be
performed so as to protect dietary
ingredients and dietary supplements
against adulteration. Compliance
with this requirement may be
accomplished by providing adequate
physical protection of dietary products
from contact with adulterants.
Protection may be provided by
adequate cleaning and sanitizing of all
processing equipment between each
manufacturing step.
(8) Performing mechanical
manufacturing steps (such as
cutting, sorting, inspecting,
shredding, drying, grinding,
blending, and sifting) by any
effective means to protect the
dietary ingredients or dietary
supplements against contamination.
Such steps must include
consideration of:
(i) Cleaning and sanitizing contact
surfaces;
(ii) Using temperature controls; and
(iii) Using time controls.
...(8) Effective measures shall be
taken to protect against the inclusion
of metal or other extraneous
material in food. Compliance with
this requirement may be
accomplished by using sieves,
traps, magnets, electronic metal
detectors, or other suitable effective
means.
(9) Effective measures shall be
taken as necessary to protect against
the inclusion of metal or other
extraneous material in product.
Compliance with this requirement
may be accomplished by using
sieves, traps, magnets, electronic
metal detectors, or other suitable
effective means.
(9) Using effective measures to
protect against the inclusion of
metal or other foreign material in
components, dietary ingredients, or
dietary supplements. Compliance
with this requirement must include
consideration of the use of:
(i) Filters or strainers;
(ii) Traps;
(iii) Magnets; or
(iv) Electronic metal detectors.
Page 65 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(8) All raw material containers,
compounding and storage containers,
processing lines and major
equipment used during the production
of a batch shall be properly identified
at all times to indicate their contents
and when necessary, the phase of
processing of the batch.
(10) Segregating and identifying all
containers for a specific batch of
dietary ingredients or dietary
supplements to identify their
contents and, where necessary, the
phase of manufacturing; and
(11) Identifying all processing lines
and major equipment used during
manufacturing to indicate their
contents including the name of the
dietary ingredient or dietary
supplement and the specific batch
or lot number and, when necessary,
the phase of manufacturing.
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.
(9)...If the adulterated food is
capable of being reconditioned, it
shall be reconditioned using a
method that has been proven to be
effective or it shall be reexamined
and found not to be adulterated within
the meaning of the act before being
incorporated into other food.
(12) Written procedures shall be
established and followed prescribing
the method for reprocessing batches
or operational start-up materials that
do not conform to finished goods
standards or specifications. Finished
goods manufactured using such
materials shall meet all established
purity, composition and quality
standards.
(d) You must conduct a material
review and make a disposition
decision in accordance with
111.35(i) for any component, dietary
ingredient, or dietary supplement
that fails to meet specifications or
that is or may be adulterated. If the
material review and disposition
decision allows you to reprocess
the component, dietary ingredient,
or dietary supplement, you must
retest or reexamine the component,
dietary ingredient, or dietary
supplement to ensure that it meets
specifications and is approved by
the quality control unit.
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.
(8) Approved raw materials 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.
211.87 Retesting of approved
components, drug product containers,
and closures.
Components, drug product containers, and
closures shall be retested or reexamined,
as appropriate, for identity, strength,
quality, and purity and approved or rejected
by the quality control unit in accordance
with 211.84 as necessary, e.g., after
storage for long periods or after exposure
to air, heat or other conditions that might
adversely affect the component, drug
product container, or closure.
(9) Raw materials shall be retested
or reexamined and approved or
rejected by the quality control after a
specified time in storage or after
exposure to air, heat, or other
conditions that are likely to adversely
affect the purity, quality or
composition of the raw material.
Page 66 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(11) Heat blanching, when required
in the preparation of food, should be
effected by heating the food to the
required temperature, holding it at
this temperature for the required
time, and then either rapidly cooling
the food or passing it to subsequent
manufacturing without delay.
Thermophilic growth and
contamination in blanchers should
be minimized by the use of adequate
operating temperatures and by
periodic cleaning. Where the
blanched food is washed prior to
filling, water used shall be safe and
of adequate sanitary quality.
(14) Heat blanching, when required
in the preparation of a dietary product,
should be effected by heating the
product to the required temperature,
holding it at this temperature for the
required time, and then either rapidly
cooling the material or passing it to
subsequent manufacturing without
delay. Thermophilic growth and
contamination in blanchers should be
minimized by the use of adequate
operating temperatures and by
periodic cleaning. Where the
blanched product is washed prior to
filling, potable water shall be used.
(12) Batters, breading, sauces,
gravies, dressings, and other similar
preparations shall be treated or
maintained in such a manner that
they are protected against
contamination. Compliance with
this requirement may be
accomplished by any effective
means, including one or more of the
following:
(i) Using ingredients free of
contamination.
(ii) Employing adequate heat
processes where applicable.
(iii) Using adequate time and
temperature controls.
(iv) Providing adequate physical
protection of components from
contaminants that may drip, drain, or
be drawn to them.
(v) Cooling to an adequate
temperature during manufacturing.
(vi) Disposing of batters at
appropriate intervals to protect
against the growth of
microorganisms.
(16) When ice is used in contact
with food, it shall be made from
water that is safe and of adequate
sanitary quality, and shall be used
only if it has been manufactured in
accordance with current good
manufacturing practice as outlined in
this part.
(17) When ice is used in contact
with dietary products, it shall be made
from potable water, and shall be used
only if it has been manufactured in
accordance with current good
manufacturing practice as outlined in
21 CFR Part 110.
(17) Food manufacturing areas and
equipment used for manufacturing
human food should not be used to
manufacture nonhuman food grade
animal food or inedible products,
unless there is no reasonable
possibility for the contamination of
the human food.
Page 67 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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:
(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.
Page 68 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(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.
(13) Filling, assembling,
packaging, and other operations
shall be performed in such a way
that the food is protected against
contamination. Compliance with
this requirement may be
accomplished by any effective
means, including:
(i) Use of a quality control
operation in which the
critical control points
are identified and
controlled during
manufacturing.
(ii) Adequate cleaning and
sanitizing of all food-
contact surfaces and
food containers.
(iii) Using materials for food
containers and food-
packaging materials that
are safe and suitable, as
defined in 130.3(d) of
this chapter.
(iv) Providing physical
protection from
contamination,
particularly airborne
contamination.
(v) Using sanitary handling
procedures.
(e) Packaging and labeling
operations.
(1) Filling, assembling, packaging,
and other operations shall be
performed in such a way that dietary
products are protected against
adulteration. Compliance with this
requirement may be accomplished by
any effective means, including:
(i) Adequate cleaning and
sanitizing of all filling
and packaging
equipment, utensils and
product containers, as
appropriate.
(ii) Using materials for
product containers and
packaging materials
that are safe and
suitable.
(iii) Providing physical
protection from
adulteration, particularly
airborne contamination.
(iv) Using sanitary handling
procedures.
111.70 What requirements
apply to packaging and label
operations?
(a) You must take necessary
actions to ensure that each
packaging container for holding
dietary ingredients or dietary
supplements meets specifications
so that the condition of the
packaging container will not
contaminate your dietary
ingredients or dietary supplements
nor cause them to deteriorate;
(b) You must fill, assemble,
package, and perform other related
operations in a way that protects
your dietary ingredients or dietary
supplements against adulteration
and misbranding. You must do this
using any effective means, including
but not limited to, the following:
(1) Cleaning and sanitizing all filling
and packaging equipment, utensils,
and dietary ingredient or dietary
supplement containers, as
appropriate;
(2) Protecting manufactured dietary
ingredients and dietary supplements
from contamination, particularly
airborne contamination;
(3) Using sanitary handling
procedures;
211.122 Materials examination and
usage criteria.
(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.
(3) For dietary supplements, labels
and other labeling materials for each
different product type, strength, or
quantity of contents shall be stored
separately with suitable identification.
(4) Establishing physical or spatial
separation of packaging and labels
from operations on other dietary
ingredients and dietary supplements
to prevent mixups;
(5) Identifying, by any effective
means, filled dietary ingredient or
dietary supplement containers that
are set aside and held in unlabeled
condition for future label operations,
to prevent mixups;
211.130 Packaging and labeling
operations.
(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.
(6) Dietary ingredient and dietary
supplement packages shall be
identified with a lot number that
permits determination of the history of
the manufacture and control of the
batch.
(6) Identifying the dietary ingredient
or dietary supplement with a batch,
lot, or control number that can be
used to determine the
manufacturing history and control of
the batch;
Page 69 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(7) Packaged and labeled dietary
supplements shall be examined to
provide assurance that containers and
packages in the lot have the correct
label and lot number. Products not
meeting specifications shall be
rejected by the quality control unit.
(7) Examining a representative
sample of each batch of the
packaged and labeled dietary
ingredient or dietary supplement to
ensure that the dietary ingredient or
dietary supplement meets
specifications and that the label
specified in the master
manufacturing record has been
applied; and
211.122 Materials examination and
usage criteria.
(e) Obsolete and outdated labels, labeling,
and other packaging materials shall be
destroyed.
(4) Obsolete labels, labeling, and
other packaging materials for dietary
products shall be destroyed.
(8) Suitably disposing of labels and
other packaging for dietary
ingredients or dietary supplements
that are obsolete or incorrect to
ensure that they are not used in any
future packaging and label
operations.
(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.
(c) You must conduct a material
review and make a disposition
decision of any packaged and
labeled dietary ingredients or
dietary supplements that do not
meet specifications.
(d) You must only repackage or
relabel dietary ingredients or dietary
supplements after the quality control
unit has approved and documented
such repackaging or relabeling.
Page 70 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(e) You must retest or reexamine
any repackaged or relabeled dietary
ingredients or dietary supplements.
They must meet all specifications
and the quality control unit must
approve or reject their release for
distribution.
211.125 Labeling issuance.
(a) Strict control shall be exercised over
labeling issued for use in drug product
labeling operations.
(b) Labeling materials issued for a batch
shall be carefully examined for identity and
conformity to the labeling specified in the
master or batch production records.
(c) Procedures shall be used to reconcile
the quantities of labeling issued, used, and
returned, and shall require evaluation of
discrepancies found between the quantity
of drug product finished and the quantity of
labeling issued when such discrepancies
are outside narrow preset limits based on
historical operating data. Such
discrepancies shall be investigated in
accordance with 211.192. Labeling
reconciliation is waived for cut or roll
labeling if a 100-percent examination for
correct labeling is performed in
accordance with 211.122(g)(2).
(5) Written procedures shall be
established and followed to assure
that correct labels, labeling, and
packaging materials are issued and
used for dietary products.
(f) (1) You must control the
issuance and use of packaging, and
labels and reconciliation of any
issuance and use discrepancies;
and
(2) You must examine, before
packaging operations, packaging
and labels for each batch of dietary
ingredient or dietary supplement to
ensure that the label and packaging
conform to the master
manufacturing record.
(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.
(g) The person that performs the
requirements of this section must
document at the time of
performance that the requirements
are performed including, but not
limited to, documentation in the
batch-production record of:
(1) The identity and quantity of the
packaging and labels used and
reconciliation of any discrepancies
between issuance and use;
(2) The examination conducted, in
accordance with paragraph (b)(7) of
this section;
(3) The conclusions you reached
from retests conducted in
accordance with paragraph (e) of
this section; and
(4) Any material reviews and
disposition decisions for packaging
and labels.
Page 71 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(h) You must keep packaging and
label operations records required
under this section in accordance
with 111.125.
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.
Page 72 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(c) Labeling.
(1) In order to alert consumers to the
specific tamper-evident feature(s) used,
each retail package of an OTC drug
product covered by this section (except
ammonia inhalant in crushable glass
ampules, containers of compressed
medical oxygen, or aerosol products that
depend upon the power of a liquefied or
compressed gas to expel the contents from
the container) is required to bear a
statement that:
(i) Identifies all tamper-evident
feature(s) and any capsule sealing
technologies used to comply with
paragraph (b) of this section;
(ii) Is prominently placed on the
package; and
(iii) Is so placed that it will be
unaffected if the tamper-evident
feature of the package is breached or
missing.
(2) If the tamper-evident feature chosen to
meet the requirements in paragraph (b) of
this section uses an identifying
characteristic, that characteristic is
required to be referred to in the labeling
statement. For example, the labeling
statement on a bottle with a shrink band
could say "For your protection, this bottle
has an imprinted seal around the neck."
(d) Request for exemptions from
packaging and labeling requirements. A
manufacturer or packer may request an
exemption from the packaging and labeling
requirements of this section. A request for
an exemption is required to be submitted in
the form of a citizen petition under 10.30
of this chapter and should be clearly
identified on the envelope as a "Request for
Exemption from the Tamper-Evident
Packaging Rule." The petition is required
to contain the following:
(1) The name of the drug product or, if the
petition seeks an exemption for a drug
class, the name of the drug class, and a list
of products within that class.
(2) The reasons that the drug product's
compliance with the tamper-evident
packaging or labeling requirements of this
section is unnecessary or cannot be
achieved.
(3) A description of alternative steps that
are available, or that the petitioner has
already taken, to reduce the likelihood that
the product or drug class will be the
subject of malicious adulteration.
(4) Other information justifying an
exemption.
Page 73 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(e) OTC drug products subject to approved
new drug applications. Holders of
approved new drug applications for OTC
drug products are required under 314.70
of this chapter to provide the agency with
notification of changes in packaging and
labeling to comply with the requirements of
this section. Changes in packaging and
labeling required by this regulation may be
made before FDA approval, as provided
under 314.70(c) of this chapter.
Manufacturing changes by which capsules
are to be sealed require prior FDA
approval under 314.70(b) of this chapter.
(f) Poison Prevention Packaging Act of
1970. This section does not affect any
requirements for "special packaging" as
defined under 310.3(l) of this chapter and
required under the Poison Prevention
Packaging Act of 1970.
111.72 What requirements
apply to packaging of iron-
containing dietary
supplements?
(a) The use of iron and iron salts as
iron sources in dietary supplements
offered in solid oral dosage form
(e.g., tablets or capsules), and
containing 30 milligrams or more of
iron per dosage unit, is safe and in
accordance with current good
manufacturing practice only when
such supplements are packaged in
unit-dose packaging. Unitdose
packaging means a method of
packaging a product into a
nonreusable container designed to
hold a single dosage unit intended
for administration directly from that
container, irrespective of whether
the recommended dose is one or
more than one of these units. The
term dosage unit means the
individual physical unit of the
product (e.g., tablets or capsules).
Iron-containing dietary supplements
that are subject to this regulation are
also subject to child-resistant
special packaging requirements in
16 CFR parts 1700, 1701, and 1702.
(b)(1) Dietary supplements offered
in solid oral dosage form (e.g.,
tablets or capsules), and containing
30 milligrams or more of iron per
dosage unit, are exempt from the
provisions of paragraph (a) of this
section until January 15, 1998, if the
sole source of iron in the dietary
supplement is carbonyl iron that
meets the specifications of
184.1375 of this chapter.
(2) If the temporary exemption is
not extended or made permanent,
such dietary supplements shall be
in compliance with the provisions of
paragraph (a) of this section on or
before July 15,1998.
Page 74 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
(9) Food, raw materials, and other
ingredients that are adulterated
within the meaning of the act shall be
disposed of in a manner that protects
against the contamination of other
food...
(10) Rejected raw materials, shall
be identified and controlled under a
system that prevents their use in
manufacturing or processing
operations for which they are
unsuitable.
(10) Dietary products, raw materials,
and in-process materials that are
rejected or adulterated within the
meaning of the act shall be identified,
stored and disposed of in a manner
that protects against the adulteration
of other products.
111.74 What requirements
apply to rejected components,
dietary ingredients, dietary
supplements, packaging, and
labels?
You must clearly identify, hold, and
control under a quarantine system
any component, dietary ingredient,
dietary supplement, packaging, and
label that is rejected and unsuitable
for use in manufacturing, packaging,
or label operations.
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.
110.93 Warehousing and
distribution.
Storage and transportation of
finished food shall be under
conditions that will protect food
against physical, chemical, and
microbial contamination as well as
against deterioration of the food and
the container.
Warehousing, Distribution and
Post-Distribution Procedures
(a) Storage and distribution.
(1) Storage and transportation of
finished product shall be under
conditions that will protect product
against physical, chemical, and
microbial adulteration as well as
against deterioration of the product
and the container.
Subpart F--Holding and
Distributing
111.80 What requirements
apply to holding components
dietary ingredients, dietary
supplements, packaging and
labels?
(a) You must hold components,
dietary ingredients, and dietary
supplements under appropriate
conditions of temperature, humidity,
and light so that the identity, purity,
quality, strength, and composition of
the components, dietary ingredients,
and dietary supplements are not
affected.
(b) You must hold packaging and
labels under appropriate conditions
of temperature, humidity, and light
so that the quality of the packaging
and labels are not affected.
(6) Effective measures shall be
taken to protect finished food from
contamination by raw materials,
other ingredients, or refuse. When
raw materials, other ingredients, or
refuse are unprotected, they shall not
be handled simultaneously in a
receiving, loading, or shipping area if
that handling could result in
contaminated food. Food
transported by conveyor shall be
protected against contamination as
necessary.
(7) Effective measures shall be
taken to protect finished dietary
ingredients and dietary supplements
from adulteration by raw materials,
in-process materials or refuse.
When raw materials, in-process
materials or refuse are unprotected,
they shall not be handled
simultaneously in a receiving,
loading, or shipping area if that
handling could result in adulterated
dietary products. Dietary ingredients
and dietary supplements transported
by conveyor shall be protected
against adulteration as necessary.
(c) You must hold components,
dietary ingredients, dietary
supplements, packaging, and labels
under conditions that do not lead to
the mixup, contamination, or
deterioration of components, dietary
ingredients, dietary supplements,
packaging, and labels.
(5) Work-in-process shall be
handled in a manner that protects
against contamination.
(6) Work-in-process shall be
handled in a manner that protects
against adulteration.
Sec. 111.82 What requirements
apply to holding in-process
material?
(a) You must identify and hold in-
process material under conditions
that will protect them against mixup,
contamination, and deterioration
(b) You must hold in process
material under appropriate
conditions of temperature, humidity,
and light.
Page 75 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
111.83 What requirements
apply to holding reserve samples
of components, dietary
ingredients and dietary
supplements?
(a) For any reserve samples of
components or dietary ingredients
you collect, you must hold such
reserve samples in a manner that
protects against contamination and
deterioration:
(2) For an active ingredient in a radioactive
drug product, except for nonradioactive
reagent kits, the reserve sample shall be
retained for:
(i) Three months after the expiration
date of the last lot of the drug product
containing the active ingredient if the
expiration dating period of the drug
product is 30 days or less; or
(ii) Six months after the expiration
date of the last lot of the drug product
containing the active ingredient if the
expiration dating period of the drug
product is more than 30 days.
(3) For an active ingredient in an OTC
drug product that is exempt from bearing
an expiration date under 211.137, the
reserve sample shall be retained for 3
years after distribution of the last lot of the
drug product containing the active
ingredient.
Page 76 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(b) An appropriately identified reserve
sample that is representative of each lot or
batch of drug product shall be retained and
stored under conditions consistent with
product labeling. The reserve sample shall
be stored in the same immediate
container-closure system in which the
drug product is marketed or in one that has
essentially the same characteristics. The
reserve sample consists of at least twice
the quantity necessary to perform all the
required tests, except those for sterility and
pyrogens. Except for those for drug
products described in paragraph (b)(2) of
this section, reserve samples from
representative sample lots or batches
selected by acceptable statistical
procedures shall be examined visually at
least once a year for evidence of
deterioration unless visual examination
would affect the integrity of the reserve
sample. Any evidence of reserve sample
deterioration shall be investigated in
accordance with 211.192. The results of
the examination shall be recorded and
maintained with other stability data on the
drug product. Reserve samples of
compressed medical gases need not be
retained. The retention time is as follows:
(1) For a drug product other than those
described in paragraphs (b) (2) and (3) of
this section, the reserve sample shall be
retained for 1 year after the expiration date
of the drug product.
(3) For an OTC drug product that is
exempt for bearing an expiration date
under 211.137, the reserve sample must
be retained for 3 years after the lot or batch
of drug product is distributed.
(b) Reserve samples. An
appropriately identified reserve
sample that is representative of each
batch of a dietary product should be
retained and stored under conditions
consistent with the product labeling
until at least one year after the
expiration date, or if no expiration date
is identified on the product, for at least
three years after the date of
manufacture. The reserve sample
should be stored in the same
immediate container-closure system
in which the finished product is
marketed or in one that provides
similar protection. The reserve
sample shall consist of at least twice
the quantity necessary to perform all
the required tests.
(b) You must hold reserve samples
of dietary supplements in a manner
that protects against contamination
and deterioration. This includes, but
is not limited to:
(1) Holding the reserve samples
under conditions of use
recommended or suggested in the
label of the dietary supplement and,
if no conditions of use are
recommended or suggested in the
label, then under ordinary conditions
of use; and
(2) Using the same container-
closure system in which the dietary
supplement is marketed or in one
that provides the same level of
protection against contamination or
deterioration.
(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.
Page 77 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
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.
211.176 Penicillin contamination.
If a reasonable possibility exists that a non-
penicillin drug product has been exposed to
cross-contamination with penicillin, the
non-penicillin drug product shall be tested
for the presence of penicillin. Such drug
product shall not be marketed if detectable
levels are found when tested according to
procedures specified in `Procedures for
Detecting and Measuring Penicillin
Contamination in Drugs,' which is
incorporated by reference. Copies are
available from the Division of Research
and Testing (HFD-470), Center for Drug
Evaluation and Research, Food and Drug
Administration, 200 C St. SW.,
Washington, DC 20204, or available for
inspection at the Office of the Federal
Register, 800 North Capitol Street, NW.,
suite 700, Washington, DC 20408.
Page 78 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.204 Returned drug products.
Returned drug products shall be identified
as such and held. If the conditions under
which returned drug products have been
held, stored, or shipped before or during
their return, or if the condition of the drug
product, its container, carton, or labeling,
as a result of storage or shipping, casts
doubt on the safety, identity, strength,
quality or purity of the drug product, the
returned drug product shall be destroyed
unless examination, testing, or other
investigations prove the drug product
meets appropriate standards of safety,
identity, strength, quality, or purity. A drug
product may be reprocessed provided the
subsequent drug product meets
appropriate standards, specifications, and
characteristics. Records of returned drug
products shall be maintained and shall
include the name and label potency of the
drug product dosage form, lot number (or
control number or batch number), reason
for the return, quantity returned, date of
disposition, and ultimate disposition of the
returned drug product. If the reason for a
drug product being returned implicates
associated batches, an appropriate
investigation shall be conducted in
accordance with the requirements of
211.192. Procedures for the holding,
testing, and reprocessing of returned drug
products shall be in writing and shall be
followed.
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.
(e) Returned products. Returned
dietary products shall be identified as
such and held. If the conditions under
which returned dietary products have
been held, stored, or shipped before
or during their return, or if the
condition of the product, its container,
carton, or labeling as a result of
storage or shipping, casts doubt on
the purity, composition or quality of
the product, the returned product shall
be destroyed unless examination,
testing or other investigations prove
the product meets appropriate
standards of purity, composition and
quality. A product may be
reprocessed provided the subsequent
product meets appropriate
specifications. Records pertaining to
returned products that are
subsequently reprocessed and/or
redistributed shall be maintained and
shall include the name and
description of the product, lot number,
reason for the return, quantity
returned, date of disposition, and
ultimate disposition of the returned
product.
(f) Product salvaging. Dietary
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 products have
been subjected to such conditions,
salvaging operations may be
conducted only if there is (a) evidence
from laboratory tests that the products
meet all applicable standards of
purity, quality and composition, and
(b) evidence from inspection of the
premises that the products and their
associated packaging were not
subjected to improper storage
conditions as a result of the disaster
or accident. Records including
name, lot number, and disposition
shall be maintained for products
subject to this section.
111.85 What requirements
apply to returned dietary
ingredients or dietary
supplements?
(a) You must identify and quarantine
returned dietary ingredients or
dietary supplements until the quality
control unit conducts a material
review and makes a disposition
decision.
(b) You must not salvage returned
dietary ingredients and dietary
supplements, unless:
(1) Evidence from their packaging
(or, if possible, an inspection of the
premises, where the dietary
ingredients and dietary supplements
were held) indicates that the dietary
ingredients and dietary supplements
were not subjected to improper
storage conditions; and
(2) Tests demonstrate that the
dietary ingredients or dietary
supplements meet all specifications
for identity, purity, quality, strength,
and composition.
(c) You must destroy or suitably
dispose of the returned dietary
ingredients or dietary supplements
if such dietary ingredients or dietary
supplements do not meet
specifications for identity, purity,
quality, strength, and composition,
unless the quality control unit
conducts a material review and
makes a disposition decision to
allow reprocessing.
(d) If the reason for a dietary
ingredient or a dietary supplement
being returned implicates
associated batches, you must
conduct an investigation of your
manufacturing processes and those
other batches to determine
compliance with specifications.
(e) You must establish and keep
records for this section on the
material review and disposition
decision and any testing conducted
to determine compliance with
established specifications in the
master manufacturing record for the
type of dietary ingredient or dietary
supplement that was returned.
(f) You must keep returned dietary
ingredient and dietary supplement
records in accordance with
111.125.
Page 79 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
111.90 What requirements
apply to distributing dietary
ingredients or dietary
supplements?
Distribution of dietary ingredients
and dietary supplements must be
under conditions that will protect the
dietary ingredients and dietary
supplements against contamination
and deterioration.
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.
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.
(2) Adequate distribution records
shall be maintained and retained by
the manufacturer at least one year
beyond expected product shelf life,
whereby an effective product recall
can be achieved should one become
necessary.
Page 80 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.198 Complaint files.
(a) Written procedures describing the
handling of all written and oral complaints
regarding a drug product shall be
established and followed. Such procedures
shall include provisions for review by the
quality control unit, of any complaint
involving the possible failure of a drug
product to meet any of its specifications
and, for such drug products, a
determination as to the need for an
investigation in accordance with 211.192.
Such procedures shall include provisions
for review to determine whether the
complaint represents a serious and
unexpected adverse drug experience
which is required to be reported to the
Food and Drug Administration in
accordance with 310.305 of this chapter.
(d) Complaint files.
(1) Written procedures describing
the handling of all written and oral
complaints regarding a dietary
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
product to meet any of its
specifications and, for such products,
a determination as to the need for an
investigation.

Subpart G--Consumer
Complaints
111.95 What requirements
apply to consumer complaints?
(a) A qualified person must review
all consumer complaints to
determine whether the consumer
complaint involves a possible
failure of a dietary ingredient or
dietary supplement to meet any of
its specifications, or any other
requirements of this part, including
those specifications and other
requirements that, if not met, may
result in a possible risk of illness or
injury.
(b) Your quality control unit must
review all consumer complaints
involving the possible failure of a
dietary ingredient or dietary
supplement to meet any of its
specifications, or any other
requirements of this part, including
those-specifications and other
requirements that, if not met, may
result in a possible risk of illness or
injury, to determine whether there is
a need to investigate the consumer
complaint.
(c) Your quality control unit must
investigate a consumer complaint
when there is a reasonable
possibility of a relationship between
the quality of a dietary supplement
and an adverse event.
(d) Your quality control unit's
investigation of a consumer
complaint must include the batch
records associated with the dietary
ingredient or dietary supplement
involved in the consumer complaint.
Your quality control unit must
extend the investigation to other
batches of dietary ingredients or
dietary supplements that may have
been associated with an adverse
event.
Page 81 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(b) A written record of each complaint
shall be maintained in a file designated for
drug product complaints. The file regarding
such drug product complaints shall be
maintained at the establishment where the
drug product involved was manufactured,
processed, or packed, or such file may be
maintained at another facility if the written
records in such files are readily available
for inspection at that other facility. Written
records involving a drug product shall be
maintained until at least 1 year after the
expiration date of the drug product, or 1
year after the date that the complaint was
received, whichever is longer. In the case
of certain OTC drug products lacking
expiration dating because they meet the
criteria for exemption under 211.137,
such written records shall be maintained
for 3 years after distribution of the drug
product.
(2) A written record of each
complaint shall be maintained, until at
least 1 year after the expiration date of
the product, or 1 year after the date
that the complaint was received,
whichever is longer.
(4) Where an investigation is
conducted, the written record shall
include the findings of the
investigation and follow-up action
taken.
(e) You must make and keep a
written record of every consumer
complaint that is related to good
manufacturing practices. For the
purposes of the regulations in this
part, a consumer complaint about
product quality may or may not
include concerns about a possible
hazard, to health. However, a
consumer complaint does not
include an adverse event, illness, or
injury related to the safety of a
particular dietary ingredient
independent of whether the product
is produced under good
manufacturing practices.
(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.
(3) The written record shall include,
where known: the name and
description of the product, lot number,
name of complainant, nature of
complaint, and reply to complainant, if
any.
The consumer complaint written
record must include, but is not
limited to, the following:
(1) The name and description of the
dietary ingredient or dietary
supplement;
(2) The batch or lot number of the
dietary supplement, if available;
(3) The name of the complainant, if
available;
(4) The nature of the complaint
including how the consumer used
the product;
(5) The reply to the complainant if
any; and
(6) Findings of the investigation and
follow-up action taken when an
investigation is performed.
(2) Where an investigation under 211.192
is conducted, the written record shall
include the findings of the investigation and
followup. The record or copy of the record
of the investigation shall be maintained at
the establishment where the investigation
occurred in accordance with 211.180(c).
(3) Where an investigation under 211.192
is not conducted, the written record shall
include the reason that an investigation
was found not to be necessary and the
name of the responsible person making
such a determination.
(f)(1) The person who performs the
requirements in accordance with
this section must document at the
time of performance that the
requirement was performed.
(2) You must keep consumer
complaint records in accordance
with 111.125.
Page 82 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
211.180 General requirements.
(a) Any production, control, or distribution
record that is required to be maintained in
compliance with this part and is
specifically associated with a batch of a
drug product shall be retained for at least 1
year after the expiration date of the batch
or, in the case of certain OTC drug
products lacking expiration dating because
they meet the criteria for exemption under
211.137, 3 years after distribution of the
batch.
(b) Records shall be maintained for all
components, drug product containers,
closures, and labeling for at least 1 year
after the expiration date or, in the case of
certain OTC drug products lacking
expiration dating because they meet the
criteria for exemption under 211.137, 3
years after distribution of the last lot of drug
product incorporating the component or
using the container, closure, or labeling.
(c) Records retention.
(1) Any laboratory, production,
control or distribution record
specifically associated with a batch of
product shall be retained for at least
one year after the expiration date of
the batch, or if no expiration date is
identified on the product, for at least
three years after the date of
manufacture.
(2) Raw material records shall be
maintained for at least one year after
the expiration date of the last batch of
product incorporating the raw
material, or if no expiration date is
identified on the product, for at least
three years after the date of
manufacture of the finished product.
Subpart H--Records and
Recordkeeping
111.125 What requirements
apply to recordkeeping?
(a) You must keep written records
required by this part for 3 years
beyond the date of manufacture of
the last batch of dietary ingredients
or dietary supplements associated
with those records.
(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.
(b) Records required under this part
must be kept as original records, as
true copies (such as photocopies,
microfilm, microfiche, or other
accurate reproductions of the
original records), or as electronic
records. If you use reduction
techniques, such as microfilming,
you must make suitable reader and
photocopying equipment readily
available to FDA. All electronic
records must comply with part 11 of
this chapter.
(c) You must have all records
required under this part, or copies of
such records, readily available
during the retention period for
authorized inspection and copying
by FDA when requested.
(e) Written records required by this part
shall be maintained so that data therein can
be used for evaluating, at least annually,
the quality standards of each drug product
to determine the need for changes in drug
product specifications or manufacturing or
control procedures. Written procedures
shall be established and followed for such
evaluations and shall include provisions
for:
(1) A review of a representative number of
batches, whether approved or rejected,
and, where applicable, records associated
with the batch.
(2) A review of complaints, recalls,
returned or salvaged drug products, and
investigations conducted under 211.192
for each drug product.
Page 83 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(f) Procedures shall be established to
assure that the responsible officials of the
firm, if they are not personally involved in
or immediately aware of such actions, are
notified in writing of any investigations
conducted under 211.198, 211.204, or
211.208 of these regulations, any recalls,
reports of inspectional observations issued
by the Food and Drug Administration, or
any regulatory actions relating to good
manufacturing practices brought by the
Food and Drug Administration
Subpart G--Defect Action Levels
110.110 Natural or unavoidable
defects in food for human use that
present no health hazard.
(a) Some foods, even when
produced under current good
manufacturing practice, contain
natural or unavoidable defects that at
low levels are not hazardous to
health. The Food and Drug
Administration establishes
maximum levels for these defects in
foods produced under current good
manufacturing practice and uses
these levels in deciding whether to
recommend regulatory action.
(g) Defect Action Levels.
(1) Some dietary ingredients and
dietary supplements, even when
produced under current good
manufacturing practice, contain
natural or unavoidable defects that at
low levels are not hazardous to
health. The Food and Drug
Administration establishes maximum
levels for these defects in dietary
products produced under current good
manufacturing practice and uses
these levels in deciding whether to
recommend regulatory action.
(b) Defect action levels are
established for foods whenever it is
necessary and feasible to do so.
These levels are subject to change
upon the development of new
technology or the availability of new
information.
(2) Defect action levels are
established for dietary products
whenever it is necessary and feasible
to do so. These levels are subject to
change upon the development of new
technology or the availability of new
information.
PART 112--RESTRICTIONS,.
FQR SUBSTANCES USED IN
DIETARY SUPPLEMENTS
Subpart A--General Provisions
[Reserved]
Subpart B--New Dietary
Ingredients [Reserved]
Subpart C--Restricted Dietary
Ingredients [Reserved]
(c) Compliance with defect action
levels does not excuse violation of
the requirement in section 402(a)(4)
of the act that food not be prepared,
packed, or held under unsanitary
conditions or the requirements in
this part that food manufacturers,
distributors, and holders shall
observe current good manufacturing
practice. Evidence indicating that
such a violation exists causes the
food to be adulterated within the
meaning of the act, even though the
amounts of natural or unavoidable
defects are lower than the currently
established defect action levels. The
manufacturer, distributor, and holder
of food shall at all times utilize
quality control operations that reduce
natural or unavoidable defects to the
lowest level currently feasible.
(3) Compliance with defect action
levels does not excuse violation of the
requirement in section 402(a)(4) of
the act that dietary products not be
prepared, packed, or held under
unsanitary conditions or the
requirements in this part that dietary
product manufacturers, distributors,
and holders shall observe current
good manufacturing practice.
Evidence indicating that such a
violation exists causes a dietary
product to be adulterated within the
meaning of the act, even though the
amounts of natural or unavoidable
defects are lower than the currently
established defect action levels. The
manufacturer, distributor, and holder
of a dietary product shall at all times
utilize quality control operations that
reduce natural or unavoidable defects
to the lowest level currently feasible.
Page 84 of 84
PHARMACEUTICAL cGMP
(21 CFR Part 210 & 211)
Food cGMP (21 CFR Part 110) Advanced Notice of Proposed
Rulemaking (ANPR) (FR: 2-6-97)
Proposed cGMP for Dietary
Ingredients and Dietary
Supplements (FR: 3-13-03)
(d) The mixing of a food containing
defects above the current defect
action level with another lot of food is
not permitted and renders the final
food adulterated within the meaning
of the act, regardless of the defect
level of the final food.
(4) The mixing of a dietary
ingredient or dietary supplement
containing defects above the current
defect action level with another lot of
dietary ingredient or dietary
supplement is not permitted and
renders the final product adulterated
within the meaning of the act,
regardless of the defect level of the
final product.
(e) A compilation of the current
defect action levels for natural or
unavoidable defects in food for
human use that present no health
hazard may be obtained upon
request from the Industry Programs
Branch (HFF-326), Center for Food
Safety and Applied Nutrition, Food
and Drug Administration, 200 C St.
SW., Washington, DC 20204.
(5) A compilation of the current
defect action levels for natural or
unavoidable defects in dietary
products that present no health hazard
may be obtained upon request from
the Industry Programs Branch (HFF-
326), Center for Food Safety and
Applied Nutrition, Food and Drug
Administration, 200 C St. SW.,
Washington, DC 20204.