of dietary supplements and that the dietary supplement is packaged and
labeled as specified in your master manufacturing record (final §
111.65); establish specifications (final § 111.70); determine whether
specifications are met (final § 111.73 and § 111.75); collect
representative samples (final § 111.80); hold reserve samples of
packaged and labeled dietary supplements (final § 111.83); have the
quality control unit personnel conduct all required material reviews and
makes all required disposition decisions (final § 111.87); and adhere
to certain requirements for treatment, in-process adjustments, and for
reprocessing (final § 111.90).

	In considering whether we should require that you establish and follow
written procedures to fulfill the requirements of final subpart E, we
evaluated whether requirements in other subparts that address specific
operations for the production and process control system substitute for
the requirement of written procedures in final subpart E.

	Final subparts F through M establish specific requirements for
manufacturing, packaging, labeling, and holding dietary supplements,
including requirements for quality control operations (final subpart F);
components, packaging, labels, and product that is received for
packaging and labeling as a dietary supplement (final subpart G);
establishing a written master manufacturing record and batch record
(final subparts H and I); laboratory operations (final subpart J);
manufacturing operations (final subpart K); packaging and labeling
operations (final subpart L); and holding operations (final subpart M).
We require you to establish and follow written procedures to fulfill the
requirements of final subparts F, G, J, K, L, and M.  Given these
requirements, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill the requirements of
final §§ 111.55, 111.60, and 111.65 in subpart E.

	Final subpart J requires you to establish and follow laboratory control
processes that include the use of criteria for establishing appropriate
specifications (final § 111.315(a); use of sampling plans for obtaining
representative samples (final § 111.315(b)); use of criteria for
selecting appropriate examination and testing methods (final §
111.315(c)); use of criteria for selecting standard reference materials
used in performing tests and examinations (final § 111.315(d)); and use
of test methods and examinations in accordance with established criteria
(final § 111.315(e)).  In addition, under final § 111.303 you must
establish and follow written procedures for laboratory operations.
Given the requirements of final subpart J, we conclude it would be
redundant to require you to establish and follow written procedures to
fulfill the requirements of final §§ 111.70, 111.75, and 111.80 in
subpart E.

	Final subpart M establishes requirements for holding reserve samples.
Under final § 111.453 you must establish and follow written procedures
for holding operations.  Given the requirements of final subpart M, we
conclude that it would be redundant to require you to establish and
follow written procedures to fulfill the requirements of final § 111.83
in subpart E for reserve samples.

	Final subpart F establishes requirements for the quality control unit
personnel to conduct a material review and make a disposition decision
(final § 111.113); approve any reprocessing (final § 111.123(a)(5));
and document any material review and disposition (final §
111.140(b)(3)).  In addition, as discussed, under final § 111.103 you
must establish and follow written procedures for quality control
operations.  Given the requirements of final subpart F, we conclude that
it would be redundant to require that you establish and follow written
procedures to fulfill the requirements of final §§ 111.87 and 111.90
in subpart E.

	We conclude that it would be redundant to require you to establish and
follow written procedures for each of the requirements established in
final subpart E.  We, therefore,  do not require you to establish and
follow written procedures to fulfill the requirements established in
subpart E.

	b.  Written procedures for preparing the master manufacturing record
(final subpart H) and for preparing the batch record (final subpart I).

	As discussed in the 2003 CGMP proposal (68 FR 12157 at 12203), a master
manufacturing record is analogous to a recipe that sets forth the
ingredients to use, the amounts of ingredients to use, the tests to
perform, and the instructions for preparing the quantity the recipe
calls for.  This master manufacturing record helps ensure that you
manufacture each ingredient or dietary supplement in a consistent and
uniform manner.  If you neglect to follow the master manufacturing
record, you might not add all of the necessary components in the
appropriate strength or amount, and this could result in a final product
not consistent with the master manufacturing record.  Thus, you must
follow a written master manufacturing record in a consistent manner,
regardless of who conducts the operation or when it is conducted.

	However, we agree with the comments that the specific requirements for
what must be in the master manufacturing record make it unnecessary to
require written procedures for preparing the master manufacturing
record.  Under final subpart H, the master manufacturing record must
include written instructions, including specifications for each point,
step, or stage in the manufacturing process where control is necessary
to ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record; procedures for sampling, testing, and
examinations; specific actions necessary to perform and verify points,
steps, or stages in the manufacturing process where control is necessary
to ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record; special notations and precautions to be followed;
and corrective action plans for use when a specification is not met.
With all of this detail specified for the written instructions the
master manufacturing record must include, we believe a written procedure
for developing a master manufacturing record can be optional.
Therefore, we do not require you to establish and follow written
procedures for preparing the master manufacturing record.

	A batch is prepared by following the written instructions provided in
the master manufacturing record.  The master manufacturing record
functions as a written procedure for the production of the batch.
Therefore, we do not require you to establish and follow written
procedures for the batch production record because such practices would
be redundant with the requirements for the master manufacturing record
in final subpart H.

	c.  Written procedures for Records and Recordkeeping (final subpart P)

	Final subpart P establishes general requirements for making and keeping
records required in other subparts.  We did not request comments on
written procedures nor did we receive any comments that supported such a
requirement.  Because we believe that requiring written procedures to
fulfill Subpart P requirements would be redundant or unnecessary, we do
not require such written procedures.

d.  Written procedures for product recalls.

	We acknowledge that a product recall by persons who manufacture,
package, label, or hold dietary supplements must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted.  However, the final rule does not establish any
requirements for product recalls.  Therefore, we do not require you to
establish and follow written procedures for product recalls.  However,
we encourage you to refer to our “Guidance for Industry: Product
Recalls, Industry removals and Corrections” (Ref. 128) (available at
http://www.fda.gov/opacom/7alerts.html).

D.  Other Comments on Written Procedures

	(Comment 9) One comment stresses the need for flexibility in requiring
written procedures, based on differences between individual activities
and companies.  The comment suggests companies should be required to
review and determine the need for written procedures at each critical
step of their operations and be prepared to defend those determinations
as necessary.

	(Response) To the extent the comment suggests we do not require any
written procedures specific to a particular function or requirement, and
allow firms to decide when and when not to include them, we disagree.
We believe that written procedures for the specific operations we have
identified should not be optional.  We have no objection if firms decide
to establish and follow additional written procedures, beyond those we
require in this final rule.  Although we require written procedures for
entire subparts, or specific requirements within certain subparts, we
provide flexibility for firms to establish those written procedures that
will ensure the requirements are met.

	(Comment 10) Some comments stress the importance of written procedures
in enabling FDA to ensure compliance with the dietary supplement CGMP
requirements.

	(Response) We believe written procedures will help us to ensure
compliance with these CGMP requirements, because they will clearly
communicate the steps the firm must take to satisfy the requirements.
During an inspection, we observe the practices that employees follow.
However, to ensure that a firm is consistently complying with CGMP
requirements, our investigators need access to records that both
describe a firm’s processes and procedures and demonstrate whether the
firm has been following them.  Under the final rule, we require you to
make and keep records of the written procedures in each applicable
subpart.  Such records would be available to us under the requirements
of final subpart P, Records and Recordkeeping.

	(Comment 11)  Many comments object to FDA’s stated reasons for not
requiring written procedures for most activities, including concerns
about cost control and burden reduction.  The comments contend that
written procedures actually save time and other resources because they
greatly facilitate employee training and ensure that activities are
performed consistently and correctly.  Some comments assert most
companies already have written procedures in place, so start-up costs
associated with such requirements would be minimal.  One comment notes
written procedures would be among the least costly of all the procedural
requirements proposed by FDA.

	(Response) We agree that requiring that operations be conducted using
written procedures can save time and other resources by facilitating
employee training and ensuring operations are performed consistently and
correctly.  Because following written procedures can help ensure
uniformity in the process and ensure the quality of the dietary
supplement at every step, periodic end product testing can be sufficient
to determine whether your manufacturing process is controlled.   CGMP is
premised upon quality assurance at every step of the process.  It is
less costly to establish and follow written procedures than it would be
to test each finished batch for conformance with specifications.  As
suggested by these comments, our analysis (section XXIV) shows that the
overall costs are reduced, in part, because requiring that certain
operations be conducted using written procedures enables us to reduce
requirements for testing at the finished batch stage.

	(Comment 12) One comment states training employees on the required
hygienic practices prior to their first day of handling product is
critical to ensuring product safety.

	(Response) The requirement to establish and follow written procedures
to fulfill the requirements of subpart B does not establish any fixed
requirement for when an employee must receive such training relative to
when the employee handles product.  However, final § 111.12(c) requires
that any person engaged in manufacturing, packaging, labeling or
holding, or in performing any quality control operations, must have the
education, training, or experience to perform the person's assigned
functions.  We therefore assume that employees will have the necessary
education, training, or experience for each operation that they perform
before they perform it.

	(Comment 13) Some comments make recommendations for what written
procedures should contain, including general parameters that should be
included in all written procedures and specific parameters that should
be included in specific written procedures.  The general parameters
include identification of the company; title that reflects the
activities to be performed; identification or control number with a
revision level code; effective date; the number of pages in the
procedure (e.g., by a procedure such as listing page numbers using a
convention such as “page 1 of 4”); approval date and signature(s);
references to linked or related procedures or forms; definitions of
technical terms and acronyms; list of equipment, materials, and supplies
needed in performing the task; who has the responsibility for performing
each task; when and where a task is to be performed; concise step by
step instructions for performing the task; the expected results from
performing the task; what data to collect; and how to analyze, file, or
report the collected data.  In the specific case of written procedures
for cleaning equipment and utensils, some comments suggest the written
procedures include descriptions of appropriate cleaning agents, methods
of cleaning, and the intervals and schedules for cleaning equipment.

	(Response) We agree the suggestions provided by these comments are
useful to include in any written procedures.  However, to provide the
flexibility necessary to address diverse dietary supplement
manufacturing processes, we are leaving details such as these to the
judgment of the company rather than prescribing them within the final
rule.

	(Comment 14) Some comments request the final rule include requirements
for managing changes to written procedures. One comment states changes
to written procedures should be reviewed, justified, documented,
approved, and implemented in a defined manner.  The comments explain
that “Change control procedures” define what is and what is not
covered by the written procedure and how proposed changes will be
identified or recommended, processed, reviewed and approved.

	(Response) As discussed in final Subpart F, the final rule requires
that the quality control unit personnel approve all written procedures.
“All” written procedures includes revisions to written procedures.
As discussed in this section, the final rule requires you to establish
and follow written procedures for quality control operations.  We
believe that procedures for managing changes to written procedures can
be addressed within the written procedures for quality control
operations.

	(Comment 15) Some comments assert the final rule should not require
written procedures for key operations because the rule should stay
focused on end results and not process.

	(Response) We disagree.  The essence of good manufacturing practice
that is established by this final rule is a production and process
control system that is designed to ensure the quality of the dietary
supplement.

E.  What Other General Comments Did We Receive?

	(Comment 16) Some comments say any final rule should not require
written procedures, should not propose a definition of appropriate
tests, and generally should not include requirements for procedures
better left to “normal business practices.”  The comments cited
Executive Order 12866 and the Small Business Regulatory Enforcement
Flexibility Act (SBREFA).  The comment added that there is no such
requirement in the food CGMPs or in the 1997 ANPRM.

	(Response)  We disagree the final rule violates either Executive Order
12866 or SBREFA and discuss this in section XXIV.  We address SBREFA’s
regulatory flexibility issues by staggering compliance dates so that
certain businesses would have 24 and 36 months, respectively, to comply
with the final rule.  As for the assertion that food CGMPs do not
require written procedures, we discuss the requirements of food CGMPS in
relation to the requirements of these dietary supplement CGMPs in
section V.  The comment’s assertion that the 1997 ANPRM did not
contain written
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●	Cleaning and maintaining equipment and utensils used in the
manufacture of products;

●	The receipt, identification, examination, handling, sampling,
testing, and approval or rejection of raw materials;

●	Appropriate tests and/or examinations to be conducted to assure the
purity, composition, and quality of the finished product;

●	The method for reprocessing batches or operational start-up
materials that do not conform to finished goods standards or
specifications;

●	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;

●	Ensuring correct labels, labeling, and packaging materials are
issued and used for dietary products; and

●	Describing the handling of all written and oral complaints regarding
a product.

(62 FR 5699 at pages 5704 through 5706).

	(Comment 17) In the analysis of impacts in the 2003 CGMP Proposal (68
FR 12157 at 12222), we stated that we had considered imposing fewer CGMP
requirements for the manufacture of vitamins and minerals.  Although
this issue arose as a discussion of regulatory options that we had
considered and rejected, we received several comments on this subject.
Some comments state we should not create different CGMP standards based
upon the type of dietary ingredient.  These comments state that one set
of appropriately flexible standards would be more efficient and less
confusing to industry than separate standards for each portion of the
industry.  Some comments say that different requirements for vitamins
and minerals would cause problems because most people who use these
products take a multivitamin/mineral preparation as their primary and
sole dietary supplement, so the risk of adverse events arising from
adulteration, misidentification, or misformulation of products would be
much higher if vitamins and minerals were subject to fewer requirements
compared to other dietary supplements.  Other comments supported the
concept of differing standards.  Some comments assert, in order for the
CGMP regulations to set minimum quality standards for all dietary
supplements, we would have to regulate each facet of the manufacture,
packaging, and storage of a dietary supplement independently of product
type.  These comments state reducing the requirements for vitamin and
mineral manufacturers would not allow the development of minimum quality
standards across the entire dietary supplement industry.

	(Response) The concept of fewer requirements for vitamins and minerals
was simply one regulatory option we considered as part of the 2003 CGMP
Proposal’s analysis of impacts (see 68 FR 12157 at 12220 through
12223).  We rejected it (id).  We disagree with the comments that there
should be fewer CGMP requirements for vitamins and minerals.  Neither
the 2003 CGMP Proposal, nor this final rule, imposes fewer requirements
on vitamin or mineral firms compared to firms that make other types of
dietary supplements.

V. What Legal Authority Comments Did We Receive?

	Many comments were submitted from individuals, companies, and trade
groups concerning our legal authority for this rule.  Most of the
comments question the scope of the rule based on the language in section
402(g) of the act (21 U.S.C. 342(g)) stating that “regulations shall
be modeled after current good manufacturing practice regulations for
food.”  Other comments question our authority for records access.
Some comments assert that certain provisions of the proposed rule are
unconstitutionally vague, and therefore violate the Fifth Amendment.  A
few comments disagree with our rationale for why dietary supplements are
different than conventional food and need separate CGMP requirements.
We address these comments immediately below in this section.

1.	Modeled After CGMP for Food

	(Comment 18)  Some comments support our approach of proposing
requirements that are more comprehensive than the CGMP requirements for
food.  One comment states that the current requirements for food CGMP
are less comprehensive than the CGMP requirements in current use by both
the food and dietary supplement industries and the current “best
practices” should be incorporated into the dietary supplement CGMP
rule.  Several comments state that the requirements for dietary
supplement CGMP do not need to be identical to the requirements in
existing food CGMP regulations; that appropriate manufacturing controls
are needed for dietary ingredients contained in dietary supplements to
protect the public health; that some borrowing of drug CGMP concepts may
be necessary; and that we should balance effective control with
necessary flexibility in the dietary supplement CGMP rule.  In addition,
one comment states that the USP manufacturing guidelines, which contain
wording from the drug CGMP requirements, are a model for dietary
supplement CGMP for many in industry.

	Several comments express concern about not deviating too drastically
from the requirements in existing food CGMP regulations.  Although
several comments recognize that additional CGMP provisions for dietary
supplements, such as those related to identity, purity, strength,
quality, and composition, are needed, the comments say that we should
not regulate dietary supplement manufacturing in the same manner as drug
manufacturing because it would entail overly burdensome methods for
production and process controls.  Some comments contend that some of the
proposed rule requirements exceed the drug CGMP requirements.

	Most of the comments assert that the proposed dietary supplement CGMP
requirements are not modeled after the current good manufacturing
practice regulations for food.  The reasons for this assertion vary.
Some assert that certain provisions in the proposed rule were not found
in, or differ from, the provisions in part 110.  Examples of proposed
requirements that comments indicate exceeded food CGMP included batch
testing, packaging and labeling, recordkeeping, consumer complaints, and
the use of validated methods.  Other comments state that the proposed
requirements exceeded those for food because the proposed rule provided
for finished testing of certain substances when used as dietary
supplements, such as garlic and ginger, whereas no such testing is
required under existing food CGMP regulations when those same substances
are used as conventional food.  One comment says the rule was modeled
after juice hazard analysis critical control point (HACCP) and therefore
goes beyond existing food CGMP regulations.

	Some comments assert that the proposed requirements exceed the existing
food CGMP regulations because certain proposed provisions contained a
level of detail that is not in the food or the drug CGMP regulations, or
because elements of a provision in the proposed rule were similar to a
provision in part 210 (drug CGMP regulation).  Other comments disagree
with our rationale that the proposed rule was designed on the same
principles as the existing food CGMP regulations to address the
characteristics and hazards specific to dietary supplements, or to
prevent adulteration in preparing, packaging, or holding dietary
supplements.  The comments also disagree that we may include provisions
in the dietary supplement CGMP final rule that were not found in the
food CGMP regulations at the time DSHEA was enacted.

	Several comments state that we exceed our legal authority for the
proposed rule because it used too broad a definition of “modeled
after.”  Some comments offer their own definitions of “model”;
others object to the use of the noun form “model” and provide
dictionary definitions of the verb form “modeled.”  A few comments
assert that the meaning of “model” is clear, despite different
dictionary meanings, and that the statute is not ambiguous under Chevron
U.S.A. Inc. v. Natural Resources Defense Council, 467 U.S. 837
(1984)(“Chevron”).  One comment states that, even if the language is
ambiguous and our interpretation merits deference, our interpretation is
too expansive and not based on a permissible construction of the
statute.  Another comment states that we did not explain why our
interpretation was consistent with our Congressional mandate.

	(Response)  We agree with the comments stating that the dietary
supplement CGMP requirements in this final rule need not be identical to
the existing food CGMP regulations and that a system of manufacturing
controls specific to dietary supplements is needed.  We do not agree
that we exceeded the scope of our authority under section 402(g) of the
act in issuing the proposed requirements for dietary supplement CGMP or
these final requirements.  Our interpretation of the language in section
402(g) of the act, including the “modeled after” language, as to
what requirements of the act we have authority to issue, is based on a
permissible construction of the statute.

	The comments present the following general questions:  (1) Whether the
statute gives us authority to promulgate CGMP requirements for dietary
supplements that are not identical to the requirements in existing
current good manufacturing practice regulations for food; and 2) if so,
whether the requirements in this final rule that differ from those in
existing CGMP regulations for food are fairly encompassed within
Congress’s direction that the dietary supplement regulations shall be
“modeled after” food regulations and, therefore, are based on a
permissible construction of the statute.

	Under section 402(g)(1) of the act, a dietary supplement is deemed to
be adulterated if it has “been prepared, packed, or held under
conditions that do not meet current good manufacturing practice
regulations, including regulations requiring, when necessary, expiration
date labeling, issued by the Secretary under subparagraph (2).”
Section 402(g)(2) of the act authorizes the Secretary, by regulation, to
“prescribe good manufacturing practices for dietary supplements.”
Congress further provided that such regulations “shall be modeled
after current good manufacturing practice regulations for food” and
“may not impose standards for which there is no current and generally
available analytical methodology.”

	In construing the meaning of section 402(g) of the act, and, in
particular, the language in that section stating that such regulations
shall be “modeled after current good manufacturing practice
regulations for food,” we are confronted with two questions.  First,
has Congress directly and unambiguously spoken to the precise question
at issue? (“Chevron step one”) (see Chevron, 467 U.S. at 842.)  To
find no ambiguity, Congress must have clearly manifested its intention
with respect to the particular issue (see Young v. Community Nutrition
Institute, 476 U.S. 974, 980 (1986)).  If Congress has spoken directly
and plainly, we must implement Congress’s unambiguously expressed
intent (see Chevron, 467 U.S. at 842-843).  Second, if the act is silent
or ambiguous with respect to a particular issue in section 402(g) of the
act, is our interpretation based on a permissible construction of the
statute (“Chevron step two”) (Chevron, 467 U.S. at 843; FDA v. Brown
& Williamson Tobacco Corp., 529 U.S. 120, 132 (2000))?  When Congress
leaves a gap for the agency to fill by regulation, the regulation will
pass muster so long as it is not “arbitrary, capricious, or manifestly
contrary to the statute”  (Chevron, 467 U.S. at 843-844).

	We believe that the language in section 402(g) of the act provides an
express delegation of authority to us to promulgate a regulation to
“prescribe good manufacturing practices for dietary supplements” so
long as those regulations are “modeled after the current good
manufacturing practice regulations for food.”  The express language in
section 402(g) of the act contemplates broad, but not unlimited, agency
discretion as to what to include in a dietary supplement CGMP
regulation.

Congress has also spoken to the precise question of whether the dietary
supplement CGMP requirements must be identical to the requirements in
existing food CGMP regulations.  If Congress had wanted dietary
supplement CGMP to be identical to food CGMP, it easily could have
required that by statute.  Indeed, if Congress had intended for CGMPs
for dietary supplements to be the same as food CGMPs, there would have
been no need for Congress to have addressed the issue at all; as a type
of food, dietary supplements would otherwise be governed by the food
CGMPs.  See section 201(ff) of the act (21 U.S.C. 321(ff)).  Instead,
the statute calls for us to issue regulations that are “modeled
after” CGMP regulations for food.  The plain meaning of a “model”
or “modeled after,” as discussed in the 2003 CGMP Proposal (68 FR at
12165) and in the comments, relates to a pattern, plan, representation,
or simulation.  The use of the term “modeled after” makes it clear
that the regulations need not be identical to the original, but instead
are contemplated to differ from the original.

	Thus, the additional, independent authority to promulgate current good
manufacturing practice regulations for dietary supplements that Congress
provided in section 402(g) of the act, without delineating what
requirements such a regulation could or could not include, left us with
considerable authority to fill in the gaps in ways that recognize the
differences between dietary supplements and other foods that warrant
different manufacturing controls.  A contrary interpretation, as some
comments suggested, that the “modeled after” language means the
requirements for dietary supplement CGMP must be precisely found in
current part 110, or other food CGMP regulations, would so narrowly
circumscribe our discretion as to make it impossible to tailor the
regulation to fit the products it is designed to address.  Such an
interpretation would lead to a rule that would “frustrate the success
of the regulation undertaken by Congress” because it would not take
into consideration the characteristics, hazards, and manufacturing
practices specific to dietary supplements (American Trucking Ass’ns v.
U.S., 344 U.S. 298, 311 (1953)).

	Congress has also spoken to the precise question of which requirements
constitute current good manufacturing practice “regulations for
food.”  The plain meaning of “regulations” is plural (more than
one), and the plain meaning of “food” is as Congress defined in
section 201(f) of the act, including articles “used for food or
drink.”  At the time DSHEA was enacted, there were five food CGMP
regulations: those for infant formula (part 106), thermally processed
low-acid canned food (part 113), acidified food (part 114), bottled
water (part 129), and general food (part 110, often referred to as the
“umbrella”  regulations).  All of these regulations appear in
Subchapter B of Chapter 1 of Title 21 of the Code of Federal
Regulations, entitled “Food for Human Consumption.”  Nothing in the
language of section 402(g) or elsewhere suggests that Congress meant to
limit the term CGMP “regulations for food” to only the regulation in
part 110.  Thus, it is consistent with our statutory authority for us to
look to all of our food CGMP regulations--including infant formula,
low-acid canned foods, acidified foods, and bottled water, as well as
our general food CGMP regulations--after which to model our dietary
supplement CGMP regulations.

	Congress has not spoken to the precise question of what specific
requirements for dietary supplements may be imposed under the “shall
be modeled after” language.  Given this ambiguity, therefore, under
Chevron step two, we may determine what requirements to include in this
final rule for dietary supplement CGMP, provided that our interpretation
is not arbitrary, capricious, or manifestly contrary to the statute
(Chevron, 467 U.S. at 844).

	Accordingly, we considered the types of requirements in the existing
food CGMP regulations and used those as models for the dietary
supplement CGMP requirements.  We considered both the objectives and the
means of achieving the objectives in the existing food CGMP regulations.
 These CGMP food regulations include those for infant formula (part
106), general food (“umbrella” regulations) (part 110), thermally
processed low-acid canned food (part 113), acidified food (part 114),
and bottled water (part 129).  Each of these food CGMP regulations
provides objectives and means upon which we modeled the dietary
supplement CGMP regulations.  Just as the precise requirements of the
other food CGMP regulations are tailored to the particular
characteristics and hazards of the foods and manufacturing processes
being addressed, the dietary supplement CGMP requirements are also so
tailored.

	For example, the infant formula CGMP regulation is intended to ensure
that the “safety and nutritional potency” of a formula are “built
into the manufacturing process” in order to establish a quality
control system to make sure that infant formula products are properly
manufactured (47 FR 17016 and 17017 (April 20, 1982)).  The specific
criteria in the regulations apply in determining whether the infant
formula meets the safety, quality, and nutrient requirements of the act
(§ 106.1(a)).  The means to achieving the objectives in the infant
formula regulations include, for example, requirements for ingredient
control (through a supplier’s guarantee or certification or through
analysis of the ingredient) (§ 106.20); preparation of a master
manufacturing order and a system to assure and verify the addition of
each ingredient (§ 106.25); either in-process batch testing (§
106.25(b)) or sampling and testing of each batch to ensure nutrient
requirements are met (§ 106.30); and coding to enable ready
identification of lots during their sale and distribution (§ 106.90).

	The infant formula CGMP regulation also includes numerous requirements
that manufacturers maintain records: e.g., records on certain
food-packaging materials; records on nutrient premix testing;
certificate and guarantees from premix suppliers for required nutrients;
records of results of testing conducted by suppliers; records of tests
to establish the purity of each nutrient, the weight, and amounts of
nutrients; records to ensure proper nutrient quality control; records to
ensure required nutrient control at the final product stage;
distribution records; records on microbiological quality and purity of
raw materials; and records of audits (§ 106.100).  The infant formula
CGMP regulation also requires manufacturers to maintain procedures
describing how complaints will be handled; to follow those procedures;
and to investigate when a complaint shows a possible health hazard (§
106.100(K)).  Quality control records must contain enough information to
permit a public health evaluation of any batch of infant formula (§
106.100(o)).  All required records must be available for authorized
inspection (§ 106.100(l)).

	Many provisions of the dietary supplement CGMP final rule are similar
in objective and means and are “modeled after” the provisions of the
infant formula CGMP regulation.  For example, like the infant formula
regulation, the dietary supplement CGMP regulation is designed to
establish a quality control system to make sure that dietary supplements
are properly manufactured.  The dietary supplement regulation uses
similar means to ensure this goal, such as requirements for ingredient
control (through supplier’s certificate of analysis or testing or
examination) (final § 111.75(a)); preparation of a master manufacturing
record (final § 111.205); in-process batch monitoring (final §
111.75(b)) or batch testing or examination (final § 111.75(c)); and
coding to provide a batch, lot, or control number (final § 111.260(a)).
 Like the infant formula CGMP regulations, the dietary supplement CGMP
final rule contains recordkeeping requirements related to packaging
materials; certificates of analysis from suppliers; results of tests
that you conduct, for example, on ingredients or the finished batch; and
results of chemical, microbiological, or other tests that you conduct as
necessary to prevent the use of contaminated components (final §§
111.180(b)(2), 111.95, 111.260(h), 111.325(b)(2), and 111.365(d)).  Also
similar to the infant formula CGMP regulation, the dietary supplement
CGMP final rule requires manufacturers to maintain procedures for
handling complaints (final §§ 111.553 and 111.570(b)(1)); to
investigate certain complaints (final § 111.560(a)(2)); and to keep
records of complaints (final § 111.570(b)(2)).  Required dietary
supplement records must also, as with infant formula records, be
available for inspection by FDA (final § 111.610(a)).

	The “umbrella” food CGMP regulation in part 110 details practices
to ensure “(1) that food is manufactured, processed, packed, and held
under conditions that are sanitary, and (2) that such food is safe,
clean, and wholesome” (44 FR 33239 (June 8, 1979)).  Promulgated
primarily under the adulteration provisions of sections 402(a)(3) and
402(a)(4) of the act, as well as section 361 of the Public Health
Service Act (PHS Act), the umbrella CGMP food regulation requires a
quality control operation whose main purpose is “to provide a
systematic procedure for taking all actions necessary to prevent food
from being adulterated within the meaning of the act” (51 FR 22461,
(June 19, 1986)), as well as to prevent the spread of food-borne
communicable diseases (44 FR 33239 (June 8, 1979))(See § 110.5(a)).
Part 110 also “specifies requirements that must be met to produce safe
and wholesome food” (51 FR 22461 (June 19, 1986)).  These umbrella
food CGMP requirements not only pertain to food safety, but also are
“concerned with contamination by filth or decomposition which may or
may not raise safety concerns” (51 FR 22462 (June 19, 1986)).

	The detailed requirements of the umbrella food CGMP regulation
accomplish these objectives through a variety of means.  For example,
there are specific personnel provisions requiring employees who may be
sources of microbial contamination to be excluded from certain
operations (§ 110.10(a)); persons working in contact with food,
food-contact surfaces, and food-packaging materials to follow hygienic
practices (§ 110.10(b)); and that certain personnel have sufficient
education or experience to produce clean and safe food (§ 110.10(c)).
The umbrella food CGMP regulation also includes detailed requirements
concerning the grounds surrounding a food plant and the design of
buildings and structures to protect against contamination or to maintain
sanitary operations and produce safe food (§ 110.20).  Detailed
provisions also require that physical facilities be maintained in
sanitary condition and in sufficient repair to prevent food from being
adulterated (§ 110.35).  Any water that contacts food or food-contact
surfaces must be “safe and of adequate sanitary quality” (§
110.37(a)); plumbing, sewage and other disposal, as well as toilet
facilities, must also protect against contamination (§ 110.37(b), (c),
and (d)).  Similarly, equipment and utensils must be designed and
maintained to preclude adulteration and food contact surfaces must be
maintained to protect food from being contaminated by any source,
including unlawful indirect food additives (§ 110.40(a)).  All
operations for receiving, inspecting, transporting, segregating,
preparing, manufacturing, packaging, and storing food must be conducted
using adequate sanitation principles (§ 110.80).  Appropriate quality
control operations must be used to ensure that food is suitable for
human consumption and that food-packaging materials are safe and
suitable (§ 110.80).  Foods must be stored and transported under
conditions to protect against physical, chemical, and microbial
contamination, as well as against deterioration of the food and the
container (§ 110.93).

	The provisions of the umbrella food CGMP regulation serve as the model
for many dietary supplement CGMP provisions.  For example, the dietary
supplement CGMP requirements concerning personnel and microbial
contamination (final § 111.10(a)); hygienic practices (final §
111.10(b)); and education, training, or experience (final § 111.12) are
very similar to provisions in part 110.  In addition, the dietary
supplement CGMP requirements concerning the grounds, physical plant
facilities, cleaning materials, pest control, water supply, plumbing,
sewage disposal, bathrooms, and trash disposal (final §§ 111.15 and
111.20) closely resemble the analogous part 110 requirements.

	Because of the particular hazards associated with low-acid canned foods
and with acidified foods, the CGMP regulations for these foods contain
detailed provisions to ensure safe manufacturing.  Specifically, the
CGMP regulations for these foods protect the public health against
microbial contamination from these foods.  Part 113 sets out safe
manufacturing, processing, and packaging procedures for low-acid foods
in hermetically sealed containers.  The CGMP criteria in this part apply
in determining whether the facilities, methods, practices, and controls
used by commercial processors of such foods are operated “in a manner
adequate to protect the public health” (§ 113.5).  Processors of
low-acid canned foods must have a “scheduled process” that is
established by a qualified person and is “adequate under the
conditions of manufacture for a given product to achieve commercial
sterility” (§§ 113.3 and 113.83).  “Commercial sterility” of
thermally processed food means a condition achieved by applying heat to
render the food free of certain microorganisms (§ 113.3).  Part 113
requires that supervisors satisfactorily complete training at a school
approved by FDA (§ 113.10).

	Part 113 also contains extremely detailed requirements on equipment and
procedures.  For example, each vessel used for pressure processing in
steam must be equipped with a mercury thermometer that is tested for
accuracy at least once a year, or more frequently if necessary, to
ensure its accuracy (§ 113.40(a)(1)).  Critical factors (variation of
which may affect the attainment of commercial sterility) must be
specified in the scheduled process and must be measured and recorded on
processing records frequently enough to ensure that the factors are
within the specified limits (at least every 15 minutes) (§§
113.40(a)(13); 113.83).  Observations and measurements of certain
operating conditions must be made and recorded at intervals of
sufficient frequency to ensure that commercial sterility of the food
product is being achieved (at least every hour) (§
113.40(g)(2)(ii)(c)).  There must also be a system to stop packaging
operations (or to segregate products) when the packaging conditions fall
below scheduled processes (§ 113.40(g)(2)(ii)(b)).  Regular
observations of container closures are required to be made and recorded
(§ 113.60).  Each container must be coded “to enable ready
identification of lots during their sale and distribution” (§
113.60(c)).

	Before using raw materials and ingredients susceptible to
micro-biological contamination, the low-acid food processor must ensure
that they are “suitable for use in processing low-acid food” (§
113.81(a)).  Complete records covering all aspects of the establishment
of the scheduled process and of certain confirmation tests must be
maintained permanently (§ 113.83).  Scheduled processes must be readily
available to any duly authorized FDA employee (§ 113.87(a)).  Whenever
any process is less than the scheduled process or when critical factors
are not in control, the low-acid food must be reprocessed or set aside
for further evaluation as to public health significance (§ 113.89).
Unless the evaluation demonstrates that the product is free of
microorganisms of potential public health significance, the product
either must be reprocessed to render it commercially sterile or
destroyed (§ 113.89).

	All process deviations involving a failure to satisfy the minimum
requirements of the scheduled process must be recorded and kept in a
separate file detailing the deviations and actions taken (§ 113.89).
Detailed information on processing and production must be entered on
forms (§ 113.100(a)).  Not later than 1 working day after the actual
process, and before the food is shipped or released for distribution, a
qualified representative of management must review all processing and
production records for completeness and to ensure that the product was
subjected to the scheduled process (§ 113.100(b)).  Records to identify
the initial distribution of the finished product must be kept to
facilitate segregation of lots that may have become contaminated or
otherwise rendered unfit for their intended use (§ 113.100(d)).
Records must be maintained at the processing plant for at least one year
after the date of manufacturing and at a reasonably accessible location
for another two years (§ 113.100(e)).

	Similarly, the CGMP regulation for acidified food in part 114 requires
supervision by personnel trained at an FDA-approved school (§ 114.10);
manufacturing in accordance with a scheduled process established by a
qualified person (§§ 114.80 and 114.83); processing sufficient to
destroy the vegetative cells of certain microorganisms (§
114.80(a)(1)); sufficient control, including frequent testing and
recording of results, to ensure that the finished pH values are not
higher than 4.6 (§ 114.80(a)(2)); testing and examinations of
containers to ensure that the food is suitably protected from leakage or
contamination (§ 114.80(a)(4)); and coding to enable ready
identification of lots during their sale and distribution (§
114.80(b)).

	Whenever any acidified food process operation deviates from the
scheduled process or the pH of the finished product exceeds 4.6, the
processor must reprocess it, process it under part 113 requirements, or
set it aside for evaluation as to any potential public health
significance (§ 114.89).  Unless the evaluation demonstrates that the
food has undergone a process that has rendered it safe, the food must be
fully reprocessed to render it safe or be destroyed (§ 114.89).

	A record must be made of the procedures used in the public health
evaluation and the results of the evaluation (§ 114.89).  Records must
be kept of examinations of raw materials, packaging materials, and
finished products, and of suppliers’ guarantees or certifications that
verify compliance with our regulations (§ 114.100(a)).  Processing and
production records showing adherence to scheduled processes must be
maintained and must have sufficient additional information such as
product code, date, container size, and product, to permit a public
health hazard evaluation of the processes applied to each lot, batch, or
other portion (§ 114.100(b)).  Departures from scheduled processes
having a possible bearing on public health or the safety of the food
must be recorded and kept in a separate file or log, along with the
action taken to rectify the departure and the product disposition (§
114.100(c)).  Records must be kept identifying initial distribution of
the finished product to facilitate segregation of lots that may have
become contaminated or otherwise unfit for their intended use.  Copies
of certain required records must be kept at a reasonably accessible
location for 3 years from the date of manufacture (§ 114.100).  The
criteria in the part 114 regulation, as well as those in part 110, apply
in determining whether an article of acidified food is adulterated under
section 402(a)(3) of the act in that it has been manufactured under such
conditions that it is unfit for food or under section 402(a)(4) of the
act in that it has been prepared, packed, or held under insanitary
conditions whereby it may have become contaminated with filth, or
whereby it may have been rendered injurious to health (§ 114.5).

	Many provisions of parts 113 and 114 also serve as models for
provisions in the dietary supplement final rule.  In many instances, the
analogous provision in the dietary supplement final rule allows more
flexibility in the means to achieve the goal.  For example, under final
§ 111.13 qualified personnel must be assigned to supervise the
manufacturing, packaging, labeling, or holding of dietary supplements.
Although the supervisor must be qualified by education, training, or
experience to supervise, the more restrictive requirement of parts 113
and 114 to attend an FDA-approved school is not included.  The
“scheduled process”  for low-acid and acidified food manufacturing,
processing, and packing, is analogous to the required “system of
production and process controls” that dietary supplement manufacturers
must design and implement (final §§ 111.55, 111.60(a)).  Similarly,
the “critical factors” required to be specified in the scheduled
process for low-acid and acidified foods are akin to the
“specifications” that dietary supplement manufacturers must
establish for certain points in the manufacturing process (final
§ 111.70).  Just as low-acid food processors must establish procedures
to ensure that ingredients are suitable for use, so too must dietary
supplement manufacturers establish component and finished product
specifications (final § 111.70(b)and (e)).  Just as containers for
acidified food must ensure suitable protection from contamination,
packaging that comes into contact with dietary supplements must be safe
and suitable for use (final § 111.70(d)).  Dietary supplement
in-process points, like the “critical factors” for low-acid and
acidified food, must be monitored to detect any deviation or
unanticipated occurrence that may result in adulteration (final §
111.75(b)(2)).

Rejected dietary supplements must also be held under quarantine (final
§§ 111.370, 111.425); dietary supplements which have been reprocessed,
treated, or which have had in-process adjustments must meet all
established product specifications and be approved before release (final
§ 111.90(c)).  Similar to coding low-acid or acidified foods, dietary
supplements must have assigned batch, lot, or control numbers (final §
111.415(f)).  The design, calibrations, and cleaning of equipment and
utensils must also result in the equipment and utensils being suitable
for their intended uses and not result in contamination of components or
dietary supplements (final § 111.27).  Written procedures for the
various controls are required (see, e.g., final §§ 111.8, 111.25,
111.103), and required written records (see, e.g., final §§ 111.14,
111.23, 111.35, 111.95) must be kept for 1 year past the shelf life
date, if shelf-life dating is used, or 3 years after the date of
distribution of the last associated batch of dietary supplement (final
§ 111.605).  All required dietary supplement CGMP records must be
readily available for inspection and copying by FDA (final §
111.610(a)).

	Finally, the bottled water CGMP regulation was promulgated to ensure
the safety and sanitary quality of these products, which include all
water processed and bottled for human consumption (38 FR at 32563 and
32564 (November 26, 1973)).  The criteria in part 129, as well as in
part 110, apply in determining whether the facilities, methods,
practices, and controls used to process, bottle, hold, and ship bottled
drinking water conform with good manufacturing practice “to assure
that bottled drinking water is safe and that it has been processed,
bottled, held, and transported under sanitary conditions” (§ 129.1).
Part 129 requires plant construction and design features, such as a
separate bottling room and an enclosed room for washing and sanitizing
containers, to protect against contamination (§ 129.20).  All plant
equipment and utensils must be suitable for their intended use (§
129.40(a)).

	Both the product water supply and the operations water supply must be
of a “safe, sanitary quality” in conformance with “the applicable
laws and regulations of the government agency or agencies having
jurisdiction” (§ 129.35(a)).  Samples of source water must be
analyzed at least once a year for chemical contaminants and once every 4
years for radiological contaminants (§ 129.35(a)(3)).  Source water
from other than a public water system must be sampled and analyzed for
microbiological contaminants at least once a week (id.).  The product
water-contact surfaces of all containers and equipment must be clean and
adequately sanitized and protected from contamination (§ 129.37(a)
and(b)).  Filling, capping, closing, sealing, and packaging of
containers must be done so as to preclude contamination of the water (§
129.37(d)).  All product water contact surfaces must be nontoxic and in
compliance with section 409 of the act (concerning food additives) (§
129.40(a)(2)).

	Numerous production processes and controls for bottled water are also
required.  For example, all treatment of product water must be effective
in accomplishing its intended purpose and in accordance with section 409
of the act (§ 129.80(a)).  The treatment processes must be performed
with equipment and substances that will not adulterate the product (§
129.80).  Product water samples must be taken before bottling and
analyzed as often as necessary to assure uniformity and effectiveness of
the processes performed by the plant (§ 129.80(a)).  Cleaning and
sanitizing solutions must be sampled and tested to assure adequate
performance (§ 129.80(c)).

	Each unit package from a batch or segment of continuous production run
must be identified by a production code (§ 129.80(e)).  The plant must
maintain information on the kind of product, volume, date, lot code, and
distribution of finished product to wholesale and retail outlets (id.).
During the process of filling, capping, or sealing the containers,
performance must be monitored and the filled containers inspected to
assure that they are sound, properly capped or sealed, and coded and
labeled (§ 129.80(f)).  All containers and closures must be sampled and
inspected to ascertain that they are free from contamination (id.).

	To assure that the plant’s production of bottled water complies with
applicable standards, laws, and regulations, the plant must analyze
product samples at specified intervals (§ 129.80(g)).  The methods used
to analyze the samples must be approved by the government agency with
jurisdiction (§ 129.80(g)(3)).  Records of the date of sampling, type
of product sampled, production code, and results of analysis must be
maintained (§ 129.80(g)(3)).  All required records must be maintained
at the plant for at least 2 years (§ 129.80(h)) and be available for
official review by FDA at reasonable times (id.).

	Provisions of the bottled water CGMP regulation also serve as a model
for provisions of the dietary supplement CGMP regulation.  For example,
water that is used in a manner such that the water may become a
component of a dietary supplement must at a minimum comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplements (final §§ 111.15(e)(2), 111.365(c)).
Precautions that must be taken to prevent contamination of components or
dietary supplements include performing chemical, microbiological, or
other testing (final § 111.365(d)).  Filling, assembling, packaging,
labeling, and related operations must be performed to protect the
dietary supplement against adulteration (final § 111.415).  Equipment
and utensils must be suitable for their intended use (final §
111.27(a)).  Safe and adequate cleaning compounds and sanitizing agents
must be used (final § 111.15(c)(1)).  Representative samples of each
batch must be examined to ensure that the product meets established
specifications (final § 111.415(g)).  Each lot of packaged and labeled
dietary supplement must be assigned a batch, lot, or control number
(final § 111.415(f)).

	Moreover, our interpretation of permissible requirements for the
dietary supplement CGMP regulation is also consistent with the use of
the terms “good manufacturing practice” and “current good
manufacturing practice” in section 402(g) of the act.  Although these
terms are not defined in the act, GMP is generally used to refer to
methods used in, and the facilities and controls used for, product
manufacturing and related activities.  The umbrella food CGMP
regulation, for example, defines the “plant” covered by the
requirements of that regulation as the facility used for, or in
connection with, “the manufacturing, packaging, labeling, or holding
of human food” (§ 110.3(k)).  As we have described in detail, the
objectives of the existing food CGMP regulations and the precise means
(or requirements) used to achieve the objectives vary depending on the
particular hazards and characteristics of the products and their
manufacturing.  For example, the umbrella food CGMP regulation is
specifically designed to ensure that food is manufactured, processed,
packed, and held under sanitary conditions and that the food is safe,
clean, and wholesome.  Low-acid and acidified food CGMP requirements
focus on facilities, methods, practices, and controls to protect the
public health against the particular risks of microbial contamination
from these foods.  The infant formula CGMP regulation is aimed at
ensuring both the safety and nutritional potency of these special foods.
 Infant formula is often the sole item in the diet.  An infant formula
that does not meet the requirements for nutritional potency may cause a
hazard to the health of the infant (see, 61 FR 36154).  The bottled
water CGMP regulation embodies requirements for facilities, methods,
practices, and controls used in processing, bottling, holding, and
shipping of bottled water to ensure its safety and sanitary quality.

	Like the food CGMP regulations after which they are modeled, the
dietary supplement CGMP final rule contains criteria for facilities,
methods, practices, and controls used in manufacturing, packaging,
labeling, or holding dietary supplements to ensure the quality of the
dietary supplement.  Quality includes consistently meeting the
established specifications for identity, purity, strength, and
composition of the dietary supplement and limits on contaminants, in
addition to manufacturing the dietary supplement under conditions to
prevent adulteration.  As Congress recognized in DSHEA, identity,
purity, strength, and composition are essential characteristics for
dietary supplements (see, e.g., section 403(s)(2) of the act (a dietary
supplement is misbranded if its labeling fails to list the name and
quantity of each dietary ingredient and if it fails to have the identity
and strength or the quality, purity, or compositional specifications it
is represented to meet)).  Yet without information about the identity,
purity, strength, or composition, the manufacturer could not know the
final contents of the dietary supplements it manufactures or whether its
processes are reliably and consistently producing the correct
combination and amounts of ingredients in a dietary supplement.
Accordingly, the final rule requires a manufacturer to establish
specifications for the identity, purity, strength, and composition and
for limits on contaminants of the dietary supplements it manufactures
and ensure that such specifications are consistently met in the finished
batch of dietary supplement (§  111.75(e)).  Dietary supplements, like
infant formula, are relied upon by consumers not only to be safe, but
also in many instances to provide specific and important claimed health
benefits (see, e.g., section 403(r) of the act).  In the preamble to the
2003 CGMP Proposal, we discussed a number of examples illustrating
adulteration and improper formulation of dietary supplements caused by
manufacturing, packaging, or holding practices (49 FR at 12162 and 12163
(March 13, 2003)).  These dietary supplement CGMP requirements will help
to protect consumers against similar types of adulteration and against
reliance on products that are not properly formulated.

	Generally recognized principles underlying CGMP also support our
interpretation of section 402(g) of the act.  Our  interpretation of
permissible CGMP regulations is reasonable based on recognized
principles for controlling the quality of manufactured products in
general. (Ref. 9)  As many comments asserted, if the dietary supplement
CGMP requirements are to be meaningful, they must ensure quality in the
finished product (see, for example, the discussion of comments regarding
the production and process control system in section X).  Controls to
ensure quality include planning processes to determine desired product
features or characteristics, a system of controls to ensure that the
desired product will be consistently produced, and making necessary
improvements to the process (id., at 2.6).  Manufacturers must plan what
they intend to produce, institute adequate controls to achieve the
desired outcome, and ensure that the controls work so that the desired
outcome is consistently achieved.  If the outcome is not consistently
achieved, corrective actions need to be implemented in order to reach
the desired outcome.

	This final rule, like the other food CGMP regulations, embodies the
basic concepts of controlling quality, i.e., planning, control, and
improvement.  As discussed earlier in the “Overview of CGMP,” we
have defined the term “quality” for this dietary supplement CGMP
regulation to mean “that the dietary supplement consistently meets the
established specifications for identity, purity, strength, and
composition and has been manufactured, packaged, labeled, and held under
conditions to prevent adulteration under sections
402(a)(1),(a)(2),(a)(3), and (a)(4) of the Federal Food, Drug, and
Cosmetic Act.”  Identifying the desired characteristics of identity,
purity, strength, and composition of a dietary supplement, as required
in this final rule, is an essential part of the planning process to
manufacture a dietary supplement.  Without identifying specifications
for each of these characteristics of a dietary supplement, it is not
possible to control for, and repeatedly and reliably produce, the
desired end product.  Similarly, requirements for batch testing ensure
that there is consistency from batch to batch.  Packaging and labeling
requirements ensure that suitable packaging is used and that the label
identified in the master manufacturing record for the product is placed
on the finished product.  In addition, requirements related to consumer
complaints help to ensure that manufacturers are made aware of problems
related to their manufacturing processes, including those that may
result in illness or injury, so that they can take corrective actions to
prevent any future problems from occurring.  The procedures for
production and process control in this final rule also include as key
elements measures to prevent contamination that could adulterate the
product.  Requirements to protect against contamination during the
manufacturing, packaging, labeling, and holding operations help ensure
that this aspect of “quality” is also achieved for dietary
supplements.  In sum, this final rule embodies principles for
controlling quality through requirements designed to ensure both that
the dietary supplement meets its established specifications for
identity, purity, strength, and composition and that it is not
adulterated.

	The dietary supplement CGMP requirements are also reasonable because
they take into consideration the different product forms in which these
products will be manufactured.  Unlike conventional foods, such as
fruit, vegetables, cereals, and dairy products, dietary supplements will
be sold in tablet, capsule, powder, or softgel form.  They may also be
sold as a concentrate, metabolite, constituent, or extract of a vitamin,
mineral, herb, botanical, or dietary substance.  Because dietary
supplements are often sold in different forms than conventional foods,
different processes and controls are needed to manufacture dietary
supplements than to manufacture conventional foods.  For example,
equipment must be able to manufacture dietary supplements in tablet or
softgel form.  Therefore, the final rule requires that controls be
established to ensure that the equipment functions in accordance with
its intended use (final § 111.30(e)) and will consistently manufacture
a product in whatever form is desired.  Consistent with basic CGMP
principles, ensuring the quality of the dietary supplement product
requires that the manufacturer establish precisely what it will produce
(specifications for its product), how it will make the product
(processes), and which process controls and tests it will use to ensure
reliable, reproducible results.  These CGMP requirements will help to
achieve these results.

	The dietary supplement CGMP requirements are also reasonable when
viewed in the context of the act as a whole.  See Brown & Williamson,
529 U.S. at 133.  Our mission is, in part, to protect the public health
by ensuring that foods are safe, wholesome, sanitary, and properly
labeled (21 U.S.C. 393(b)(2)(A)).  Section 701(a) of the act (21 U.S.C
371(a)) gives us the authority to promulgate regulations for the
efficient enforcement of the act in order to “effectuate a
congressional objective expressed elsewhere in the Act” (Association
of American, Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204
(D.D.C. 2002) (citing Pharm. Mfrs. Ass’n. v. FDA, 484 F. Supp. 1179,
1183 (D. Del. 1980)).  The final rule is designed to help ensure that
dietary supplements consistently are manufactured to produce the product
established by the manufacturer, to bear the label identified in the
master manufacturing record, and to prevent adulteration.  The
requirements are written to facilitate efficient and effective action to
enforce their terms when necessary.

	Some provisions of the dietary supplement CGMP final rule may be
similar to the existing drug CGMP regulations.  However, we have not
modeled these regulations after the drug CGMP regulations.  Controls
that relate to certain product forms (e.g., tablets, capsules, powder,
softgel) are required in this final rule based on the specific
characteristics of dietary supplements and the hazards associated with
these forms, not, as some comments imply, based on a desire to emulate
drug CGMP requirements.  The act does not state that there may not be
similarities between the dietary supplement CGMP requirements and the
CGMP requirements for drugs or other non-food products.  Inasmuch as
food CGMP regulations and other CGMP regulations are all based on CGMP
principles, it is neither surprising nor impermissible that there are
similarities between the dietary supplement CGMP requirements and drug
or device CGMP requirements.  Although we do not agree that any of the
CGMP requirements exceed drug GCMP requirements, even if a particular
requirement did, it is not prohibited under the statute.  As long as the
CGMP final rule is “modeled after” the food CGMP regulations, we
have satisfied the statutory requirements.  As noted, our interpretation
of “modeled after” means that the dietary supplement CGMP final rule
provisions share similar objectives and/or use similar means as the
existing food CGMP regulations.  To the extent that there are
similarities to drug CGMP regulations, those similarities are
appropriate and not prohibited by section 402(g) of the act.

	Consistent with our role “to fill in, through interpretation, matters
of detail related to [the statute’s] administration,” Barnhart v.
Walton, 535 U.S. 212, 225 (2002), we applied our scientific expertise,
policy judgment, and experience to promulgate dietary supplement CGMP
requirements that will protect the public health and effectively
implement our statutory authority to prescribe dietary supplement CGMP.
See United States v. Mead, 533 U.S. 218, 227-228 (2001); Nationsbank of
North Carolina v. Variable Annuity Life Ins.  Co., 513 U.S. 251, 256-58
(1995); Chevron, 467 U.S. at 844; Forester v. Consumer Product Safety
Com., 559 F.2d 774, 783 (D.C. Cir.  1977).

2.	Records Authority

	(Comment 19)  Some comments state that requirements related to record
keeping and access to such records are necessary to allow our inspectors
to assess the adequacy of a dietary supplement manufacturer’s
practices.  Additional comments state that access to records is
necessary to ensure that CGMP requirements are followed and to protect
the public health.  Several comments identify specific types of records
we should require in a final rule, including written procedures, batch
and master manufacturing records, distribution records, and lot numbers.
 Another comment states that training records should be required because
the qualifications and training of employees affects product quality.

	Other comments, however, state that the record retention and access
requirements seem to be modeled after drug CGMP and not food CGMP.
Other comments state that, even though records may be necessary to
ensure that CGMP requirements are followed, we do not have authority to
require access to and copying of such records.  Some comments assert the
authority to establish regulations for dietary supplement CGMP does not
imply there is authority to inspect records.  Several comments state we
cannot rely on section 701 of the act because there is not another
section of the act that authorizes us access to company records for
dietary supplement CGMP and section 701(a) of the act does not itself
give us the authority we need to require records inspection.  Another
comment suggests that the absence of an express grant of records
inspection authority means that records inspection is not necessary for
the efficient enforcement of the act.

	Some comments assert that we have no record inspection authority under
section 704(a) of the act (21 U.S.C 374(a)).  A few comments suggest
that, because records inspection authority was not expressly granted in
DSHEA’s statutory language, as it was for OTC drugs and medical
devices, Congress provided no authority for records inspection for
dietary supplement CGMP.  The comments state that we have a longstanding
interpretation that section 704 of the act does not give us access to a
food manufacturer’s records.  Several comments state that it was
sufficient to have voluntary records access, stating that many companies
are willing to provide access to records.

	Other comments say that our record inspection authority for dietary
supplement CGMP is limited to that under section 306(a) of the Public
Health Security and Bioterrorism Preparedness and Response Act of 2002
(Bioterrorism Act) (21 U.S.C. 350(c)), i.e., when we have a
“reasonable belief that an article of food is adulterated and presents
a threat of serious adverse health consequences . . ..”  Another
comment suggests an alternative standard to that in section 306(a) of
the Bioterrorism Act of a “reasonable belief that there is a public
health hazard” for when we may access records.

	One comment cites In the Matter of Establishment Inspection of
Medtronic, Inc., 500 F. Supp 536 (D. Minn. 1980), to support its
assertion that we exceeded our statutory inspection authority in the
dietary supplement CGMP record requirements.  One comment states that a
warrantless inspection of dietary supplement CGMP records and criminal
consequences that may be imposed under the act for failure to comply
with the act provide a “powerful argument against expanding the
Agency’s inspection authority any further” and raise “serious
constitutional concerns.”  Several comments ask us to clarify our
jurisdiction for records inspection requirements or delete proposed §
111.125(c).

	Still other comments seek confirmation that the confidential and trade
secret information obtained by us under the rule would be protected from
disclosure under applicable statutes.  Among other things, the comments
cite the Trade Secrets Act, 18 U.S.C. 1905, and the Freedom of
Information Act (FOIA), 5 U.S.C. 552(b)(4).  Some comments express
concern that records inspection would violate “rights to privacy of
corporate manpower” or would compromise trade secrets.  The comments
request the rule specifically reconfirm our obligations under these
laws.

	(Response)  We disagree with the comments suggesting that we have no
authority to require dietary supplement manufacturers to maintain
records to comply with CGMP under section 402(g) of the act; that the
absence of an express grant of records authority means records are not
needed for the efficient enforcement of the act; and that Congress
meant, by its silence, that we have no authority to issue records
requirements.  Clearly, just as Congress is not expected to express
“every single evil sought to be corrected” in a grant delegation of
authority to promulgate a rule, it can not be expected to articulate
every requirement that is within an agency’s delegated authority
(American Trucking Assoc. v. United States, 344 U.S. 298, 309-10
(1953)).

	Agencies are expected to bring their expertise to bear on what
requirements are necessary that will not “directly frustrate the
success of the regulation undertaken by Congress”  (id. at 311).  In
this instance, Congress has not expressed any specific intent regarding
recordkeeping for dietary supplements but has directed FDA to use other
food CGMP regulations, which require record-keeping and FDA access to
records, as models for these regulations.  Congress has delegated
substantial and sufficiently specific authority to us to promulgate
recordkeeping and access regulations  (Cf. United States v. Storer
Broadcasting, 351 U.S. 192, 202-03 (1956) (upholding a rule that
established limitations on broadcast licensing that were “not
specifically authorized by statute”)).  As stated earlier in this
section, the “modeled after” language in section 402(g) of the act
is ambiguous with respect to what specific CGMP requirements we are to
include in this final rule.  At the time Congress enacted section 402(g)
of the act there were several food regulations that contained
recordkeeping and record access requirements.  We included records
requirements in the food CGMP regulations for infant formula (part 106),
low acid food (part 113), acidified food (part 114), and bottled water
(part 129).  Accordingly, the directive in section 402(g) of the act is
sufficient authority for our recordkeeping requirements in this final
rule.  In addition, our authority to establish records requirements has
been upheld under other provisions of the act, which lacked explicit
recordkeeping authority for FDA, where we have found records to be
necessary (National Confectioners Assoc. v. Califano, 569 F.2d 690,
693-94 (D.C. Cir. 1978) (upholding requirements for source coding and
distribution records based on the statutory scheme as a whole)).

	Moreover, records are an indispensable component of CGMP.  The records
required by this final rule provide the foundation for the planning,
control, and improvement processes that constitute a quality control
system.  Implementation of these processes in a manufacturing operation
serves as the backbone to CGMP.  The records will show what is to be
manufactured; what was, in fact, manufactured; and whether the controls
that the manufacturer put in place to control the identity, purity,
strength, and composition and limits on contaminants and to prevent
adulteration were effective.  Further, records will show whether and
what deviations from control processes occurred, facilitate evaluation
and corrective action concerning these deviations (including, where
necessary, whether associated batches of product should be recalled from
the marketplace), and enable a manufacturer to assure that the
corrective action was effective.  Written procedures also will help
ensure that personnel follow hygienic practices; permit evaluation of
whether equipment, including software that may run the equipment,
performs as it is intended; and help ensure that the equipment is
properly maintained and adequately cleaned.

	The CGMP final rule establishes the parameters for the production and
process control system in which dietary supplements are to be
manufactured.  The dietary supplement manufacturer establishes the
identity, strength, purity, and composition of the supplement it
manufactures (final § 111.70); determines whether the established
specifications are met (final § 111,73); uses the tests it needs to
ensure that those characteristics are consistently met (final §§
111.75 and 111.315); identifies the steps necessary to ensure that any
necessary tests or examinations are completed, reviewed, and recorded in
a timely fashion before the dietary supplement is released for
distribution to the public (final §§ 111.110 and 111.325(b)(2).  The
CGMP final rule also requires that the manufacturer establish written
procedures for its quality control unit operations to ensure those the
personnel performing this function provide proper review and oversight
of the production and process control system, have the knowledge and
experience to identify and anticipate possible problems in the
manufacturing of the dietary supplement, and ensure corrective measures
are taken promptly when problems occur (final §§ 111.103 to 111.140).
The final rule also requires that the manufacturer establish the
“master recipe(s)” for the dietary supplement(s) it manufactures so
that such recipe(s) can be followed for each batch produced (final §§
111.205 through 111.210).  In sum, manufacturers cannot operate without
records because critical elements in a manufacturing process are
entirely dependent on information written or captured in the form of a
record.  Such records are also necessary to protect consumers by
enabling manufacturers to identify and recall problematic products as
necessary and make necessary corrections to deviations in their
processes.

	The authority granted us under sections 402(g) and 701(a) of the act
not only includes the authority to establish record requirements, but
also includes access to such records.  Without such authority, the
dietary supplement CGMP requirements are, practically speaking, not
enforceable.  Under section 402(g)(1) of the act, the failure to meet
any current good manufacturing practice requirements, including the
failure to have a record that is required by this final rule, renders a
dietary supplement so manufactured to be adulterated as a matter of law.
 The introduction or delivery for introduction into interstate commerce
of an adulterated dietary supplement is a prohibited act under section
301(a) of the act (21 U.S.C. 331(a)), and acts done to an ingredient in
a dietary supplement, or to a dietary supplement, while held for sale
after shipment in interstate commerce that result in the ingredient or
dietary supplement being adulterated violates section 301(k) of the act
(21 U.S.C. 331(k).  Thus, in order for us to determine whether the
dietary supplement product is adulterated and whether a manufacturer has
committed a prohibited act, we must have access to the manufacturer’s
records that we are requiring to be kept under section 402(g) of the
act.

	In light of the foregoing, without access to such records, we would not
know whether a manufacturer was complying with the procedures and
processes required in this final rule.  For example, our investigator
must have access to the test results for the identity of a dietary
ingredient to determine whether such ingredient meets the
manufacturer’s specification for identity.  The investigator needs to
understand, by reviewing a record, what the software that runs a
production operation is set up to do and whether it performs those
functions to achieve the desired product characteristics.  Observation
of these processes alone, by an investigator, would not allow that
investigator to evaluate compliance with this final rule.  Moreover,
records often cannot be thoroughly evaluated by the investigator on
site.  In such cases, records must be readily available to food experts
at the Center for Food Safety and Applied Nutrition (CFSAN) and agency
consultants.  We must have accurate, reliable, and objective data about
the manufacturing specifications to be able to achieve an enforceable
rule.

	We also disagree with comments stating our records inspection authority
is limited to that provided by section 306(a) of the Bioterrorism Act.
There is no basis to conclude that Congress intended to limit our
authority to inspect records, to enforce section 402(g) of the act, to
the records inspection authority under the Bioterrorism Act.  The
Bioterrorism Act, enacted almost 8 years after section 402(g), to
address credible threats of serious adverse health consequences or death
to humans and animals, required record keeping to identify the immediate
previous sources and the immediate subsequent recipients of food  (21
U.S.C. 350c).

	There is nothing in the Bioterrorism Act that reflects any
Congressional intent to modify section 402(g) of the act.  In fact,
section 414(d)(1) of the act, added by section 306(a) of the
Bioterrorism Act, shows a contrary intent.  Section 414(d)(1) provides
that “This section shall not be construed -(1) to limit the authority
of the Secretary to inspect records or to require establishment and
maintenance of records under any other provision of this Act.”
Moreover, Congress, in the legislative history to the Bioterrorism Act,
supported our general approach of requiring recordkeeping pursuant
tousing authority in section 701(a) of the act in combination with other
provisions.  We are not relying on section 704 of the act for its
underlying authority to require recordkeeping and records access in this
final rule.  Those comments asserting that we do not have such authority
and the underlying references, for example, to past hearings on records
inspection authority under section 704 of the act, are not controlling
with regard to the action we are taking under sections 402(g) and 701(a)
of the act.  When there are other bases for jurisdiction and tools to
protect the public interest, we may use what “will be the most
effective in advancing the Congressional objective” (U.S. v. Midwest
Video Corp., 406 U.S. 649, 656 (1972)).

	Some comments stated that our access to dietary supplement records is
not consistent with constitutional jurisprudence.  We disagree.  The
comment which expressed concern about “constitutional issues” in the
context of an FDA inspection of records during a warrantless FDA
inspection expressed concern about the criminal liability that could be
imposed on a manufacturer under the act (citing United States v.
Dotterweich, 320 U.S. 277 (1944) and United States v. Park, 421 U.S. 658
(1975)).  To the extent that the comment asserts that the records access
established in this final rule constitutes an improper search and
seizure under the Fourth Amendment, we disagree.

	The dietary supplement industry, as the food industry as a whole, is a
pervasively regulated industry that is subject to warrantless
inspections (see, e.g., United States v. Biswell, 406 U.S. 311, 315
(1972) (“In the context of a regulatory inspection system of business
premises . . . the legality of the search depends not on consent but on
the authority of a valid statute.”); United States v. New England
Grocers Supply Co., 488 F. Supp. 230, 238 (D. Mass. 1980) (holding that
a warrantless inspection under 21 U.S.C. § 374 is ‘fully consistent
with the Fourth Amendment”); United States v. Acri Wholesale Grocery
Co., 409 F. Supp. 529, 533 (S.D. Iowa 1976) (holding that a warrantless
inspection, which includes photographic activities, conducted under 21
U.S.C. § 374 does not violate the Fourth Amendment); United States v.
Business Builders, Inc., 354 F. Supp. 141, 143 (N.D. Okla. 1973) (“the
statute takes the place of a valid search warrant”); United States v.
Del Campo Baking Mfg. Co., 345 F. Supp. 1371 (D. Del 1972) (finding
warrantless inspection of food establishment lawful under 21 U.S.C.
§ 374)).

	As explained earlier in this section, we have ample authority, under
sections 402(g) and 701(a) of the act, to require that certain records
be kept and accessible to us upon inspection.  Records access is
imperative to the efficient enforcement of the dietary supplement CGMP
final rule, and we are not prohibited from requiring access to these
records under sections 402(g) and 701(a) of the act (See Permian Basin
Area Rate Cases, 390 U.S. 747, 780 (1968) (“in the absence of
compelling evidence that such was Congress’ intention . . . [the court
should not] prohibit administrative action imperative for the
achievement of an agency’s ultimate purposes.”)).

	We also disagree with the comment suggesting that  voluntary records
access is sufficient.  In our experience, many manufacturers are not
willing, as the comments suggest, to provide records voluntarily to us.
(Ref. 152).  Moreover, it is often the case that the most uncooperative
manufacturers are the very ones whose records and processes are
deficient.  Without mandatory requirements for agency access to records
required by the final rule, we could not enforce and there would be
minimal incentives for manufacturers to comply with the rule, which
would frustrate Congressional intent in enacting section 402(g) of the
act.

	We also disagree with the comment that cited In the Matter of
Establishment Inspection of Medtronic, Inc., 500 F. Supp. 536 (D. Minn.
1980), to suggest that our proposed recordkeeping requirements exceed
our statutory inspection authority.  As already discussed, we are not
relying on section 704 of the act for our authority to require access to
dietary supplement CGMP records.  Thus, to the extent the comment cited
to Medtronic as an example of the statutory authority for inspection of
device records under section 704 of the act, Medtronic is not pertinent
to our authority for records access in this final rule.

	Finally, we disagree that the records access in this final rule will
violate any protection a manufacturer has with respect to protection of
confidential commercial or financial information or trade secrets.
Trade secrets and commercial or financial information that is privileged
or confidential are protected from disclosure under FOIA and other laws
(Ssee, e.g., 21 U.S.C. 331(j), 18 U.S.C. 1905).  Further, our FOIA
regulations set forth the specific procedures for assuring such
protection.

	It was not clear from the comments what was meant by “rights to
privacy of corporate manpower.”  We note that §§ 20.63 and 20.64
contain provisions for the protection of personal privacy.

3.	Public Health Service Act Authority

	(Comment 20) One comment acknowledges that we have authority under the
PHS Act to regulate intrastate activities that may cause the spread of
communicable diseases.  The comment states that, in any situation in
which we need to exercise our authority over any disease-causing
substance within the state where a component or dietary supplement is
manufactured, packed or held, we can and should exercise our authority
under the PHS Act.  However, the comment asserts that nothing in the
preamble clearly states whether we believe that the final rule will be,
in its entirety, binding on manufacturers, packers, and holders of
dietary supplements who are engaged solely in intrastate commerce, and
that we have not requested comment on this specific issue.  The comment
requests that we clearly state that the final rule applies only to
interstate commerce, except for activities that may spread communicable
diseases.

	(Response)  We address each of these issues in turn.

	a.  The communicable disease risk posed by dietary supplements

	There are communicable disease risks related to the manufacture of
dietary supplements that are appropriately addressed not only under the
act, but, as the comment acknowledges, also under the PHS Act.
Microorganisms, including Salmonella enterica (Salmonella),
Campylobacter jejuni, and enterohemorrhagic Escherichia coli
0157:H7(EHEC), are well-known causes of communicable diseases, and may
be present in dietary supplements and their components.  There are a
number of microorganisms that cause communicable diseases and that may
be found in components or dietary supplements.  These microorganisms
cause serious effects and symptoms.  For example, Salmonella causes
salmonellosis, which affects the gastrointestinal (GI) tract and is
characterized by diarrhea, fever, abdominal cramps, headache, nausea,
and vomiting. (Ref. 163).  In a small portion of healthy people [1-4%],
infection spreads from the GI tract into the blood stream, which can be
life-threatening.  Persons with immune compromising conditions (such as
cancer, AIDS, autoimmune disorders) are at greater risk of blood stream
infection. (Ref. 163).

	 Campylobacteriosis, often due to infection with Campylobacter jejuni,
is characterized by diarrhea, fever, and abdominal cramps, which can be
severe. (Ref. 174).  These symptoms frequently relapse, and the disease
may become chronic in immune compromised persons.  People with
campylobacteriosis are also at increased risk of developing certain
post-infectious complications, which will prolong their recovery.

	E. coli O157:H7 may cause infections with a very low infectious dose
(as low as 2 to 45 organisms), and may result in non-bloody and bloody
diarrhea, hemolytic-uremic syndrome (a cause of red blood cell
destruction, damage of blood vessel walls, and, in severe cases, kidney
failure (especially in young children), thrombotic thrombocytopenic
purpura (i.e., a blood disorder characterized by low platelets, low red
blood cell count, abnormalities in kidney function, and neurological
abnormalities (especially in adults), and death) (Ref. 185).

	Animal tissues (e.g., organs from livestock), as well as botanicals,
used as components in dietary supplements may contain EHEC, Salmonella,
and Campylobacter jejuni.  In addition, because the same microorganisms
are also present in the environment, they may contaminate components
during manufacturing activities.  Moreover, people who harbor those
pathogens could transmit them to components and dietary supplements
during processing.  Therefore, components and dietary supplements, as
potential sources of communicable diseases, may be regulated under the
PHS Act.

	For these microorganisms (e.g., EHEC, Salmonella, and Campylobacter
jejuni) humans carry and transmit infections through their feces or by
direct contact with other persons.   For other microorganisms, domestic
and wild animals serve as the reservoir, and humans become infected when
contaminated tissues of infected animals are used in dietary
supplements.  For both categories of microorganisms, dietary supplements
can also become contaminated indirectly by human and animal fecal
contamination of water or through the production or processing
environment.

	Dietary supplements may contain a variety of components derived from
domestic and wild animals, such as powders prepared from whole or
partial gecko, deer antler velvet, and organs, such as cow liver and
brain, pork stomach, or sheep spleen from common domestic livestock.
Each of these tissues may be contaminated with microorganisms such as
Salmonella, Campylobacter jejuni, and EHEC.  Even clinically normal
animals obtained from safe sources may harbor these communicable
pathogens and result in contaminated products. (Ref. 196). (Information
on these animals and potential pathogens can be accessed at (  HYPERLINK
"http://www.fsis.usda.gov/Science/Microbiology/"
http://www.fsis.usda.gov/Science/Microbiology/ index.asp).  Dietary
supplements also may contain crustacean or molluscan shellfish or
components prepared from them, such as glucosamine from shrimp
exoskeletons and oyster extract, that may be contaminated with Vibrio
species, including V. parahaemolyticus.  Vibrio species are natural
inhabitants of shellfish harvest waters, and shellfish are commonly
naturally contaminated, especially during times of the year when harvest
waters are warm (Refs. 2017 through 230)).  V. parahaemolyticus most
often causes gastroenteritis characterized by diarrhea, abdominal
cramps, nausea, vomiting, and fever.  (Ref. 241).

	Dietary supplements may also contain botanicals (plants) that may
harbor microorganisms, including organisms from animal feces (Salmonella
and Shigella spp., Escherichia coli), and organisms arising from
handling (Staphylococcus aureus), harvesting, processing, and
transportation.

	Components contaminated with microorganisms must be treated to prevent
the finished dietary supplements from being contaminated.  The processes
used to manufacture dietary supplements do not, by themselves, always
eliminate the microorganisms.  Studies show, for example, that
microorganisms, such as EHEC and Salmonella, can even survive the tablet
production process and thereby expose consumers. (Ref. 252).

	The industry is aware of the dangers of using components contaminated
with Salmonella and other microorganisms.  For example, in 2001, a
component manufacturer recalled 2,400 pounds of pepsin contaminated with
Salmonella.  As a result, a number of dietary supplement manufacturers
issued recalls for their dietary supplements that contained the pepsin.
In the press releases accompanying the recalls, the dietary supplement
manufacturers warned consumers of the possible dangers of Salmonella
contamination, and encouraged consumers to either destroy or return the
supplements. (Ref. 263).

	Therefore, because of the communicable disease concerns associated with
dietary supplements, we are asserting legal authority under the PHS Act
in support of the final rule.  As discussed in this section immediately
below, our authority under the PHS Act is not limited to interstate
activities.  It also covers intrastate activities.

	b. Activities for which we are asserting legal authority under the PHS
Act

	There are many opportunities for components and dietary supplements to
become contaminated with microorganisms that spread communicable
diseases.  The final rule requires firms to take all the necessary
precautions during the manufacture of a dietary supplement to prevent
such contamination.

  	These precautions, for example, include: performing manufacturing
operations under conditions and controls that protect against potential
microorganism growth; washing or cleaning components that contain soil
or other contaminants; performing microbiological testing, as necessary,
to prevent the use of contaminated components; sterilization,
pasteurization, freezing, refrigeration, and controlling hydrogen-ion
concentration (pH), humidity, and water activity (aw), or using  other
effective means to remove, destroy, or prevent the growth of
microorganisms and decomposition; and holding components and dietary
supplements that can support the growth of infectious microorganisms of
public health significance in a manner that prevents them from becoming
adulterated.

	Failure to properly clean components, or take any other appropriate
steps, such as those listed in the previous paragraph, could lead to
pathogen growth and the spread of communicable diseases.  If, for
example, a dietary supplement manufacturer purchased an animal-derived
ingredient that harbored Salmonella enterica, but failed to take the
steps necessary to inactivate the pathogen, the consumption of the
dietary supplement could lead to the spread of salmonellosis.

	The final rule also requires firms to take measures to exclude from
certain operations any sick persons who might contaminate material,
including components, dietary supplements, and contact surfaces used to
manufacture, package, label, or hold a dietary supplement.

	c.  The interstate commerce nexus for the final rule

		i.  The PHS Act

	 (Comment 21) Several comments assert that, although the PHS Act may
extend to some intrastate activities, its reach is very limited.  The
comments appear to conclude that the reach of the PHS Act and the act
extends only to situations in which the finished dietary supplement is
shipped in interstate commerce.

	(Response) We do not agree that this view is correct. 	The  PHS Act
extends to intrastate commerce.  Under section 361 of the PHS Act, we
may “make and enforce such regulations as in [our] judgment are
necessary to prevent the introduction, transmission, or spread of
communicable diseases from foreign countries into the States or
possessions, or from one State or possession into any other State or
possession.” (42 U.S.C. 264).  	In Louisiana v. Mathews, 427 F. Supp.
174, 176 (E.D. La. 1977), the court upheld FDA’s regulation that
banned the sale of small turtles to prevent the spread of disease caused
by turtles harboring Salmonella and Arizona microorganisms.  The ban
covered both interstate and intrastate sales.  The court held that the
intrastate ban is not only authorized by the law, but, under modern
conditions of transportation and commerce “is clearly reasonable to
prevent the interstate spread of disease”  (Id.).

	We are authorized under the PHS Act to regulate conduct that occurs
within a state to the extent necessary to prevent the interstate spread
of communicable diseases.  Such is the present case with respect to the
provisions of the dietary supplements CGMP final rule for which PHS Act
§ 361 provides authority.

	ii.	The act

	The act extends to the sale of a dietary supplement that was
manufactured and distributed entirely in one state, if the supplement
contains any ingredient or uses any component that came from outside of
that state.  Such a dietary supplement is subject to section 301(k)of
the act, which prohibits “[t]he alteration, mutilation, destruction,
obliteration, or removal of the whole or any part of the labeling of, or
the doing of any other act with respect to, a food, drug, device, or
cosmetic, if such act is done while such article is held for sale
(whether or not the first sale) after shipment in interstate commerce
and results in such article being adulterated or misbranded.”  21
U.S.C. 331(k) (emphasis added).  See also 21 U.S.C. 321(b)(3) (defining
food to include articles used as components of food).

	The interstate commerce prerequisite under section 301(k) or section
304(a) of the act is established when one or more components used in the
manufacture of the product have crossed state lines.  This principle is
known as “component jurisdiction” (See, e.g., Baker v. United
States, 932 F.2d 813, 814-15 (9th Cir. 1991); United States v. Article
of Food . . . Coco Rico, Inc., 752 F.2d 11, 14 (1st Cir. 1985);  United
States v. Dianovin Pharmaceuticals, Inc., 475 F.2d 100, 103 (1st Cir.),
cert. denied, 414 U.S. 830 (1973)(“appellants’ use of components
shipped in interstate commerce to make vitamin K for injection brought
their activities within § 331(k)”); United States v. Cassaro, Inc.,
443 F.2d 153, 155-56 (1st Cir. 1971); United States v. Detroit Vital
Foods, Inc., 330 F.2d 78, 81-82 (6th Cir.), cert. denied, 379 U.S. 832
(1964); United States v. Allbrook Freezing & Cold Storage, Inc., 194
F.2d 937, 939 (5th Cir. 1952); United States v. Varela-Cruz, 66
F.Supp.2d 274, 277-281 (D. P.R. 1999)).

	  SEQ CHAPTER \h \r 1 Nor does it matter that the interstate product
component comprises only a minute part of the article,   SEQ CHAPTER \h
\r 1 United States v. Miami Serpentarium Laboratories, [1981—1982
Transfer Binder] Food Drug Cosm. L.Rep. (CCH) paragraph 38,164 at
38,930 (S.D. Fla. 1982); United States v. 14 Cases . . . Naremco, 374
F.Supp. 922, 925 (W.D. Mo. 1974), or if the interstate ingredient
combines with others to form a different product. Detroit Vital Foods,
330 F.2d at 81; United States v. 40 Cases . . . Pinocchio Brand . . .
Oil, 289 F.2d 343, 346 (2d Cir.), cert. denied, 368 U.S. 831 (1961).

	Finally, we note that section 709 of the act creates a presumption of
interstate commerce (Ssee 21 U.S.C. 379a (“In any action to enforce
the requirements of this Act respecting a device, food, drug, or
cosmetic the connection with interstate commerce required for
jurisdiction in such action shall be presumed to exist.”)).

	In conclusion, the final rule covers not only finished products that
have moved in interstate commerce but also products made from
ingredients or components that have moved in interstate commerce.  This
is true regardless of the amount of the ingredient or component in the
product and regardless of whether the finished dietary supplement has
itself moved in interstate commerce.  The final rule also covers
products, components, and ingredients that may contribute to the spread
of communicable disease, regardless of whether the component,
ingredient, or product has itself moved in interstate commerce.

iii.	Commerce Clause

	(Comment  22) One comment states that we must be “mindful of the
limits” imposed on the regulation of intrastate commerce by the
Supreme Court in United States v. Lopez, 514 U.S. 549 (1995).  The
comment asserts that we may only regulate intrastate activity that has a
“substantial effect” on interstate commerce and activity that
“exerts a substantial economic effect on interstate commerce.”

	(Response)  The final rule is consistent with the Lopez decision.
Among the cases cited by the Court in Lopez as support for its decision
is Wickard v. Filburn, 317 U.S. 111 (1942), which involved the
production and consumption of homegrown wheat.  In that case, the Court
explained: “although Filburn’s own contribution to the demand for
wheat may have been trivial by itself, that was not enough to remove him
from the scope of federal regulation where, as here, his contribution,
taken together with that of many others similarly situated, is far from
trivial” (Lopez, 514 U.S. at 556).  The same is true for dietary
supplement manufacturers.  Therefore, the requirements of the final rule
are entirely consistent with the Commerce Clause of the Constitution.

iv.	Fifth Amendment

	(Comment 23)  Several comments allege a number of the sections of the
proposed regulation are unconstitutionally vague and violate the
Administrative Procedure Act (APA) because the rule would be “contrary
to constitutional right, power, privilege, or immunity.”  The comments
express concern that if such terms are not defined or deleted, there
would be no fair notice on what conduct is prohibited and would result
in “unbridled discretion” in how the rule will be enforced.  The
comments focus on provisions containing words such as “adequate,”
“qualified,” “readily accessible,” “convenient,”
“suitable,” “appropriate,” and “necessary.”  For example,
one comment notes that proposed § 111.15(e) would require physical
plant plumbing to be of an adequate size and design and to be adequately
installed and maintained.  The comment objects to the section on the
ground that “what constitutes ‘adequate’ in those contexts is left
undefined.”

	(Response)  We disagree these terms are vague or that the identified
terms should be deleted from the final rule.  The qualifying terms
objected to in the comments have been in use since the umbrella food
CGMP rule (part 110) was first promulgated in 1969.  For example, this
regulation included requirements that: “[p]lant buildings and
structures shall be suitable in size;” there must be “sufficient
space” for equipment and storage materials; there must be “adequate
lighting;” and protection against pests must be provided “where
necessary” (See 34 FR 6977 at 6978 (April 26, 1969)).  The court in
National Association’n. of Pharmaceutical Manufacturersfrs. v.
Department of Health & Human Services, 586 F.Supp. 704 (S.D.N.Y 1986),
addressed the very question of whether terms such as “adequate,”
“appropriate,” “proper,” “sufficient,” and “suitable,”
in the drug CGMP regulation were vague.  The court found that the drug
CGMP regulation containing such terms was “sufficiently definite to
give notice of the required conduct to one who would avoid [their]
penalties, and to guide the judge in [their] application . . .” (Id.
at 753).  The court so held, in part, in light of the fact that the drug
CGMP statute was upheld against a constitutional vagueness attack in
United States v. Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 883
(E.D.N.Y. 1968) (“the phrase ‘current good manufacturing practice’
is not strange to those in the trade to whom the subject section is
directed.”).  Furthermore, the use of such “ordinary terms to
express ideas which find adequate interpretation in common usage and
understanding” are not the types of terms that have been held to be
unconstitutionally vague (Boyce Motor Lines v. United States, 342 U.S.
337, 342 (1952)).  Some of these very terms have been in use for over 30
years in food CGMP regulations.

	No comments were submitted objecting to the use of such terms, when the
umbrella food CGMP rule was revised in 1986 (See 51 FR 22458 (June 19,
1986)).  Also, when we began work on the dietary supplement CGMP rule,
we received and published for comment an industry draft of a CGMP
regulation for dietary supplements.  The industry draft used many of the
same terms.  For example, it provides in part: “Plumbing shall be of
adequate size and design and adequately installed and maintained” (62
FR 5700 at 5703 (Feb. 6, 1997)).  Thus, there has been sufficient common
usage of these terms in the food industry and, in particular, the
dietary supplement industry to enable manufacturers, and those who
enforce the requirements, to comprehend and apply such terms “with a
reasonable degree of certainty” to their particular operations  (Boyce
Motor Lines v. United States, 342 U.S. at 340 (“[F]ew words possess
the precision of mathematical symbols, most statutes must deal with
untold and unforeseen variations in factual situations, and the
practical necessities of discharging the business of government
inevitably limit the specificity with which legislators can spell out
prohibitions [and therefore] no more than a reasonable degree of
certainty can be demanded.”) ).  The same reasoning applies here.  It
addresses “untold and unforeseen variations in factual situations”
and, as such, “no more than a reasonable degree of certainty can be
demanded.”

	Agencies are permitted to, and indeed must, use such qualifying terms
to address the variety of conditions that exist at different companies.
We do not need to, nor could we, predict with mathematical precision how
many inches or feet, for example, would be “adequate space” to allow
for cleaning a particular piece of equipment that could be applied to
every size of facility and every operation (id.).  Moreover, defining
such terms too precisely would unduly restrict the application of the
regulation to a very narrow, limited set of circumstances and not
provide industry with the needed flexibility to address the number and
variety of types of manufacturing operations that Congress intended for
this rule to cover (Ssee Freeman United Coal Mining Company v. Federal
Mine Safety and Health Review Commission, 108 F.3d 358, 363 (D.C. Cir.
1997) (citations omitted)(upholding a regulation that required equipment
to be “maintained in good repair,” the court rejected the vagueness
challenge: “specific regulations cannot begin to cover all of the
infinite variety of [conditions at firms and that]  . . .  [b]y
requiring regulations to be too specific [courts] would be opening up
large loopholes allowing conduct which should be regulated to escape
regulation.”); United States v. Bel-Mar Laboratories, Inc., 284 F.
Supp. at 883 (rejecting a vagueness challenge to the CGMP requirements
for drugs, noting that “[a]s a matter of fact, there are responsible
segments of opinion within the industry itself which oppose a greater
degree of specificity in this area.”).

	Finally, it is important to understand that rules are not
unconstitutionally vague simply because they require interpretation by
regulated persons.  For example, courts have held that the term
“insanitary conditions” in the act is not unconstitutionally vague
(See Golden Grain Macaroni Co. v. United States, 209 F.2d 166, 168 (9th
Cir. 1953) (citing Boyce Motor Lines, supra); Berger v. United States,
200 F.2d 818 (8th Cir. 1952)).  In Berger, the court rejected the claim
that the term “insanitary condition” is unconstitutionally vague on
the ground that it does not specify the “degree of insanitation”
required for a violation (Id. at 822).  A law may require a person to
make “estimates of the degree of dirtiness and lack of sanitation”
which may result in a violation (Id.  See also Boyce Motor Lines v.
United States, 342 U.S. at 340 (It is not “unfair to require that one
who deliberately goes close to an area of proscribed conduct shall take
the risk that he may cross the line”.)).  There are sufficient
protections under the act to overcome any concerns related to how it
will be criminally enforced.  We disagree that such terms will lead to
“unbridled discretion” on how the rule is enforced.

	In short, we find that the rule is not unconstitutionally vague, and
does not violate section 706(2)(B) of the APA.

6.	Miscellaneous

	(Comment 24) One comment states that the proposed rule violates section
402(f)(1)(A)(i) and (ii) of the act (21 U.S.C. 342 (f)(1)(A)(i) and
(ii)), which deem a dietary supplement adulterated if it contains a
dietary ingredient that presents an unreasonable risk of illness or
injury under conditions of use in labeling or ordinary conditions of
use, if none are suggested or recommended in labeling.  Under section
402(f) of the act, the government bears the burden of proof to show that
a dietary supplement is adulterated.  The comment states that the
proposed rule reversed the presumption under section 402(f) of the act,
and would revise the rule to require us to first show a violation under
section 402(f) of the act before we could take any enforcement action
under section 402(g).  Another comment states that, because the rule was
intended to enable manufacturers to be able to detect and avoid
adulteration through CGMP, the proposed rule created a presumption that
dietary supplements are adulterated until proven otherwise.

	(Response)  The final rule does not violate section 402(f) of the act.
Sections 402(f) and (g) of the act provide two independent bases under
which we may take enforcement action against dietary supplements.  A
dietary supplement may be adulterated either because a manufacturer has
failed to follow a CGMP requirement, or because a dietary supplement
presents an unreasonable risk of illness or injury, or both.  There
would be no reason to assert a second basis for adulteration under
section 402(g) of the act if one always had to demonstrate adulteration
under section 402(f) of the act as a prerequisite.

	We also disagree with the comment that the proposed rule creates a
presumption that the dietary supplement is adulterated simply because
the proposed requirements would enable a manufacturer to detect and
avoid adulteration.  The requirements for CGMP are prophylactic and are
designed in part to ensure that all aspects of manufacturing, from
receipt through distribution, provide the necessary controls and
monitoring to ensure the quality of the dietary supplement, including
that it is manufactured, packaged, labeled, and held in a manner to
prevent adulteration.

	(Comment 25) One comment states that, if there is reduced competition
through the enforcement of the rule, there will be a secondary effect of
elimination of speech on dietary supplement innovative uses.

	(Response)  The comment seems to conclude that, if a dietary supplement
manufacturer is not able to stay in business due to adverse enforcement
actions against it by us, or elects to not go into business based on the
possibility of enforcement action by us, there will be reduced
competition due to fewer products, less labeling, and “elimination of
speech on innovative uses.”  To the extent that the comment is
suggesting that the dietary supplement CGMP requirements are
unconstitutionally overbroad, this argument is wholly without merit (Cf.
 Wisconsin v. Mitchell, 508 U.S. 476, 488-89 (1993) (finding no merit to
an overbreadth argument that the possibility of enhanced sentences based
on prior racially motivated speech or associations constitutes an
impermissible chill on free speech)).  Manufacturing a dietary
supplement in a manner that violates the CGMP requirements causes the
product to be adulterated, and therefore, unlawful.  The fact that a
manufacturer may not stay in business, or elects not to enter business,
due to: (1) our implementation of CGMP requirements; or (2) our
enforcement against a product that violates CGMP requirements, does not
mean that we are somehow prohibiting speech.  In any event, there is no
First Amendment protection for speech that concerns unlawful activity
under the first prong of the test set out in Central Hudson Gas &
Electric Corp. v. Public Service Commission, 447 U.S. 557 (1980).
Therefore, the comment’s suggestion that there is elimination of
speech based on the rulemaking is not supportable.  The requirements in
the final rule do not infringe on a manufacturer’s right to lawfully
label and market a dietary supplement.

	VI. What Comments Did We Receive on the General Provisions?

(Subpart A)

A. Organization of Final Subpart A

	Proposed subpart A contained five provisions regarding the scope of the
proposed rule, definitions, and exclusions.  Table 2 lists the sections
in final subpart A and identifies the proposed sections that form the
basis of the final rule.

Table 2 - Derivation of Sections in Final Subpart A

Final Rule	2003 CGMP Proposal

§ 111.1 Who Is Subject to These Regulations?

§ 111.1

§ 111.2 What Definitions Apply to This Part?

§ 111.3

§ 111.5 Do Other Statutory Provisions and Regulations Apply?

§ 111.5

B.  Who Is Subject to These Regulations?

(Final § 111.1)

	Section 111.1 explains who is subject to the dietary supplement CGMP
requirements.  In brief, final § 111.1(a) states that you are subject
to the dietary supplement CGMP requirements if you manufacture, package,
label, or hold a dietary supplement.  This requirement includes a
dietary supplement you manufacture but that is packaged or labeled by
another person, and a dietary supplement that is imported, offered for
import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico.  Final § 111.1(b),
however, excludes certain persons from the rule.  Specifically, §
111.1(b) states that the requirements pertaining to holding dietary
supplements do not apply to you if you are holding those dietary
supplements at a retail establishment for the sole purpose of direct
retail sale to individual consumers.  This section also states that a
retail establishment does not include a warehouse or other storage
facility for a retailer or a warehouse or other storage facility that
sells directly to individual consumers.

	This exclusion represents specific changes sought by the comments.  We
provide detail on the comments and our reasons for revising final §
111.1 immediately below.

	(Comment 26) Some comments interpret the proposal as not applying to
persons who perform labeling operations.  For example, one comment
claims that proposed § 111.35(e), which would require manufacturers,
packagers, and persons who hold dietary supplements to establish
specifications, did not apply to “labelers” because the proposed
definition of “you” did not expressly mention persons who label
dietary supplements.

     (Response) We disagree with the comments.  Various provisions in
the proposal expressly mentioned or pertained to labels and labeling
operations (see, e.g., proposed §§ 111.20(c)(6) (which would require
your physical plant to have separate or defined areas for packaging and
label operations), 111.30(a) (which would impose certain requirements on
automatic, mechanical, or electronic equipment used to “manufacture,
package, label, and hold” a dietary supplement), 111.35(a) (which
would require you to implement a system of production and process
controls that cover, among other things, all stages of labeling dietary
supplements), 111.37(a) (which would require you to use a quality
control unit to ensure, among other things, your label operations are
performed in a manner that prevents adulteration and misbranding),
111.40(b) and (c) (which would impose certain requirements on packaging
and labels you receive and on persons who perform label requirements),
and 111.70 (which would impose various requirements on packaging and
label operations)).  Although the proposed definition of “you” and
proposed § 111.1 did not include the word “label” or
“labeling,” we considered label operations to be part of a broader
manufacturing process, and it would be illogical to interpret the
proposal’s specific references to label operations as somehow being
inapplicable to labelers simply because a proposed definition of
“you” or a general “scope” provision did not mention labels or
otherwise distinguish label operations from the broader context of
manufacturing.

	In any case, to correct such misinterpretation, we have revised §
111.1 to include the word “label.”  Thus, under final § 111.1(a),
you are subject to the dietary supplement CGMP requirements if you
“manufacture, package, label, or hold a dietary supplement.”  We
also have made corresponding changes to other sections in this final
rule; for example, we have revised the definition of “you” in final
§ 111.3 to state that “you” means “a person who manufactures,
packages, labels, or holds” a dietary supplement, and we also have
inserted the word “labeling” in the title to this final rule.  We
have not explained this change in the preamble each time it is made in
the codified provision.

	In addition, we refer to “label” and “labeling” in the context
of CGMP requirements related to operations for ensuring the correct
label is on the product.  To help clarify that we are referring to
labeling requirements in this final rule for labeling operations and
not, for example, to the labeling requirements in part 101, we inserted
the word “operations” in the title of part 111 to read “Current
Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements.”

	(Comment 27) Several comments ask for clarification about the rule’s
applicability to different types of businesses and practices.  Some
comments ask for a clear listing of who is subject to the rule, stating
that it is difficult to apply the rule’s specific provisions.
According to these comments, the rule’s level of detail and
inflexibility does not account for variations in manufacturing needs
within the entire industry.

Several comments on various proposed sections ask who would be
responsible for complying with CGMP requirements if more than one party
was involved in the manufacturing, packaging, labeling, or holding of
the dietary supplement.  For example, some comments ask whether
consultants are subject to a specific proposed section; others ask who
would be responsible if a firm employed another firm to handle packaging
or labeling operations.

Other comments request clarification regarding the rule’s
applicability to distributors.  Some comments claim that a person who
holds and sells packaged products should not be subject to dietary
supplement CGMP requirements.  Other comments state that dietary
supplement CGMPs should apply to distributors as well as manufacturers.
These comments assert many supplement distributors are merely marketers
who employ contract manufacturers.  The comments said that, because
marketers are the parties providing supplements to consumers, we should
hold marketers responsible for their products and require marketers to
ensure that their contract manufacturers adhere to CGMP requirements.
These comments argue we should not permit marketers to transfer their
responsibilities in delivering safe supplements.  Other comments assert
questions about the rule’s applicability are underscored by typical
dietary supplement labeling practices where the contact information
listed on the product label pertains to the distributor/marketer instead
of the actual manufacturer.

Collectively, these comments raise a basic question as to which party or
parties are responsible for complying with the dietary supplement CGMP
requirements where more than one party is involved in the manufacture,
packaging, labeling, or holding of that dietary supplement.

	(Response) In the 2003 CGMP Proposal, we stated that it would apply to
a wide variety of activities associated with the manufacture, packaging,
and holding of a dietary supplement, including labeling, testing,
quality control, holding, and distribution (68 FR 12157 at 12175).  We
stated under proposed part 111 you would need to comply with those
regulations directly applicable to the operations that you perform and
provided examples (id.).  All activities may not be performed by the
same person.  For example, a manufacturer may contract with another firm
to package and label the dietary supplement in the containers used for
distribution to consumers.  Alternatively, a distributor may contract
with one firm to manufacture a dietary supplement, and another firm to
package and label the dietary supplement that the distributor ultimately
distributes under its own name.

	Under this final rule, you must comply with the CGMP requirements that
apply to your operations related to the manufacture, packaging,
labeling, and holding of dietary supplements.  It is not practical to
list all possible contractual relationships that persons may enter into
in the manufacture of a dietary supplement, or to list all businesses or
practices that may be subject to the requirements of this final rule in
order for persons to know whether they are subject to requirements of
this final rule.  To provide additional clarity about how this rule may
apply to various persons, we provide some examples in the following
paragraphs.

A manufacturer that manufactures a dietary supplement, and then packages
and labels and distributes the dietary supplement, is subject to all the
requirements in this final rule.  If that manufacturer contracts with
another person to package and label the dietary supplement, then the
packager/labeler is responsible for complying with the requirements for
packaging and labeling operations, in addition to other relevant
requirements.  The packager/labeler, in this example, would need to
comply, not only with the specific requirements related to packaging and
labeling operations in subpart L, but also with the general requirements
related to personnel, physical plant, quality control, and other
requirements that apply to that firm's operations.  However the
packager/labeler would not need to comply with requirements that do not
apply to it; for example, the packager/relabeler would not have to
conduct testing on the finished batch of dietary supplement since it
does not manufacture the finished batch of dietary supplement.

     A manufacturer who contracts with a person to do packaging, and
labeling, but who later distributes the packaged and labeled product, is
ultimately responsible for the dietary supplement it releases for
distribution.  The manufacturer would be responsible for the CGMP
requirements for the operations that it performs, including those
related to the release of the product for distribution.  For example,
the manufacturer must determine whether the packaged and labeled dietary
supplement it receives from the packager/labeler conforms to applicable
specifications (final § 111.127(d)), and must approve the release of
the packaged and labeled dietary supplement for distribution (final
§ 111.127(h)).  Although the manufacturer is not performing the
specific activities related to the packaging and labeling operations
done by another person, the manufacturer has an obligation to know what
and how such activities are performed so that it can make decisions
related to whether the packaged and labeled product conforms to
applicable specifications and whether to approve and release the product
for distribution.

Some manufacturers may sell their finished batch of dietary supplement
to a packager/labeler that the packager/labeler may package, label, and
then hold and distribute.  The manufacturer and packager/labeler would
each be responsible for complying with the applicable CGMP requirements
related to the operations that they perform.  The manufacturer would not
be responsible for the oversight of the packager/labeler, since the
packager/labeler is not under the control of the manufacturer and has
control over the release of the packaged and labeled dietary supplement.

A manufacturer may decide to hire a contractor or a consultant for
specific operations within the scope of the manufacturer’s
responsibilities under the final rule.  For example, a manufacturer may
hire a person to calibrate its equipment.  The manufacturer is
responsible for complying with the requirements related to its
responsibilities, e.g., calibration requirements in this example, even
though the manufacturer has hired another person to perform that job
task.

In another example, a distributor who purchases a packaged and labeled
dietary supplement and who then holds the product in a warehouse for
distribution to another physical location is subject to the requirements
related to its operations.  The codified uses the word “hold” since
it is a broad term which encompasses the activities of a distributor.
Thus, the distributor would be responsible for complying with
requirements in subpart M, Holding and Distributing, in addition to
other requirements related to its operations (e.g., Personnel, Physical
Plant).

In cases where a distributor contracts with a manufacturer to
manufacture a dietary supplement that the distributor then distributes
under its own label, the distributor has an obligation to know what and
how manufacturing activities are performed so that the distributor can
make decisions related to whether the packaged and labeled product
conforms to its established specifications and whether to approve and
release the product for distribution.

	(Comment 28) Some comments state that the proposed rule requirements
would require the manufacturer to report adverse events to us, but would
not require those who distribute the product and whose name is likely to
be on the product label, to report adverse events to us.  The comments
state that reports of adverse events submitted by consumers to those who
distribute, but do not make, dietary supplements could be hidden from
the public if such persons are not required to submit those reports to
us.