(Response)  The comments may have misinterpreted the proposed rule.
The requirement to review and investigate a product complaint is
distinct from any report about the product complaint to us.  Reporting a
complaint to us is voluntary and is not covered by these CGMP
requirements and would be voluntary, unless the complaint is subject to
the statutorily mandated reporting requirements for “significant
adverse events” pursuant to the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006.  (See discussion in section XX).

	Under the procedures that are set forth in subpart O, Product
Complaints (see section XX), a distributor and a manufacturer are both
subject to the requirements related to the review and investigation of a
product complaint that they receive.

	(Comment 29) Some comments argue against including minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary ingredients in the final rule.  Several comments
argue the proposed rule is overly broad and inconsistent with
Congressional intent.  These comments question whether Congress intended
that CGMP apply to persons involved in the manufacture, packaging,
labeling, and holding of dietary ingredients.  The comments also argue
that, if the rule applies to dietary ingredient manufacturers, we would
be establishing precedent and that we lack legal authority to regulate
ingredients rather than the finished products themselves.  The comments
state that neither food CGMP nor drug CGMP offers precedent or guidance
on regulating ingredients.  The comments argue those who provide dietary
ingredients should be subject to the existing general food CGMP
requirements in part 110 rather than to the dietary supplement CGMP
requirements.

     Several comments argue that many dietary ingredients are used in
regular foods and in drugs as well as in dietary supplements.  The
comments argue, for some dietary ingredients, their use in dietary
supplements represents a very small percentage of the dietary
ingredient’s worldwide usage.  The comments say we should allow those
who deal only with dietary ingredients to operate under one set of
regulations, such as the general food CGMP requirements in part 110.
According to these comments, we have not demonstrated either a failure
of the current system or a compelling need to create different
regulations for raw materials common to both the food and dietary
supplement industries.  The comments would revise the title of part 111
and proposed § 111.1 and make conforming revisions throughout the
proposed rule to limit the rule’s applicability to dietary
supplements.

	In contrast, other comments say the rule should apply to dietary
ingredient manufacturers as well as to dietary supplement manufacturers.
 The comments state that excluding those who provide or supply dietary
ingredients would mean those who have the greatest expertise in these
goods would not be subject to dietary supplement CGMP requirements and
thus fail to cover a crucial step in preventing the adulteration or
contamination of dietary supplements.  The comments argue that, for some
dietary ingredients (especially raw botanical and agricultural goods),
the most critical point in ensuring an ingredient’s quality and purity
is at time of harvest or creation, and that this is particularly true
with new or original ingredients.

	The comments state problems with dietary supplements often arise from
substandard ingredients, and the difficulty in testing the properties of
some botanical and other dietary ingredients at the in-process or
finished product stage makes it necessary to include dietary ingredient
manufacturers in the final rule.  Furthermore, these comments assert a
flexible testing scheme that they recommend (which emphasizes
establishing specifications for components, relying on certificates of
analysis from qualified suppliers, qualifying component suppliers, and
establishing written procedures, with testing of finished batches
serving as a check on the overall manufacturing process) makes it
important to regulate dietary ingredient manufacturers.

	Other comments suggest we issue a separate or modified set of CGMP
requirements that would apply to persons who manufacture, package,
label, or hold dietary ingredients.  These comments say the proposed
rule does not work for all dietary ingredients, especially those
converted from non-food grade to food grade during the manufacturing
process.  These comments said the rule should be modified for dietary
ingredients.

	(Response) Two issues seem to be raised by these comments: (1) whether
dietary ingredients are within the scope of this final rule; and (2)
whether dietary ingredient manufacturers are subject to this final rule.
 Dietary ingredients are included within the scope of this final rule
but dietary ingredient manufacturers are not necessarily subject to this
rule.  The definition of “component” in this final rule includes
“any substance intended for use in the manufacture of a dietary
supplement including those that may not appear in the finished batch of
the dietary supplement.  Component includes dietary ingredients (as
described in section 201(ff) of the act) and other ingredients”(final
§ 111.3).  The proposed rule, § 111.3, recognized that “dietary
ingredients” are “components” (68 FR 12157 at 12176) (describing
how dietary ingredients would fall within the proposed definition of
“component”).

	There are specific requirements in this final rule that relate to
components, and thus dietary ingredients, that are used in the
manufacture of a dietary supplement.  For example, final § 111.70(b)
requires you to establish certain component specifications.  Such
requirements would include specifications for dietary ingredients as
“components.”  It is important to control the components used in the
manufacture of dietary supplements to ensure consistency and to ensure
the quality of the dietary supplement.  Since dietary ingredients are
considered components, the various requirements apply to dietary
ingredients as part of the production and process control.   Therefore,
we disagree to the extent comments were suggesting that there should be
no CGMP requirements related to the dietary ingredients used by a
manufacturer in the manufacture of dietary supplements.

	Dietary ingredients are included within the meaning of “component.”
 In those requirements in the proposed rule where “component”
encompasses “dietary ingredient” we are, in the final rule, removing
“dietary ingredient” in those requirements and only refer to
“component.”  Given the scope of the final rule, it is redundant to
refer to both “component” and “dietary ingredient” where the
latter is subsumed in the former.

     In response to comments that questioned the need to include
manufacturers of dietary ingredients within the scope of part 111, we
have made changes to the scope of the rule, as applied to dietary
ingredient manufacturers.   As we explain more fully in our discussion
of final §§ 111.70, 111.73, 111.75, and 111.77 (see section X), after
considering comments about the overall production and process control
system, we revised the final rule’s approach to ensuring product
quality.  This approach emphasizes that it is important to ensure the
quality of the dietary supplement throughout the production and process
control system.  This approach emphasizes establishing specifications
for components and ensuring those specifications are met.  You may rely
on a certificate of analysis for specifications (except for the identity
of the dietary ingredient) only if you satisfy certain criteria, which
include qualifying the supplier of the components.  With this approach,
the goal of ensuring the quality of dietary supplements can be achieved
without applying the rule specifically to persons who manufacture,
package, label, or hold dietary ingredients that will be further
processed as a dietary supplement by other persons.

     Consequently, we revised § 111.1 by deleting “dietary
ingredient.”  Therefore, those who manufacture, package, label, or
hold dietary ingredients are not subject to the final rule.  To
illustrate, assume you manufacture a dietary ingredient and sell that
bulk dietary ingredient to Company X.  Company X then utilizes the bulk
dietary ingredient in a dietary supplement.  Under final § 111.1(a),
you would not be subject to these dietary supplement CGMP requirements
because you are not manufacturing a dietary supplement, rather you are
manufacturing a dietary ingredient for further incorporation into a
dietary supplement by Company X.  If, however, you sell herbs in bulk to
Company X, and Company X simply packages the herbs into smaller units
for sale as a dietary supplement, you would be subject to the dietary
supplement CGMP requirements because you are manufacturing a dietary
supplement that Company X is simply packaging and labeling, and not
further processing into a dietary supplement.  In other words, in the
latter example, you would have acted as a manufacturer whose finished
product is simply repackaged or relabeled.

	Under final § 111.1(a) persons engaged solely in activities relating
to the harvesting, storage, or distribution of raw agricultural
commodities that will be incorporated into a dietary supplement by
others are not included within the scope of the rule as a dietary
supplement manufacturer.  This is because those persons simply
“supply” a component (i.e., the raw agricultural commodity) that
another person will process into a dietary supplement; thus you do not
manufacture, package, label, or hold a dietary supplement.

	Note, too, that if you manufacture and supply a component directly to
consumers as a dietary supplement, you would be considered a dietary
supplement manufacturer within the scope of final § 111.1(a).
Likewise, if you manufacture a component and sell part of the batch to
another person who, in turn, will further process the component as a
dietary supplement and sell the remainder of the batch to consumers as a
dietary supplement, you would be subject to the dietary supplement CGMP
requirements, as a manufacturer, for the product sold to consumers and
not subject to an exclusion under final § 111.1(b), discussed in this
section.  In other words, final § 111.1(a) refers to the nature of your
activity, and simply engaging in some activities that do not bring you
within the scope of the final rule does not necessarily mean that all
your activities are outside the scope of the final rule.

	We do not agree, as some comments suggested, that we need to issue a
separate or modified set of CGMP requirements for dietary ingredients.
That is because there are adequate controls established in this final
rule for the use of dietary ingredients used by the manufacturer of a
dietary supplement. However, if you manufacture, package, label, or hold
dietary ingredients that will be further processed as a dietary
supplement by another person, you must comply with food CGMP
requirements in part 110.  A dietary ingredient is a food under section
201(f) of the act, as a food, or as a component of food.  Because the
final rule gives manufacturers an incentive to qualify suppliers of
dietary ingredients, persons who manufacture, package, label, or hold
dietary ingredients may wish to familiarize themselves with these
dietary supplement CGMP requirements and use them in manufacturing,
packing, labeling, or holding operations for dietary ingredients.

	(Comment 30) Some comments argue if the final rule ultimately covers
dietary ingredient suppliers then we should clarify what constitutes a
“consumer.”  According to these comments, dietary ingredient
suppliers do not typically supply their products directly to those
individuals who will ultimately consume or ingest them.  Thus,
“consumers” of dietary ingredients are other companies, not
individuals.  The comments express concern about the possible
application of proposed § 111.95 which would require procedures for
handling complaints.

     (Response) The final rule applies only to persons who manufacture,
package, label, or hold dietary supplements and are not subject to an
exclusion in final § 111.1.  However, as explained above in the
previous response to comment 29), if a dietary ingredient manufacturer
also supplies or sells a dietary ingredient as a dietary supplement,
such manufacturer would be subject to final § 111.1(a) and subject to
all relevant dietary supplement CGMP requirements.

	Some comments expressed concern about dietary ingredient manufacturers
having to comply with proposed § 111.95 on product complaints.  If a
dietary ingredient manufacturer receives a product complaint, we
encourage the manufacturer to evaluate the complaint to determine if it
may involve a problem with the manufacture of the dietary ingredient.
In addition, we encourage the dietary ingredient manufacturer to notify
the dietary supplement manufacturer so that it can review the complaint
and investigate, as needed.

	(Comment 31) Several comments question the proposal’s applicability
to persons who sell packaged products or seek clarification as to
whether the rule applies to dietary supplement manufacturers that
operate from homes and those that distribute product to other
distributors.

	(Response) To the extent that the comments question whether retailers
or individuals who sell dietary supplements directly to individual
consumers are subject to the dietary supplement CGMP requirements, we
have revised the final rule by creating a new § 111.1(b) which 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.  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 means, for example, if you operate a storefront retail
establishment where you stock dietary supplements on your shelves for
purchase by individual consumers, we do not consider you to be
“holding” those dietary supplements in a manner that would require
you to comply with the holding provisions in this final rule.  Sale to
individual consumers, where you are not storing bulk dietary supplements
as one would in a warehouse or storage facility, does not fall within
the manufacturing, packaging, labeling, or holding activities that would
subject you to dietary supplement CGMP requirements.

	However, if you operate storefront retail establishments, and those
retail establishments obtain their stocks from your warehouse, we would
consider your warehouse operations to be “holding” dietary
supplements and expect your warehouse operations to comply with the
rule’s holding requirements.  Such distribution is no different than
other warehouse operations that are normally subject to CGMP
requirements.  Consequently, to distinguish between “holding”
dietary supplements for retail sale to consumers and “holding”
dietary supplements in a warehouse for further distribution, final §
111.1(b) limits the exclusion to persons holding dietary supplements
“at a retail establishment for the sole purpose of direct retail sale
to individual consumers.”  Final § 111.1(b) also makes it clear that
a retail establishment does not include a warehouse or other storage
facility that a retailer uses to hold the dietary supplements or an
operation that sells directly to consumers, but that itself distributes
the product to the consumer from a warehouse or storage facility and not
from a storefront retail establishment.

	(Comment 32)  Many comments question the rule’s applicability to
various practitioners such as herbalists, acupuncturists, naturopaths,
and other health care providers who prepare individualized herbal
formulas for specific individuals on a
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●	These practitioners do not broadly sell products;

●	These practitioners make very small quantities of individualized
formulas, and can therefore be very selective as to the quality of
ingredients used;

●	The testing and storage requirements of each finished batch cannot
apply to a small dispensary where several different modified herbal
formulas are prepared each day;

●	Based on the projected costs to implement CGMPs, it would be
virtually impossible for an individual practitioner or university clinic
to develop the necessary quality control unit, maintain reserve samples,
maintain the required paperwork, or retrofit clinics to comply with the
rule;

●	Many states regulate or license these practitioners, so further
federal regulation is unnecessary;

●	Some practitioners do not consider themselves to be manufacturers;

●	In an analogous situation, compounding pharmacists are not required
to comply with drug CGMPs; and

●	Despite the growing number of such practitioners, there is no proof
that greater harm has occurred to the general public from the herbs
these practitioners sell.

     (Response)  We stated in the 2003 CGMP Proposal (68 FR 12157 at
12175) that we declined to exempt herbalist practitioners from the
proposed rule.  We continue to believe that the risks of adulteration
are not eliminated just because the practitioner is an herbalist, and
therefore, such an exemption should not be included in this final rule.
However, after further consideration, we have determined that it would
be appropriate for us to consider the exercise of our enforcement
discretion in deciding whether to apply the  requirements of this final
rule to certain health care practitioners, such as herbalists,
acupuncturists, naturopaths, and other related health care providers.

	We find it noteworthy that the comments identified two potential
safeguards that could support the exercise of our enforcement discretion
on whether to apply the requirements of the final rule to certain
practitioners:  1) adequate training in the professional practice; and
2) an individual client and practitioner relationship.  For example,
comments claimed that the practitioners receive adequate training to
formulate dietary supplements and that they provide the dietary
supplements to individuals in the course of a one-on-one consultation on
the premises of the practitioner. One comment from a practitioner states
that she received her training from an accredited 4-year university and
it included didactic and clinical training in acupuncture and Chinese
herbs.  Another comment from an organization provides detailed training
guidelines for practitioners, including 1600 hours of training, 400
hours of which should include clinical work.  Moreover, many comments
also assert that the practitioners are different from dietary supplement
manufacturers because they formulate the dietary supplements in the
course of a one-on-one consultation at their premises.  That enables
them to ensure the formulations are made to meet the specific needs of
the individuals.

	We believe that a one-on-one consultation by a practitioner who is
adequately trained in their profession may not necessitate the same
types of controls as we are establishing in this final rule for
manufacturing activities that are on a larger scale.  Such a
practitioner may make some formulations in advance of the consultation
and still make the formulations in very limited quantities for the
individual client.  We believe that it would be appropriate to consider
the exercise of our enforcement discretion, on a case-by-case basis, to
determine whether to apply the requirements of this final rule to such
persons.

	We do not expect the number of those subject to the consideration of
our enforcement discretion to be very large.  Many products that are
manufactured by practitioners would not necessarily be considered to be
dietary supplements (e.g., certain products used by traditional Asian
medicine practitioners).  Further, we are not considering exercising our
enforcement discretion with respect to practitioners who prepare batches
of herbs and sell them to individual consumers without determining
whether the dietary supplement is appropriate for each consumer’s
needs in a one-on-one personal consultation, or those that prepare
batches of a dietary supplement for which there is a known or suspected
safety concern.

	(Comment 33)  Several comments asked us to exempt academic institutions
that provide training for therapeutic disciplines that use, for example,
herbal formulas in their practice regardless of whether the dietary
supplements they produce enter into interstate commerce.  Specifically,
these comments would revise the final rule to state that it does not
apply “to academic institutions that provide training in dispensing of
nutritional or herbal products and formulas related to courses in
therapeutic disciplines that provide such products and formulas as a
part of their therapy, for example, naturopathy, herbalism, traditional
Chinese medicine, and acupuncture.”	(Response)  Similar to what we
stated in response to comment 32, we believe that it may be appropriate
to consider the exercise of our enforcement discretion in circumstances
where an academic institution’s actions are similar to those of a
practitioner who is adequately trained in their profession and who
provides dietary supplements within the context of an individual client
and practitioner relationship.  In general, it is not our policy to
inspect an academic institution that provides training for therapeutic
disciplines that use, for example, dietary supplements in their
practice.  We intend to consider the exercise of our enforcement
discretion in those situations where there is a one-on-one consultation
that includes a practitioner with adequate training.  We intend to issue
guidance to further clarify how the agency intends to exercise its
enforcement discretion on the application of this final rule to certain
academic institutions.

	(Comment 34) Several comments discuss the position taken by certain
nations, notably Australia and Canada, that have developed CGMP
requirements and related guidance for botanicals.   According to these
comments, these nations recognize that there are various types of
practitioners who sell herbs and herbal preparations in a clinical
setting, and do not consider such persons to be manufacturers.  The
comments ask us to follow the example of these nations.

	(Response)  We intend to consider the positions taken by other nations
to inform us in our decision making in any future guidance on how we
intend to exercise our enforcement discretion on the application of this
final rule to certain practitioners.

	(Comment 35) Many comments say we should define when a dietary
supplement will be said to have entered interstate commerce.  The
comments state herbal practitioners (and academic institutions) often
purchase source herbs from outside their state, even if they prepare
these herbs for their specific customers within the state.  These
comments request we clarify that the rule does not apply to herbs
purchased out of state if prepared for local use.  Other comments
request clarification regarding clients who have moved across state
lines, yet maintain a relationship with an herbalist practitioner.

	(Response) In section V we explain the interstate and intrastate issue
related to the final rule.

	(Comment 36) A few comments assert individual practitioners and
practitioner organizations often are unaware of the opportunity to
comment on CGMP or regulatory issues.  Therefore, the comments say these
practitioners and organizations often fail to provide comment or
otherwise participate in rulemaking and say we should give these
practitioners and practitioner organizations a chance to comment.

	(Response) We provided many opportunities for comment and, therefore,
we decline to adopt the comments’ suggestion.  As we discuss in
section I, we published an ANPRM concerning dietary supplement CGMPs on
February 6, 1997 (62 FR 5700); the 1997 ANPRM provided an opportunity
for public comment.  On March 7, 2003, we issued a Talk Paper, along
with other background documents, announcing the issuance of a proposed
dietary supplement CGMP rule.  We made the rule available when it went
on display and before it published in the FEDERAL REGISTER on March 13,
2003 (68 FR 12157), and, again, provided an opportunity for public
comment.  We also held public meetings on April 29, 2003 in College
Park, MD and on May 6, 2003 in Oakland, CA.  We also held a public
meeting (via satellite downlink) on May 9, 2003, with viewing sites at
our district and regional offices throughout the country.  Thus, we
provided numerous opportunities for interested persons to learn about
the rule and to submit comments or otherwise participate in the
rulemaking process.  Consequently, we decline to provide yet another
opportunity for comment.

	(Comment 37) The preamble to the 2003 CGMP Proposal noted that comments
submitted in response to our 1997 ANPRM state we should not distinguish
between dietary supplements made in the United States and those made in
a foreign country (68 FR 12157 at 12174).  Although we agreed with the
comments and made no distinction between foreign and domestic firms in
the proposed rule, we invited comment on how we might ensure dietary
ingredients and dietary supplements exported to the United States have
been manufactured, packaged, labeled, and held consistent with part 111
(68 FR 12157 at 12175).

	 Several comments argue the rule should apply to foreign firms as well
as domestic manufacturers to ensure a “level playing field” and to
protect American consumers.  Some comments say we should work with
foreign countries to harmonize our requirements and thus avoid potential
trade disputes under international trade agreements such as the General
Agreement on Tariffs and Trade (GATT).  Other comments suggest
compliance by foreign firms could be achieved through the use of third
party certification programs, such as the dietary supplement
verification program administered by USP, or the adoption of importer
verification provisions similar to those used in our HACCP requirements
for seafood (see § 123.12).

	In contrast, another comment says we should inspect foreign firms to
ensure compliance, whereas other comments claim we lack jurisdiction
over foreign firms.

(Response) We are amending proposed § 111.1 to clarify the
regulation’s applicability to foreign firms.  We explain in this
section how we may enforce the rule against foreign firms.  We, however,
are not making any changes in response to the comments calling for the
harmonization of the rule with foreign rules because this request is
beyond the scope of the final rule.

	 In response to comments, and for clarification, we have revised final
§ 111.1(a) to clarify that the regulation applies to the extent that
you manufacture, package, label, or hold a dietary supplement, including
a dietary supplement imported or offered for import in any State or
Territory of the United States, the District of Columbia, or the
Commonwealth of Puerto Rico.

	With respect to the comments requesting that we make clear our position
for enforcing the rule against foreign firms, we explain our position as
follows.  Section 801(a) of the act authorizes us to refuse admission of
an imported food if it appears from the examination of such samples or
otherwise that such article is, among other things, adulterated.  A
foreign firm’s refusal to allow us to obtain records via an inspection
for CGMP purposes, as required by final § 111.610 (for the dietary
supplements the foreign firm offers for import into the United States),
would create the appearance that such imported dietary supplements are
adulterated under section 402(g) of the act, and thus, could lead to a
refusal of admission under section 801(a) of the act.

	Foreign firms who ship to the United States must operate under
conditions that satisfy our regulations, including the requirement that
records be made available during the course of an FDA inspection.  We
note that except in circumstances where there is a public health
emergency or we receive information that would indicate the appearance
of adulteration of products shipped to the United States, foreign
inspections are generally scheduled well, e.g., weeks, in advance.
Thus, we believe that taking action under Section 801 of the act is
appropriate if companies do not accommodate our inspectional request.

C.  What Definitions Apply to This Part?

(Final § 111.3)

Section 111.3 defines various terms that we use in the final rule and
notes that definitions or interpretations of terms in section 201 of the
act also apply.  In general, we adopted the definitions that we
proposed, although, in some cases, we deleted words or concepts as a
result of other changes we made to the final rule.  We have added a
definition of “quality” for purposes only of this final rule.

A recurring change we made is the deletion of the words “dietary
ingredient” in several definitions.  In some cases, the use of the
words “dietary ingredient” was redundant with the use of
“component” and thus not necessary in the final rule.  Because a
“dietary ingredient” is subsumed within the definition of
“component,” as explained in our response to comment 29, we deleted
“dietary ingredient” in those definitions where “component” was
used to avoid redundancy.

In other provisions, we deleted “dietary ingredient” from the
definition because the use of those words was no longer necessary given
the narrowing of the scope of the rule as it applies to dietary
ingredient manufacturers (explained in response to comment 29 and 30).
For example, we deleted “dietary ingredient” from the proposed
definition of “ingredient” that referred to the “manufacture of a
dietary ingredient or dietary supplement” and the “finished batch of
the dietary ingredient or dietary supplement.”  We did not need to
state “manufacture of the dietary ingredient” or refer to
“finished batch of dietary ingredient” because dietary ingredient
manufacturers that only supply such ingredients to other persons for
processing into a dietary supplement are not subject to the final rule.

	We discuss changes to the definitions, other than the changes we have
made globally such as the deletion of “dietary ingredients,” the
change from “include, but not limited to” to “includes” or
“include,” the addition of labels and labeling, and the deletion of
the word quality from the phrase “identity, purity, quality, strength,
and composition,” as well as comments asking us to define more terms
or to delete certain definitions, in more detail immediately below.

Actual Yield

	The final rule defines “actual yield” as “the quantity that is
actually produced at any appropriate step of manufacture or packaging of
a particular dietary supplement.”

We received no substantive comments to the proposed

definition.

2.  Batch

	The final rule defines “batch” as “a specific quantity of a
dietary supplement that is uniform, that is intended to meet
specifications for identity, purity, strength, and composition, and that
is produced during a specified time period according to a single
manufacturing record during the same cycle of manufacture.”

	This definition differs from the proposed definition of “batch” by
stating that a batch is a specific quantity of a dietary supplement that
is “uniform.”

	We inserted the word, “uniform” in response to comments asking that
we define “lot” to be consistent with “batch.”  We explain our
reasons for harmonizing the definitions and for inserting “uniform”
into the definition of “batch” in the response to comment 42.

	We discuss the comments on our proposed definition of “batch” and
our changes to the definition in our responses to the comments
immediately below.

	(Comment 38) Several comments ask us to clarify what the “same cycle
of manufacture” is in the definition of “batch.”  One comment asks
if it meant the same product made with the same lot(s) of raw materials
regardless of how many days it took to produce the batch, or if it meant
a quantity produced in one day.  The comment also asks whether batches
produced on consecutive days, using the same formula, can be considered
to be the same batch with respect to the proposed testing requirements
if the quality control unit determined that different lots of raw
materials are equivalent (e.g., by meeting all specifications).

	(Response) The “same cycle of manufacture” refers to a process
during which equipment remains dedicated to the manufacture of the
batch.  The terms do not limit you to any particular time period or
require you to operate equipment continuously until you have completed
the “same cycle of manufacture.”  The “same cycle of
manufacture” also does not limit the number of lots of components you
use.

	You may consider, as one batch, a product produced using different lots
of raw materials where the production of the batch is a continuous
process on a dedicated line.  However, for each component that you use
in the manufacture of the batch of dietary supplement, you would need to
establish specifications under final § 111.70, determine whether these
specifications are met under final § 111.73, and ensure that these
component specifications are met using the criteria under final
§ 111.75.  Further, you may not consider different batches of product
produced on consecutive days using the same formula to be the same batch
for purposes of testing requirements.  The term “different batches”
suggests that the production is not a continuous process on a dedicated
line.

	3.	Batch Number, Lot Number, or Control Number

	The final rule defines these terms as “any distinctive group of
letters, numbers, or symbols, or any combination of them, from which the
complete history of the manufacturing, packaging, labeling, and/or
holding of a batch or lot of dietary supplements can be determined.”

	We received no substantive comments on the definition.    We added the
word “and” before “or” to emphasize that the history of each
activity must be able to be determined.

	4.	Component

	The final rule defines “component” as “any substance intended for
use in the manufacture of a dietary supplement, including those that may
not appear in the finished batch of the dietary supplement.  Component
includes dietary ingredients (as defined in section 201(ff) of the act)
and other ingredients.”

	The definition of component now refers only to the manufacture of a
dietary supplement (whereas the proposal also referred to the
manufacture of dietary ingredients).  We also made a non-substantive,
editorial revision in the last sentence to put parentheses around the
reference to section 201(ff) of the act and to change the word order so
that “component” includes “dietary ingredients . . . and other
ingredients.”  (The proposed definition had “components” including
“ingredients and dietary ingredients.”)

	(Comment 39) Some comments would distinguish among “raw material,”
“components,” and “starting material” because the comments said
that defining “component” to include all these materials is
confusing.  One comment adds that many starting materials are not food
grade or approved food ingredients until they have been processed.  One
comment states the term “raw material” is typically used to describe
the materials (such as dietary ingredients, fillers, and processing
aids) that will be used to make the final product.  The comment further
states “component” is typically used to describe the specific items
used to assemble the finished product for the end user.  The components
would include packaging components such as bottles, caps, and labels, as
well as the bulk dietary supplement.  This comment also suggests that we
use the term “starting material” to distinguish substances used in
the manufacture of dietary ingredients from substances used in the
manufacture of dietary supplements.

	(Response) We decline to revise the rule as suggested by the comments.
There may be differences in how components are referred to by certain
manufacturers and how we refer to it in this final rule.  However, for
purposes of this final rule we refer to all substances used in the
manufacture of dietary supplements as “components,” whether or not
those substances appear in the finished product.

	Please note that, although ingredients are “components” under our
definition, not all components are ingredients.  For example, a solvent
used to make an herbal extract is not an ingredient when it is removed
from the extract by a process such as drying, because the solvent was
not intended to be present in the finished dietary supplement.  However,
the solvent would be a “component” because it was used in the
manufacture of the dietary supplement.

	As for materials that might not be food grade or approved food
ingredients until processing, see the discussion in response to comment
240 in section XII.

	(Comment 40) Several comments express concern that “component”
could be interpreted to mean any constituent present in a botanical
extract or other natural product.  The comments say a single botanical
can contain tens of thousands of constituents or metabolites and that
chemists have not identified all constituents of a single botanical.
According to the comments, the cost of testing for all constituents
would exceed a product’s total annual revenues.

	(Response) In general, we would consider the botanical extract or the
other natural product to be the “component” as defined in this final
rule rather than consider that all the various chemical substances
contained in the botanical extract or other natural product are
components.  Thus, if you are manufacturing a dietary supplement that is
intended to provide a certain substance (i.e. vitamin C ) and you add a
natural product which is intended to supply the Vitamin C (i.e. vitamin
C in the form of rosehips), we would consider the natural product (e.g.
rosehips that contains a certain amount of vitamin C) to be a component
which must be listed in the master manufacturing record. The component
specifications for the rosehips must include a specification for the
strength of the substance (e.g., vitamin C) in whatever amount you
determine is necessary to meet the specification for the strength of the
vitamin C in the finished batch of dietary supplement.  Under final §
111.70, we expect you to establish specifications for the natural
product and ensure that the specifications are met.   As an example
relevant to an extract, if you are manufacturing a dietary supplement
that is intended to provide a certain amount of vitamin C that derives
from the natural product rosehips, and the substance that you purchase
from a supplier to add as a component is a purified extract of rosehips
(rather than rosehips themselves), we would consider the purified
extract to be a component (as an ingredient).  The component
specifications for the purified extract must include a specification for
the strength of the substance (i.e., vitamin C) in whatever amount you
determine is necessary to meet the specification for the strength of the
vitamin C in the finished batch of dietary supplement.  However, in this
example “rosehips” would not be considered a component, because
“rosehips” is not what you added.

5.	Contact Surface

	The final rule defines “contact surface” as “any surface that
contacts a component or dietary supplement, and those surfaces from
which drainage onto the component or dietary supplement, or onto
surfaces that contact the component or dietary supplement, occurs during
the normal course of operations.”  The final rule lists containers,
utensils, tables, contact surfaces of equipment, and packaging as
examples of “contact surfaces.”

	We did not receive any substantive comments on the proposed definition.
 We deleted “ordinarily” from “ordinarily occurs during the normal
course of operations” because “ordinarily” is redundant with
“normal.”

6.	Ingredient

	The final rule defines “ingredient” as “any substance that is
used in the manufacture of a dietary supplement and that is intended to
be present in the finished batch of the dietary supplement.  An
ingredient includes, but is not necessarily limited to, a dietary
ingredient as defined in section 201(ff) of the act.”  We did not
receive any substantive comments on this definition.  We made a
non-substantive, editorial change to replace “finished dietary
supplement” with “finished batch of the dietary supplement.”

	(Comment 41) One comment says we should define “ingredient” better
to ensure consistent interpretation of CGMP at all levels throughout the
dietary supplement industry.

	(Response) We disagree with the comment.  We believe the definition is
adequate, including as it does both dietary ingredients as described in
section 201 (ff) of the act and other ingredients that do not fit that
description, such as an emulsifier used to establish a uniform
dispersion in a liquid dietary supplement or a color additive used to
color a capsule.  Moreover, the comment did not explain or specify which
aspects of the proposed definition should be revised or explain why the
proposed definition would lead to inconsistent interpretations of CGMP.

7.	In-Process Material

	The final rule defines “in-process material” as “any material
that is fabricated, compounded, blended, ground, extracted, sifted,
sterilized, derived by chemical reaction, or processed in any other way
for use in the manufacture of a dietary supplement.”

	We did not receive any substantive comments on the proposed definition.

   8.	Lot

	The final rule defines “lot” as “a batch, or a specific
identified portion of a batch, that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition; or,
in the case of a dietary supplement produced by continuous process, a
specific identified amount produced in a specified unit of time or
quantity in a manner that is uniform and that is intended to meet
specifications for identity, purity, strength, and composition.”

	The final rule differs from the proposed definition in that the
proposed definition of “lot” would have the batch or specific
identified portion of a batch be intended to have “uniform identity,
purity, quality, strength, and composition.”  	(Comment 42) One
comment agrees with the proposed definition for “lot,” but several
other comments would revise the definition to be more consistent with
the proposed definition of “batch.”  Specifically, the comments note
the proposed definition of “batch” would refer to a quantity of
dietary supplement that is “intended to meet specifications for
identity, purity, quality, strength and composition,” whereas the
proposed definition of “lot” would refer to a batch or specific
identified portion of a batch that is “intended to have uniform
identity, purity, quality, strength, and composition.”  The comments
would revise the definition of “lot” by deleting the phrase
“intended to have uniform” and inserting the phrase “intended to
meet specifications for” in order to make the definitions of
“batch” and “lot” consistent.

	(Response) We agree that the definitions for “batch” and “lot”
should be consistent, but we disagree with the comments’ suggestion to
delete the term “uniform” from the definition of “lot.”  The
attributes of a lot or batch should be uniform throughout the lot or
batch and meet established specifications for those attributes.  If
samples from a lot or batch were tested for appropriate specifications
of identity, purity, strength, and composition, the attributes should be
consistent throughout the sample and be uniform from sample to sample
regardless of whether the test samples are taken from the beginning,
middle, or end of the lot or batch.  Consequently, we revised the
definition of “lot” to state, in relevant part, that a “lot” is
a batch or specific identified portion of a batch that “is uniform and
that is intended to meet specifications for identity, purity, strength,
and composition” or, for dietary supplements produced by a continuous
process, a specific identified amount produced in a specified unit of
time or quantity in a manner that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition.”

	Similarly, we revised the definition of “batch” so that it states,
in relevant part, that a “batch” is a specific quantity of a dietary
supplement “that is intended to meet specifications for identity,
purity, strength, and composition.”

	These revisions make the definitions of “batch” and “lot”
consistent.

9.	Microorganisms

	The final rule defines “microorganisms” as “yeasts, molds,
bacteria, viruses, and other similar microscopic organisms having public
health or sanitary concern.”  It adds that the definition includes
species that: (1) May have public health significance; (2) may cause a
component or dietary supplement to decompose; (3) indicate that the
component or dietary supplement is contaminated with filth; or (4)
otherwise may cause the component or dietary supplement to be
adulterated.

	(Comment 43) One comment would revise the definition to identify
specific microorganisms that have public health or sanitary concern
(i.e., Salmonella species, Escherichia coli, Pseudomonas aeruginosa, and
Staphylococcus aureus).  The comment says this would be consistent with
USP requirements.

	(Response) We disagree with the comment.  A list of specific
microorganisms could easily become outdated as new pathogens emerge, and
constantly issuing new rules to revise the list would be both
inefficient and impractical.

	(Comment 44) One comment expresses concern that the proposed definition
for microorganisms would include microorganisms that are a natural part
of the ecology of all natural products.  The comment says certain levels
of microorganisms are expected on botanical raw materials (i.e., those
naturally occurring or introduced through organic cultivation
techniques) and that many do not present a public health risk.  The
comment expresses concern that non-pathogenic microorganisms that are
not a public health risk would be a “sanitary” concern that would
render a product adulterated.  The comment argues there should be little
concern about the presence of microorganisms that present no public
health consequence, and so we should revise the definition accordingly.
The comment further discusses the difficulties in “sterilizing”
botanicals to render them free of microorganisms associated with
insanitary conditions.  The comment notes that some international
organizations have established “upper limits” for these organisms
for botanical supplements, which, in the comment’s opinion, represent
more realistic standards than trying to attain a “sterile” botanical
supplement.

	(Response) We disagree with the comment.  We do not interpret the
definition of “microorganism” as making the presence of
nonpathogenic microorganisms that are not a public health risk a
“sanitary concern” that would render a product adulterated.
Instead, we interpret the definition as saying that microorganisms of
public health significance and microorganisms presenting sanitary
concerns are “microorganisms” under this rule.  These are the types
of microorganisms that may cause a component or dietary supplement to
become adulterated.

	As for upper limits on microbial contamination, the comment offered no
suggested limits, and we decline to establish such limits in this rule.
The final rule requires manufacturers to establish limits for those
types of contamination that may adulterate or lead to adulteration of
components or dietary supplements.  Thus, for example, a manufacturer of
a botanical dietary supplement would have to determine what, if any,
microorganisms are likely or certain to be present and establish limits,
as appropriate to prevent adulteration of the finished batch of the
dietary supplement.

	We have modified the word “have” with the word “may” to
indicate that the determination or evaluation of whether there is a
“public health significance” is not made after the fact.  There does
not have to be a factually established determination of public health
significance for you to conclude that the microorganisms “may
adulterate” the dietary supplement.  The change from “could cause”
to “may cause” is to be consistent with the previous change to
“may have.”

10.	Must

	The final rule explains that the word “must” is “used to state a
requirement.”

	(Comment 45) One comment would revise the definition to say that the
term “must” be used to state mandatory requirements “unless shown
to be inapplicable or replaced by an alternative demonstrated to provide
at least an equivalent level of quality assurance.”

	(Response) We decline to revise the rule as suggested by the comment.
The comment’s revision would undermine the reasons for issuing a rule.
 Rules create enforceable requirements.  It is not clear, nor did the
comment discuss, how we could enforce the requirements in this final
rule if firms were able to avoid a particular requirement by declaring
them to be “inapplicable” or substituting alternatives which they
felt they had demonstrated were “at least an equivalent level of
quality assurance.”  There would be inconsistency in the general CGMP
practices used within the dietary supplement industry and uncertainty as
to whether the process and production controls ensure the quality of the
dietary supplement.  Consequently, we decline to revise the rule as
suggested by the comment.

	We have, however, made a non-substantive, editorial change to the
definition so that “must” is used to state “a requirement.”  The
proposed definition had referred to “mandatory requirements.”  Since
a requirement by its nature is mandatory the word “mandatory” is
unnecessary.

11.	Pest

	The final rule defines “pest” as “any objectionable insect or
other animal, including birds, rodents, flies, mites, and larvae.”

	We did not receive any substantive comments on this definition.
However, on our own initiative, we made non-substantive, editorial
changes to delete the words, “but not limited to” after
“including” and to place the word “animals” in the singular.

12.	Physical Plant

	The final rule defines “physical plant” as “all or any part of a
building or facility used for or in connection with manufacturing,
packaging, labeling, or holding a dietary supplement.”

	We received no substantive comments on this definition.  The final rule
is substantially similar to the proposed rule’s definition of
“physical plant.”    We  added “any” and placed “part” in
the singular to clarify that individual parts of a building or facility
are subject to the CGMP requirements.

13.	Product Complaint

	The final rule defines “product complaint” as “any communication
that contains any allegation, written, electronic, or oral, expressing
concern, for any reason, with the quality of a dietary supplement, that
could be related to current good manufacturing practice.  Examples of
product complaints are: foul odor, off taste, illness or injury,
disintegration time, color variation, tablet size or size variation,
under-filled container, foreign material in a dietary supplement
container, improper packaging, mislabeling, or dietary supplements that
are superpotent, subpotent, or contain the wrong ingredient, or contain
a drug or other contaminant (e.g., bacteria, pesticide, mycotoxin,
glass, lead).”

	This definition modifies the proposed rule’s definition of
“consumer complaint,” which would define such a complaint as any
“communication that contains any allegation, written or oral,
expressing dissatisfaction with the quality of a dietary supplement
related to good manufacturing practices.  Examples of product quality
related to good manufacturing practices are: Foul odor, off taste,
superpotent, subpotent, wrong ingredient, drug contaminant, other
contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead),
disintegration time, color variation, tablet size or size variation,
under-filled container, foreign material in a dietary supplement
container, improper packaging, or mislabeling.  For the purposes of this
regulation, a consumer complaint about product quality may or may not
include concerns about a possible hazard to health.  However, a consumer
complaint does not include an adverse event, illness, or injury related
to the safety of a particular dietary ingredient independent of whether
the product is produced under good manufacturing practices.”

	We explain the reasons for revising the proposed definition in our
response to the comments immediately below.

	(Comment 46)  Some comments would broaden the definition of consumer
complaint to include complaints from dietary ingredient suppliers.  One
comment would change “consumer complaint” to “customer
complaint.”

	(Response)  As discussed in section VI, the final rule does not apply
to those who only manufacture dietary ingredients.  However, we
encourage such firms that receive complaints about a dietary supplement
to share those complaints with those in the manufacturing chain
associated with that dietary supplement’s manufacture so others may
take corrective action as needed.  Those who engage in the manufacture
of a dietary supplement, including manufacturing, packaging, labeling,
and holding operations, are responsible for complying with this final
rule’s product complaint requirements.

	Furthermore, we encourage packagers, labelers, and distributors who
receive a product complaint to notify those in a dietary supplement’s
manufacturing chain about product complaints they receive or they,
themselves, generate that may relate to operations outside the
packagers’, labelers’, or distributors’ control.  For example, a
distributor who purchases a dietary supplement in bulk for packaging and
labeling may complain about product quality to the dietary supplement
manufacturer.  The manufacturer who receives the complaint must then
take appropriate action to determine whether the complaint involves a
possible failure of a dietary supplement to meet any CGMP requirements.
Thus, the final rule revises the term “consumer complaint” to
“product complaint” to emphasize that the complaint is about the
product regardless of the complaint’s source.

	(Comment 47)  One comment disagrees that “disintegration time” and
“tablet size” are appropriate examples of complaints about product
quality specifications.

	(Response)  We disagree with this comment.  Complaints about
disintegration time or tablet size could indicate a problem with the
production and process control system that may affect the quality of the
dietary supplement.

	(Comment 48)  Some comments disagree with the proposed definition of
“consumer complaint” because it excluded an adverse event, illness,
or injury related to the safety of a particular dietary ingredient.  The
comments say there should be a consistent approach for handling all
complaints, including adverse events.  One comment states consumers will
not be able to determine whether a product quality issue related to CGMP
caused an adverse event.  This comment expresses concern that not
classifying adverse events as consumer complaints could lead
manufacturers to avoid investigating certain adverse events and,
therefore, prevent them from determining the appropriate cause and
implementing the associated corrective action.  The comments stress we
should not treat complaints related to CGMP issues differently from
other complaints and urged us to classify all adverse events as consumer
complaints, whether or not they might have been caused by a particular
dietary ingredient.

	A few comments state the proposal, which did not specifically address
adverse event reporting, but did address the broader category of
consumer complaints and would require companies to investigate
“adverse event reports,” may simply create more confusion and may
contradict the overall objective of a comprehensive adverse event
reporting system.  The comments also state neither the food CGMP
regulations nor the 1997 ANPRM defined “consumer complaints.”  The
comments say we should delete this definition and deal with consumer
complaints separately as part of the new CFSAN Adverse Event Reporting
System (CAERS).

	One comment states we should define the term “serious adverse dietary
supplement experience.”  The comment would define a “serious adverse
dietary supplement experience” as:

any adverse dietary supplement experience occurring at any dose that
results in any of the following outcomes: death, a life-threatening
adverse dietary supplement experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect.  Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse dietary
supplement experience and, based upon appropriate medical judgment, they
may jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this
definition.

	(Response)  We decline to include in the definition of “product
complaint” an adverse event related to the safety of a particular
dietary ingredient.  The final rule establishes CGMP requirements for
dietary supplements and does not focus on whether dietary ingredients
that manufacturers may use in their dietary supplements are inherently
safe.  Nevertheless, we encourage firms to investigate all complaints,
regardless of whether the complaints relate to CGMP.  Furthermore,
mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006.  In any event, consistent with
these CGMP requirements, manufacturers must establish limits on
contamination, as needed, for all ingredients or any component they use
in manufacturing a dietary supplement.

	We agree it may be unclear whether a particular product complaint is
related to CGMP.  Final § 111.560, relating to product complaints,
applies in situations where the product complaint involves a “possible
failure of a dietary supplement to meet any of its specifications or any
other requirements of this part.”  Thus, if a firm is unclear whether
a particular complaint it receives relates to a CGMP issue, we would
consider that complaint to be related to a “possible failure” to
meet CGMP.  Consequently, the firm must comply with the requirements in
subpart O, unless the firm affirmatively determines that the complaint
is not related to a “possible failure” to meet CGMP, and therefore,
is not a “product complaint.”  To make this clear, we revised the
definition so that it applies to any “communication. . . that could be
related to good manufacturing practice” rather than to be any
“communication. . . that is related to good manufacturing practice.”

	We disagree with comments that suggested that the requirements for
product complaints would somehow contradict the overall objective of the
CFSAN CAERS.  This final rule has no effect on the mandatory or
voluntary reporting of adverse events.  We agree some adverse events may
be related to a failure to ensure the quality of the dietary supplement
as required by the final rule.  To the extent that an adverse event is
associated with CGMP, it would be considered a “product complaint”
under the final rule.  The fact that it is considered a product
complaint does not mean that such complaint could not be voluntarily
reported as an adverse event through CAERS.  Such a complaint may be
required to be reported under the mandatory reporting requirements of
the “Dietary Supplement and Non-Prescription Drug Consumer Protection
Act” (Pub. L. 109-462) signed into law on December 22, 2006.  We have
added “illness or injury” to the final rule’s definition of
“product complaint” as an example of a product problem relating to
CGMP to help clarify that there may be some overlap in the type of
complaints related to product quality that may also be considered an
adverse event.

	As for defining “serious adverse dietary supplement experience,” we
decline to add such a definition to the final rule.  We define certain
terms in a rule to give those terms a clear and consistent meaning.
None of the provisions in this rule addresses or even mentions
“serious adverse dietary supplement experiences,” so there would be
no advantage in codifying a definition for the term in this final rule.
If, however, the comment meant to narrow the definition of “consumer
complaint” to “serious” illness, or injury, we decline to do so.
If a consumer reports an illness or injury, which he or she attributes
to consuming a dietary supplement, the report may indicate a problem
with the production and process control system for that dietary
supplement, even if the injury or illness is not “serious” or
severe.

	We have, however, decided to delete the last two sentences in the
proposed definition of “consumer complaint” (now “product
complaint” in the final rule).  These sentences explained, in part,
that a consumer complaint does not include an adverse event, illness or
injury related to the safety of a particular dietary ingredient
independent of whether the product is produced under CGMP.  We deleted
those sentences because they are unnecessary to include in the
definition and can be included as further explanation of what the
definition of “product complaint” means in the preamble discussion.

	The proposed definition of “consumer complaint” used the phrase
“expressing dissatisfaction with the quality of a dietary * * *
supplement;” the final rule uses the phrase “expressing concern, for
any reason, with the quality of a dietary supplement.”  This change is
to ensure that even if the consumer is not actually dissatisfied with
the product, but has a concern with the product, this is still handled
as product complaint.

	We made several editorial or grammatical changes to the definition of
product complaint in this final rule for simplicity and revised the
order of the listed examples of product complaints.  For example, the
proposed definition of “consumer complaint” states the term “means
communication that contains any allegation * * * .”  The final rule
defines “product complaint” as meaning “any communication that
contains any allegation * * *.”  Another non-substantive change was to
insert the words “dietary supplements that are” before
“superpotent, subpotent” to give the reader a clear understanding as
to the article that is superpotent or subpotent.

	Finally, we added “electronic” as an example of how a product
complaint could be communicated to ensure that all forms of
communication are included and added “current” to modify “good
manufacturing practice” for consistency.

	We discuss in section V, our general response to the comment that
stated that neither the food CGMP regulations nor the 1997 ANPRM
contains a definition of “consumer complaint,” is in our discussion
of whether this final rule exceeds our authority or it has to be
identical to the food CGMP regulations.  More specifically, we
acknowledge that the industry draft that we published in the 1997 ANPRM
did not define “consumer complaint.”  The industry draft did contain
provisions that would be directed to “complaints files.”  The
provisions for complaint files would require the use of written
procedures to handle complaints; retention of records of complaints for
a certain time period; and the inclusion of specific information in the
record of a complaint.

	14. Quality

	For purposes solely of this final rule we have decided to define
“quality.”  Quality means that the dietary supplement consistently
meets the established specifications for identity, purity, strength, and
composition and limits on contaminants 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.

	(Comment 49)  Some comments asked that we define “quality.”  Some
comments claimed the proposal described “quality” in terms of
“identity,” “purity,” and “composition.”  One comment would
define “quality” as “the total characteristics of a product that
bear on its ability to satisfy stated (i.e., labeled) or implied needs
of identity, purity, strength and composition.”  Another comment would
define “quality” as “having the appropriate identity, purity, and
strength for the intended purpose.”  Another comment would define
quality using all the other attributes of identity, purity, strength and
composition.

	(Response)  For purposes only of this final rule, we have added a
definition of quality.  This definition is not intended to apply to CGMP
requirements other than those that apply to dietary supplements.  In
section III, in the Overview discussion, we discuss the concept of
“quality” as it applies to these dietary supplement CGMP
requirements and the distinction between the use of the term in the
final rule and in the proposed rule.

	Because we have defined “quality” as encompassing identity, purity,
strength, and composition, we have revised each section with
requirements for the “identity, purity, quality, strength, and
composition” to remove the word “quality.”  The affected sections
in this final rule are: § 111.3 (definition of batch); § 111.3
(definition of lot); § 111.65 (What are the requirements to have a
quality control unitoperations?); § 111.70 (What Specifications Must
You Establish?); § 111.75 (What must You Do to Determine Whether
specifications are met?); § 111.80 (What Rrepresentative Ssamples must
Yyou Ccollect?); § 111.95 (What Records Must You Make and Keep?); §
111.105 (What Must the Quality Control Unit Personnel Do?); § 111.455
(What Requirements Apply to Holding Components, Dietary Supplements,
Packaging, and Labels?); and § 111.515 (When must a Rreturned Ddietary
Ssupplement be Ddestroyed, or Ootherwise Ssuitably Ddisposed of?).

15.  Quality Control

	The final rule defines “quality control” as “a planned and
systematic operation or procedure for ensuring the quality of a dietary
supplement.”  The proposed rule defined “quality control” as “a
planned or systematic operation for preventing a dietary ingredient or
dietary supplement from being adulterated.”

	(Comment 50) One comment suggests revising the definition to use more
positive language.  Specifically, the commenter would define “quality
control” as “a planned and systematic operation or procedure for
ensuring the quality of dietary supplement products.”

	(Response) We agree that the comment’s suggested language conveys a
positive concept about quality control’s role and value and adopt the
language in part.  The final rule’s quality control requirements will
help ensure compliance with other CGMP requirements and, therefore, will
help ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record.  We have defined the term “quality” in this
final rule as including preventing a dietary supplement from being
adulterated.  Consequently, we revised the definition of “quality
control” to state that “quality control” means a planned and
systematic operation or procedure “for ensuring the quality of a
dietary supplement."  We deleted “for preventing a dietary ingredient
or dietary supplement from being adulterated” in the proposed
definition since the concept of quality includes preventing
adulteration.

	16.  Quality Control UnitPersonnel

	The final rule defines “quality control unitpersonnel” as “any
person, persons, or group, within or outside your organization, thatwho
you designate to be responsible for your quality control operations.”

	(Comment 51)  Some comments seem to suggest that the reference in the
2003 CGMP proposal to a “quality control unit” mandates a separate
unit or department with responsibility for all quality control
operations.  One comment explains many companies do not have one quality
control unit with oversight of all operations within the facility.  This
comment states companies commonly have each separate section of an
operation perform both its function and its own quality control.  A few
comments would clarify the definition by indicating that a distinct or
separate unit need not perform the quality control function.  These
comments say the quality control function is best performed by a person
or persons qualified by training, education, or experience in the
different processing areas.

	Many comments say we should consider any individual carrying out a
quality control function to be part of the quality control unit for
purposes of this rule.

     (Response)  We agree that the quality control function is best
performed by a person or persons qualified by training, education, or
experience in relevant areas.  To the extent that the comments
interpreted the proposed definition as requiring firms to have a
separate person or group whose sole function in the company is to
perform quality control operations or that the quality control unit
functions are limited to those who are employed within the firm, we
disagree.  As discussed in the preamble to the proposal, the quality
control unit should consist of as many people as necessary to perform
the quality control operations (68 FR 12157 at 12252).  We have
reconsidered the use of the term “unit.”  In order to clarify that
we do not intend to require a separate division or office be created, we
instead use the term “personnel.”  Although we have eliminated
references to “unit,” we still agree that personnel can be a person,
persons, or a group, and as many persons as necessary, who perform the
quality control operations.  The manufacturer must identify the
appropriate person or persons to be responsible for the quality control
operations associated with a particular manufacturing operation.  For
example, the manufacturer may designate one individual as a packaging
expert who is responsible for the quality control operations related to
packaging, designate a second individual as an expert in deciding
whether to accept or reject incoming components, and designate a third
individual as an expert in deciding whether in-process specifications
are met at certain control points.  The definition does not limit the
other activities that these designated individuals may perform within
the manufacturing operations; thus, for example, the packaging expert
who performs the quality control function for packaged dietary
supplements could also have responsibilities in the actual packaging
operation. Quality control responsibilities and specific activities are
distinct and separate from any other responsibilities and specific
activities that an employee might perform for any other operation.  In
addition, the quality control operations may be performed by someone
outside the organization (such as a contractor).

	To clarify these points and to prevent potential misinterpretation of
the quality control unit’s functionoperations, we revised the
definition of “quality control unit.”  Instead of a unit, quality
control personnel who perform quality control operations may be a
person, persons, or group and may be “within or outside of your
organization,” .” and We also added a new § 111.12(b) to require
you to identify who is responsible for your quality control operations.
Under final § 111.12(b) each person who is identified to perform
quality control operations must be qualified to do so and have distinct
and separate responsibilities related to performing such operations from
those responsibilities that the person otherwise has when not performing
such operations.  Throughout the codified, we use the term “quality
control personnel” when referring to the performance of specific
quality control operations.  The term “quality control personnel”
refers to the person or persons designated to perform the particular
quality control operation.

	17.  Representative Sample

	The final rule defines “representative sample” as “a sample that
consists of an adequate number of units that are drawn based on rational
criteria, such as random sampling, and that are intended to ensure that
the sample accurately portrays the material being sampled.”  This
definition is similar to the proposed definition of “representative
sample.”  We have added “an adequate” before “number” to
emphasize that the sample must be sufficient for its purpose.  We also
made non-substantive grammatical changes to insert “that are”
between “and” and “intended.”

	(Comment 52) Some comments note the proposed rule would use the terms
“representative sample,” “reserve sample,” and “representative
reserve sample” but would only define “representative sample.”
The comments ask us to clarify the distinction, if any, between these
terms.

	(Response) A “reserve sample” is a sample that is to be held or
kept for a designated time.  It differs from a “representative
sample” in the sense that a representative sample is not always kept;
for example, one might take a representative sample to test product
quality, but one would not necessarily keep every tested sample.

	To clarify this distinction, the final rule now defines a “reserve
sample” as “a representative sample of product that is held for a
designated period of time.”  We also revised the rule to refer solely
to a “reserve sample” rather than use both  “reserve sample” and
“representative reserve sample.”

 	18. Reprocessing

	The final rule defines “reprocessing” as “using, in the
manufacture of a dietary supplement, clean, , uncontaminated components
or dietary supplements that have been previously removed from
manufacturing and that have been made suitable for use in the
manufacture of a dietary supplement.”  We modified the definition
that, in part, read “. . . dietary supplements that have been
previously removed from manufacturing

for reasons other than insanitary conditions” by removing “for
reasons other than insanitary conditions” to expand the scope of what
may be reprocessed.  We explain the reason for the latter change in our
response to the comments immediately below in this section.  We also
changed “unadulterated” to “uncontaminated” to be consistent
with the revisions we have made in other sections including the
definition of quality.

	(Comment 53) Some comments ask us to clarify whether components or
dietary supplements that have been successfully treated to reduce
microbial levels to acceptable levels can be reprocessed.  Some comments
object to the proposed definition of “reprocessing” because it did
not include components or dietary supplements removed for insanitary
conditions, and several comments object to the restrictions to
reprocessing described in proposed §§ 111.35(i)(4)(iii) and 111.50(f),
because, they argue, the definition and sections associated with
reprocessing would not permit the reprocessing of previously insanitary
ingredients even if there are processes available that are safe and
effective in removing foreign matter, microorganisms, or chemicals that
may have rendered the ingredient “insanitary.”  One comment would
revise the definition as follows: “Reprocessing means using, in the
manufacture of a dietary supplement, clean, unadulterated components * *
* or dietary supplements that have been previously removed from
manufacturing for reasons other than insanitary conditions or that have
been successfully reconditioned so that they are suitable for use.”

	(Response) We agree that materials can be treated, subjected to
in-process adjustments, or reprocessed when there are suitable processes
available, and we revised the definition of “reprocessing” to
reflect this.  However, there must be appropriate oversight of the
treatment, in-process adjustments, and reprocessing so the dietary
supplement will still meet required specifications.  Therefore, we added
a conforming requirement to final §§ 111.90(b) and 111.140(b)(3)(vi)
to require oversight by the quality control unit personnel for any
reprocessing, treatment, or in-process adjustment of a dietary
supplement that have been previously removed from manufacturing and that
have been made suitable for use in the manufacture of a dietary
supplement (see sections X and XI).

	19.  Reserve Sample

	The final rule contains a new definition of “reserve sample.”
“Reserve sample” is defined as “a representative sample of product
that is held for a designated period of time.” We explain our reasons
for creating this definition in this section under the definition of
“representative sample”.

	20. Sanitize

     The final rule defines “sanitize” as “to adequately treat
cleaned equipment, containers, utensils or any other cleaned contact
surface by a process that is effective in destroying vegetative cells of
microorganisms of public health significance, and in substantially
reducing numbers of other microorganisms, but without adversely
affecting the product or its safety for the consumer.”

	The final rule’s definition of “sanitize” differs from the
proposal in that the proposed definition would have specified a
reduction of 5 logs or 99.999 percent reduction of “representative
disease microorganisms of public health significance” and “other
undesirable microorganisms” and would have specified the use of heat
or chemicals.  The preamble to the 2003 CGMP Proposal explained that we
based the proposed definition of “sanitize” on the definition of
“sanitization” in the “Food Code” (which is a model that gives
food control authorities a scientifically sound technical and legal
basis for regulating the retail and food service segment of the
industry) because dietary supplements are often consumed without further
processing, similar to foods consumed in retail outlets (68 FR at
12179).  The preamble to the 2003 CGMP Proposal also explained that, to
achieve the reduction levels in the proposed definition, one would need
to validate control measures to ensure they are both appropriate to
their operation and scientifically sound.  The preamble explained that
in many cases, manufacturers may rely on a written certification from
the equipment manufacturer or may obtain a written scientific evaluation
of a process, especially in cases where two or more control measures are
used to accomplish the 99.999 percent reduction in the target pathogen,
to ensure the process is adequate to destroy microorganisms of public
health significance or to prevent their growth.

	(Comment 54) Many comments object to the proposed text concerning the
application of heat or chemicals to a food contact surface to yield a
reduction of 5 logs or 99.999 percent of representative disease
organisms of public health significance.  The comments state the aspect
of the proposed definition is overly prescriptive, beyond our legal
authority, and would not provide additional public health benefits.
Many comments say it is inappropriate to use the definition of
sanitization from our Food Code because retail and manufacturing
operations are distinct.  A few comments assert the process of
manufacturing dietary supplements shares more in common with food or
drug manufacturing than with retail operations.  Most comments recommend
that we define “sanitize” in the manner that was presented in the
1997 ANPRM and consistent with the current food CGMP definition at §
110.3 so that “sanitize” means “to adequately treat dietary
product contact surfaces by a process that is effective in destroying
vegetative cells of microorganisms of public health significance, and in
substantially reducing numbers of other undesirable microorganisms, but
without adversely affecting the product or its safety for the
consumer.”

	One comment states that consistently validating the effectiveness of
the sanitizing procedure is impractical and recommended we state instead
that equipment, utensils, etc., should be cleaned and sanitized in a
manner that keeps undesirable microorganisms and other adulterants from
contaminating all components, ingredients, in-process materials, and
finished product.  The comment claims that, by this approach, the
microbial and analytical test results of product produced on a
facility’s equipment, coupled with random testing of final rinse water
after cleaning and sanitizing equipment and utensils, would provide
sufficient and continuous evidence of a proper and effective cleaning
and sanitizing plan.

	Two comments claim that the proposed definition for sanitize denotes
“validation methodology” found in drug CGMP, and that we must base
dietary supplement CGMP on food rather than on drug standards.

	Other comments express concern about validating control measures to
ensure that they are scientifically sound and appropriate to operations
and the economic burden to do the testing.  A few comments state it
would be difficult to show a 100,000-fold reduction on an already
cleaned surface, particularly if the pre-sanitization level is at or
near the lower limit of the test method employed.

	One comment states the definition required the manufacturer to
demonstrate a 100,000-fold reduction in microbial count every time a
food contact surface is sanitized. A few comments express concern that
processing lines would have to be closed down each time they are
sanitized in order to test them, creating a financial hardship
especially on smaller operations.  Other comments ask us to give
companies the flexibility necessary to monitor sanitation needs based on
individual products and manufacturing operations to be consistent with
existing industry practices and food and drug CGMPs.

	One comment requests we clarify that a sanitizing agent for use on food
processing equipment must be approved in accordance with part 178
--Indirect Food Additives: Adjuvants, Production Aids and Sanitizers and
our expectations with respect to what documentation would be necessary
to prove the effectiveness of the sanitizer used.  Two comments say the
proposed definition of sanitize means that manufacturers must perform
validation studies to demonstrate that the sanitizers they are using
reduce the microbial load on equipment by 100,000-fold, a requirement
for a “sanitizer” under regulations issued by the Environmental
Protection Agency (EPA).  The comments say a sanitizer should not be
held to this standard for the purpose of reducing microbial loads on
food product contact surfaces, and that manufacturers of a solid dosage
form may not need to “sanitize” their equipment because the
processing environment is not suitable for microbial growth due to the
low water activity.  One comment recommended using the approach in the
Food Code, which specifies conditions under which chemical sanitizers
listed in § 178.1010 may be used, including the requirement that they
be used in accordance with the EPA-approved manufacturer’s label use
instructions, and be used for dietary supplements rather than imposing a
validation requirement on manufacturers.

	Some comments would divide the definition of “sanitize” by creating
separate definitions for “sanitize” and “sanitizing agent.”  The
comments would define “sanitize” as meaning “to adequately treat
equipment, containers, utensils, or any other dietary product contact
surface by applying a sanitizing agent on cleaned food contact
surfaces.”  One comment would define “sanitizing agent” as
“cumulative heat or chemicals that, when evaluated for efficacy, yield
a reduction of 5 logs, which is equal to 99.999 percent reduction, of
representative disease microorganisms of public health significance and
substantially reduce the numbers of other undesirable microorganisms,
but without adversely affecting the product or its safety for the
consumer.”  Another comment would define “sanitizing agent” in a
similar manner, except it would omit references to a 5-log reduction.

	(Response) The proposed definition of “sanitize” was intended to
give firms the flexibility to monitor sanitation needs based on their
products and operations.  We did not intend to suggest that
manufacturers had to demonstrate a 100,000 fold reduction in microbial
count every time they sanitized a contact surface, nor did we intend, as
some comments claimed, to have firms close down processing lines every
time they were sanitized to test them for microbial reduction.  Rather,
the language of the proposed rule was intended to make it clear that
processes used to sanitize contact surfaces should be effective.
However, we recognize that the proposed definition caused confusion as
to our intent.  The proposed definition may have been interpreted as
proposing validation to ensure an area was sanitized; however our intent
was simply to require that effective sanitizers and sanitizing processes
be used, just as in food establishments.  Therefore, in order to clarify
the provision, we have revised the definition of “sanitize” to be
consistent with § 110.3(o).  The final rule defines “sanitize” as
adequately treating “cleaned equipment, containers, utensils, or any
other cleaned contact surface by a process that is effective in
destroying vegetative cells of microorganisms of public health
significance, and in substantially reducing numbers of other
microorganisms, but without adversely affecting the product or its
safety for the consumer.”  The final definition of sanitize does not
include any statements about mechanisms that you may use to achieve
compliance because including such non-binding information is
inconsistent with our current practices for establishing regulations.

     We note that EPA has regulatory authority over certain uses of
sanitizers as pesticide chemicals and we have regulatory authority over
certain uses of sanitizers as food additives.  Under section
201(q)(1)(B) of the act, as amended by the Food Quality Protection Act
(FQPA) (Public Law 104-170) and the Antimicrobial Regulation Technical
Corrections Act (ARTCA) (Public Law 105-324), certain substances used as
food contact surface sanitizing solutions are subject to the
Environmental Protection Agency’s (EPA) regulatory authority as
pesticide chemicals.  EPA recently codified tolerance exemptions under
section 408 of the act for those food contact surface sanitizing
solutions that were previously subject to our authority at § 178.1010
and transferred to EPA’s authority under FQPA and ARTCA (see 40 CFR
180.940 (69 FR 23113 (April 28, 2004)).  Such pesticide chemicals must
comply with the Pesticide Tolerance regulations in 40 CFR 180.940.
Sanitizers used on food packaging must comply with our regulations at §
178.1010.  For an in depth discussion of appropriate sanitizers for food
contact surface use, see the EPA’s Pesticides; Tolerance Exemptions
for Active and Inert Ingredients for Use in Antimicrobial Formulations
(Food Contact Surface Sanitizing Solutions) (69 FR 23113 (April 28,
2004)) and DIS/TSS-4 Efficacy Data Requirements Sanitizing Rinses (for
previously cleaned food-contact surfaces) (Jan 30, 1979) (Ref. 274)
(available on the internet at

http://  HYPERLINK "http://www.epa.gov/oppad001/"  www.epa.gov/oppad001/
dis_tss_docs/dis-04.htm).

	21. Theoretical Yield

	The final rule defines “theoretical yield” as “the quantity that
would be produced at any appropriate step of manufacture or packaging of
a particular dietary supplement, based upon the quantity of components
or packaging to be used, in the absence of any loss or error in actual
production.”

	We received no substantive comments on the proposed definition.

	22. Water Activity

	The final rule defines “water activity” as “a measure of the free
moisture in a component or dietary supplement and is the quotient of the
water vapor pressure of the substance divided by the vapor pressure of
pure water at the same temperature.”

	We received no substantive comments on the proposed definition.

	23. We

	The final rule explains that “we” means the United States Food and
Drug Administration.

	The final rule’s definition is identical to the proposed definition.
We received no substantive comments on the proposed definition. and,
therefore, finalized it without change.

	24. You

	The final rule defines “you” as a “person who manufactures,
packages, labels, or holds dietary supplements.”

	25. What Other Terms Did the Comments Want Defined?

	(Comment 55) Some comments ask us to define “adulteration” (based
on the provisions of section 402 of the act), “dietary ingredient,”
and “dietary supplement” (based on the definition in section 201(ff)
of the act).

	(Response) We decline to revise the rule as suggested by the comments.
The terms have meaning within the context of the act and case law.
Further, under final § 111.3 the act’s definitions and
interpretations “apply to such terms when used in these
regulations.”  Thus, there is no need for us to define the terms as
requested by the comments.

	(Comment 56) Proposed § 111.35(e)(2) would require a person to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration, and proposed § 111.35(f) would require monitoring of the
in-process control points, steps, or stages to ensure these established
specifications are met and to detect any unanticipated occurrence that
may result in adulteration.  Some comments ask us to define the term
“control point” as “any point, step or stage in the manufacturing
process where control is necessary to prevent adulteration.”

	(Response) We decline to add a definition of “control point” as
requested by the comments.  Instead, we revised final § 111.75(b)
(formerly proposed § 111.35(f)) to state that you must monitor the
in-process points, steps, or stages where control is necessary to ensure
the quality of the finished batch of dietary supplement; this revision
eliminates the need to define “control point.”

	(Comment 57) Several comments would have us define one or more of the
following terms: identity, purity, strength, and composition.  Some
comments suggest specific text for the definitions.

	Similarly, some comments suggest codifying the preamble description
that we used for these terms – i.e., the phrase “identity, purity,
quality, strength, and composition” means that the production on a
batch-by-batch basis is consistent with the master manufacturing record
and is what it is represented on the label to be (identity); is without
impurities and is the desired product (purity); is the identity, purity,
and strength for its intended purpose (quality); is the concentration,
that is, the amount per unit of use intended (strength); and is the
intended mix of product and product-related substances (composition) (68
FR 12157 at 12176).  One comment says “identity” should mean “a
substance or product is what it is represented on the label to be.”

	One comment says that it does not seem appropriate to define the term
“purity” to mean “without impurities.”  The comment states it
would be difficult to consider an herbal extract as being “pure”
because it is a mixture of naturally occurring compounds in a solvent.
Another comment suggests the term “purity” be defined to mean
“free from objectionable and/or deleterious levels of impurities
including, but not limited to, heavy metals, pesticides, mycotoxins,
radioactivity, filth, extraneous material, molds, yeasts and bacteria.
Another comment suggests defining the term “purity” as “having the
intended identity and composition and being without significant
impurities.”  However, the comment does not explain what is meant by
“without significant impurities.”

	One comment suggests defining the term “strength” as “having the
intended concentration, that is, the amount of the dietary ingredient
per unit of use (tablet, capsule, soft gel, teaspoon, or other unit).”
 Another comment expresses concern about the use of the term
“strength” in relationship to non-standardized herbals because there
are no current industry standards for these products.  This comment
suggests we clarify the term “strength” so it refers to having the
correct amount of a stated ingredient.  One comment notes St. Johns wort
has a composition of approximately 40 different constituents in addition
to the essential oil that contains numerous constituents.  The comment
asks which constituent it should use to determine “strength.”
Another comment would use the term “quantity” instead of
“strength.”

     One comment would define “composition” as “having the
intended mix of components or ingredients, including dietary
ingredients.”  Another comment would delete “composition” from the
rule because, the comment claimed, an FDA investigator might conclude
that “composition” refers to every constituent of every botanical.
According to this comment, there are many tests that could be used to
identify the botanical constituents, but that it would be economically
exhausting considering the number of botanical constituents, and it
would not contribute to quality or safety.

	(Response) We decline to revise the rule to define identity, purity,
strength, or composition.  The exact way in which the dietary supplement
industry uses these terms may vary, and defining these terms could limit
the flexibility that is needed to accommodate such variations.

	Nevertheless, to elaborate on our interpretation of identity, purity,
strength, and composition, and to respond to the particular concerns
raised by some comments, we provide the following information.

	a.  Identity

	The “identity” of a dietary supplement refers to the dietary
supplement’s consistency with the master manufacturing record and/or
that it is the same as described in the master manufacturing record.

	b.  Purity

	The “purity” of a dietary supplement refers to that portion or
percentage of a dietary supplement that represents the intended product.
 For example, amino acids generally can exist in two forms (i.e., dextro
(D-, or right) and levo (L-, or left) forms) called enantiomers.
Enantiomers have the same chemical formula and the same chemical
structure, but differ in their three-dimensional orientation.  If you
manufacture a dietary supplement to provide the amino acid L-arginine,
and you determine that 90 percent of the manufactured product is
L-arginine and 10 percent of the manufactured product is D-arginine, you
could describe your L-arginine product as “90 percent pure.”  As
another example, if you manufacture a mixture of triglycerides that
provides polyunsaturated fatty acids in the diet, the manufactured
triglycerides may contain small amounts of free fatty acids and sterols.
 The free fatty acids, and sterols could derive, for example, from the
source of the triglycerides or could be byproducts of the manufacturing
process.  If you determine that 95 percent of the manufactured product
is the mixture of the triglycerides that provides the polyunsaturated
fatty acids, and 5 percent of the product is free fatty acids and
sterols, you could describe the purity of your product as “95 percent
pure.”

	Just as we use the term “purity” to refer to the identity and
amount of a dietary supplement that is the desired product, we use
“impurity” to refer to the identity and amount of a dietary
supplement that is not the desired product.  In the above examples, we
view the D-arginine that is present in the product that is intended to
be L-arginine as an “impurity,” and we view the free fatty acids and
sterols that are present in the product that is intended to be a mixture
of triglycerides that provide polyunsaturated fatty acids in the diet as
“impurities.”  For the purposes of these examples, we do not view
these “impurities” as “contaminants.”

	If the comments were concerned that the dietary supplement CGMP
requirements regarding a dietary supplement’s “purity” mean that
we expect you to characterize each constituent of a natural product to
determine whether each constituent is present in a certain
pre-established quantity (i.e., purity specification) to determine
whether it contributes to the “purity” of the dietary supplement or
would be considered as an “impurity,” we do not consider such
constituents to be “components” of a dietary supplement (see
discussion of the definition of component in this section). For example,
if manufacture a dietary supplement containing fish oil, we would not
consider the triglycerides, which are constituents of the fish oil, to
be components.  Likewise, we would not consider particular fatty acids
(such as the polyunsaturated fatty acids docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA)), which are constituents of the
triglycerides, to be components of the dietary supplement.  In this
example, you would be required to establish a purity specification for
the amount of triglycerides in the fish oil.  (Note that if you are
manufacturing fish oil to provide the fatty acids DHA and EPA in the
dietary supplement, the component specifications for the fish oil must
include a strength specification for DHA and EPA in whatever amount you
determine is necessary to meet the specification for strength of DHA and
EPA in the dietary supplement.) We do, however, expect you to set
appropriate limits on contaminants – e.g., toxic substances – that
are known to be constituents of botanical extracts or other natural
products that are likely or certain to contain constituents that are
harmful.

	c.  Strength

The strength of a dietary supplement relates to its concentration.  By
concentration, we mean the quantitative amount per serving (for example,
weight/weight, weight/volume, or volume/volume).  Therefore, for
purposes of this final rule, strength does not refer simply to the
quantity of an ingredient, rather it refers to the amount of a stated
ingredient per a specified unit of measure.

	If the comments were concerned that the “strength” of a dietary
supplement meant that you need to establish the quantitative amount per
unit of measure of each constituent in a dietary ingredient, such as a
botanical extract or natural product, we do not consider such
constituents to be “components” of a dietary supplement, unless you
add such constituents as components (as in an extract) (see discussion
of the definition of component in this section).

	We do not consider the rule’s requirements on dietary supplement
strength as necessarily relating to the individual constituents of such
products.  Whether the requirements regarding dietary supplement
strength apply to one or more constituents of dietary ingredients in a
dietary supplement depends on what you are manufacturing.  For example,
if you are manufacturing vitamin C, and your source of vitamin C is
rosehips, you would  establish a strength specification for vitamin C
in the finished batch of the dietary supplement (e.g., "x mg of vitamin
C per tablet"). You are required to ensure that the dietary supplement
does in fact contain "x mg of vitamin C per tablet."  Alternatively, if
you are manufacturing rosehips and not vitamin C from rosehips, the
strength specification that you establish for the finished batch of the
dietary supplement is the strength of the rosehips themselves (i.e., the
concentration of rosehips in the final product, such as “x mg of
rosehips per tablet”).  You are required to ensure that the product
does in fact contain “x mg of rosehips per tablet.”

	We discuss the requirements to establish and meet specifications in our
discussion of subpart E (see section X).

	d.  Composition

	A dietary supplement’s “composition” refers to the specified mix
of product and product-related substances in a dietary supplement.  For
example, a dietary supplement manufactured to provide vitamin C may
contain, in addition to vitamin C, a tablet coating agent and substances
used as binders.  The composition could be described as the percent of
the dietary supplement that is vitamin C, the tablet-coating agent, and
each binder.

	e. Other terms

	(Comment 58) Several comments would revise the rule to define
“manufacturer.”  Many comments ask whether the rule applies to
certain types of companies or professionals and said a definition of
“manufacturer” would clarify the rule’s applicability.

	Some comments suggest specific text for a definition.  For example, one
comment would define “manufacturer” as “a person who formulates or
changes the composition or physical characteristics of a dietary
supplement or who packages or labels the product in a container for
distribution” to clarify that a company that does not manufacture a
specific dietary supplement, but purchases a dietary supplement in bulk
and then packages or labels the bulk dietary supplement for sale to
consumers, is still subject to dietary supplement CGMP requirements.
The comment cites our proposed definition of “manufacturer” in our
infant formula CGMP proposal (see 61 FR 36153 at 36209 (July 9, 1996)
(proposing to define a “manufacturer” as “a person who prepares,
re-constitutes or otherwise changes the physical or chemical
characteristics of an infant formula or packages or labels the product
in a container for distribution”)).

	Other comments would define “manufacturer” to exclude a health care
practitioner or herbalist and noted the Canadian Natural Health Product
regulations do not apply to health care practitioners.

	(Response) We decline to define “manufacturer” in the final rule.
In section III, footnote 1, we explain that “manufacture” is a broad
term and is not limited to production, packaging, or labeling
activities.  Consequently, we prefer to explain our interpretation of
the final rule in this preamble and to have the codified provisions
state general principles rather than attempt to capture subtleties in a
definition of “manufacturer.”

	(Comment 59) Proposed § 111.35(e)(1) through (e)(3) would require you
to establish specifications for identity, purity, quality, strength, and
composition at receipt, in-process, and finished batch stages, while
proposed § 111.35(g)(1) would require you to test each dietary
supplement at the finished batch stage before release for distribution
to confirm that specifications are met, provided that there are
scientifically valid analytical methods available to perform such
testing.  If your quality control unit determined that finished batch
testing could not be completed for any specification because a
scientifically valid analytical method was not available, proposed §
111.35(g)(2) and (g)(3) would require you to perform testing on
components and at the in-process stage to determine whether that
specification is met.  The preamble to the 2003 CGMP Proposal explained
that a scientifically valid analytical method is one that is based on
scientific data or results published in, for example, scientific
journals, references, text books, or proprietary research (68 FR 12157
at 12198).

	Several comments agree that scientifically valid analytical methods are
those that are based on scientific data or results published in
scientific journals, references, textbooks, or proprietary research.
However, several comments ask us to define or better explain the terms
“test” or “scientifically valid analytical method” as used in
the dietary supplement CGMP final rule.  One comment argues that,
because of the evolving nature of methodology for ingredients used in
dietary supplements, we should give the industry more guidance as to
what can be considered authoritative for the purpose of compliance with
CGMP.  Some comments state we should acknowledge methods from the
Institute for Nutraceutical Advancement (INA), American Herbal
Pharmacopoeia (AHP), European Pharmacopoeia, and the World Health
Organization (WHO) as scientifically valid analytical methods.  One
comment notes the USP establishes scientifically valid procedures in its
compendia and encouraged us to designate compendial procedures as
"scientifically valid" by defining "scientifically valid" to include
compendial procedures.  The comment further argues that failure to
acknowledge compendial procedures as scientifically valid would be
inconsistent with section 403(s)(2)(D) of the act, which acknowledges
the role of compendia, by considering a dietary supplement misbranded if
the supplement is covered by the specifications of an official
compendium, is represented as conforming to the specifications of an
official compendium, and fails to so conform.

	Other comments would define “validation” and “verification” and
directed us to “ANSI Standard A8402-1994” (a description of
validation and verification standards).

	(Response) We decline to define “test,” “scientifically valid
analytical method,” or “scientifically valid method” in this final
rule.  As the comments recognized, the analytical methods for components
are evolving.  A regulatory definition for “test,” “scientifically
valid analytical method” or “scientifically valid method” could
become obsolete if we based it on specific sources such as INA, AHP, or
USP that may or may not themselves stay current or that may be modified
in a manner that did not enjoy widespread support.

	The preamble to the 2003 CGMP Proposal acknowledged that compendia can
have a role in establishing tests used to determine whether
specifications are met.  For example, we noted that compendial standards
may be appropriate reference materials for use in conducting tests or
examinations (68 FR 12157 at 12208).  However, we did not list specific
compendia that would be suitable sources or scientifically valid
analytical tests, and are not listing such compendia in this final rule.
 The compendia identified in the comments, i.e., INA, ANSI, AHP and USP,
may include some methods that are based on scientific data or results
published in scientific journals, references, textbooks, or proprietary
research, but also contain some methods that are not based on such data
or results.  Thus, whether or not a method is scientifically valid is
not determined solely by its inclusion in a compendium.  Rather, it is
the responsibility of quality control unit’s responsibilitypersonnel
to approve the use of those scientifically valid tests that will ensure
a product’s identity, purity, strength, and composition whether or not
such tests are contained in a particular compendium.

	 We also decline to define “validation” and “verification”
because the final rule does not establish any requirements that use
these terms.

	(Comment 60) One comment asks us to define the terms “adequate,”
“sufficient,” and “qualified” and argues that, without these
definitions, an FDA investigator may assert that something or someone is
not adequate, sufficient, or qualified.

	(Response) We decline to define “adequate,” “sufficient,” or
“qualified” in this final rule.  Deciding what is “adequate” or
“sufficient,” or who is “qualified” must be done on a
case-by-case basis, depending on the operations and the particular
facts.  As explained in section V, 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.  Furthermore, defining “adequate,” as
defined in part 110, as “that which is needed to accomplish the
intended purpose in keeping with good public health practice” would
still require context to determine whether, in a particular operation
and based on a particular set of facts the particular practice was
“adequate.”  Moreover, for terms such as “adequate,”
“sufficient,” and “qualified,” where there has been common usage
in the food industry to enable manufacturers and FDA investigators to
comprehend and apply such terms to a particular operation, we do not
believe a definition for these terms is necessary.

	(Comment 61) Several comments would define the terms “certificate of
analysis,” “certificate of compliance/ conformance,” and
“continuing product guarantee.”   Most comments include these terms
in a list of terms that they want us to define to ensure consistent
interpretation of the rule throughout the industry.  One comment says a
standard for documentation, such as a certificate of analysis, would put
greater emphasis on the firm’s responsibility to comply with CGMP.

	(Response) We decline to define these terms as suggested by the
comments.  We have included, in the codified, the use of a certificate
of analysis as an option to determine whether certain specifications
have been met.  The final § 111.75(a)(2)(ii)(B) requires that certain
information be provided in a “certificate of analysis.”  This
provision states that the certificate of analysis must include a
description of the test or examination method(s) used, limits of the
test or examinations, and actual results of the tests or examinations,
provided you satisfy certain other criteria.

	As for the claim that a standard for documentation, such as a
certificate of analysis, would emphasize a firm’s responsibility to
comply with CGMP, we encourage firms who are excepted from the scope of
the rule in final § 111.1 and who supply dietary ingredients and other
components to follow dietary supplement CGMP requirements.

	We decline to define “certificate of compliance/ conformance” or
“continuing product guarantee” because the final rule does not
establish any requirements that use these terms.

	26. What Definitions Did the Comments Want Us to Delete?

	(Comment 62) Some comments would delete certain definitions (e.g.,
“component” and “ingredient”) because these terms do not appear
in the food CGMP, the 1997 ANPRM, or both.

	(Response) We decline to delete any definition for the reasons stated
by the comments.  As discussed in section V, Congress did not require
dietary supplement CGMP requirements to be identical to the food CGMP
requirements, so the mere fact that a definition may not appear in a
food CGMP regulation does not mean we must delete that definition from
this final rule, especially when the comments offered no other
justification for deleting the definition.  Definitions provide clarity
and consistency in interpreting various terms in a rule.

D. Do Other Statutory Provisions and Regulations Apply? (Final§ 111.5)

	Final § 111.5 states: “In addition to these regulations, you must
comply with other applicable statutory provisions and regulations under
the act related to dietary supplements.” Proposed § 111.5 stated
that, in addition to the dietary supplement CGMP requirements, “you
must comply with other applicable statutory provisions and regulations
under the act related to the manufacturing, packaging or holding of
dietary ingredients or dietary supplements.”

Section 111.5 reminds you that other statutory or regulatory
requirements, not included in the dietary supplement CGMP requirements,
may apply to your particular products, operations or activities.  In our
further review of this provision, we determined that we do not need to
elaborate on the individual operations and have shortened the provision
to eliminate the references to particular operations.  You are required
to comply with other applicable statutory and regulatory requirements,
and we have retained this provision to ensure you understand that this
final rule does not relieve you of your responsibilities to comply with
other applicable statutory and regulatory requirements related to
dietary supplements.

	E.	What Sections Did We Remove From the Rule, and Why?

	The final rule omits sections that were in the proposed rule.  Proposed
§ 111.2, “What Are These Regulations Intended to Accomplish,” would
have described the rule’s purpose as establishing the minimum CGMP you
must use to the extent that you manufacture, package, or hold a dietary
supplement.    Proposed § 111.6, “Exclusions,” would have excluded
“persons engaged solely in activities related to the harvesting,
storage, or distribution of raw agricultural commodities that will be
incorporated into a dietary supplement by other persons” from the
dietary supplement CGMP requirements.

	1.  “What Are These Regulations Intended to Accomplish?”  (Proposed
§ 111.2)

	We elected to remove proposed § 111.2 from the final rule because we
realized that it created no enforceable obligations and provided little,
if any, helpful information.  The few comments that address proposed §
111.2 either disagreed with its general statement or sought to weaken
the provision; the comments’ arguments prompted us to reconsider
whether proposed § 111.2 was necessary at all, and, in the end, we
decided to delete the proposed section.  We describe the comments on
proposed § 111.2 immediately below.

	(Comment 63) Several comments argue the proposed rule went beyond the
“minimum standards” mentioned in proposed § 111.2.  These comments
also assert the proposed rule lacked flexibility.

(Response) We disagree with the comments.  In several instances, the
proposed requirement is practically identical to requirements in the
umbrella food CGMP regulations.  For example, most of the proposed
requirements for personnel, physical plants, and equipment and utensils
correspond to long-established, similar requirements in the umbrella
food CGMP regulations in part 110.  In other instances, the proposed
rule would require a particular action or result (such as establishing
specifications for components, in-process controls, manufactured dietary
supplements, and packaged and labeled dietary supplements under proposed
§ 111.35(e)), but gave firms the flexibility and the responsibility to
decide what those specifications will be.  We have included flexibility
where it is appropriate to do so, and, after we revised parts of the
rule in response to the comments, the final rule provides more
flexibility than the proposal.  For example, final § 111.75 sets forth
criteria for relying on a certificate of analysis to ensure that certain
specifications for components are met and for when you can test a subset
of finished batches for a select number of specifications; this differs
considerably from the proposal which would have required testing all
batches for all specifications.

(Comment 64) One comment would revise proposed § 111.2 to read as
follows:

These regulations recommend general minimum current good manufacturing
practices that, when modified by manufacturer product specifications,
will extend to the manufacture, package, or holding of dietary
ingredients or dietary supplements for that manufacturer.

(Response) We decline to revise the rule as suggested by the comment.
Section 402(g) of the act states that “The Secretary may by regulation
prescribe good manufacturing practices for dietary supplements.”  If a
dietary supplement has been prepared, packaged, labeled, or held under
conditions that do not meet the final rule’s requirements, the dietary
supplement is deemed to be adulterated under section 402(g)(1) of the
act.  Here, the comment’s suggestion that dietary supplement CGMP
requirements could be “modified by manufacturer product
specifications” would create uncertainty over whether manufacturers
could unilaterally “modify” their product specifications to fit a
batch that failed to meet specifications or claim that a violation was
“cured” by a manufacturer’s new product specification.  In any
event, given that we decided to omit proposed § 111.2 altogether, the
change sought by the comment is moot.

2. “Exclusions” (Proposed § 111.6)

As we stated earlier in this section, proposed § 111.6 would exclude
from the dietary supplement CGMP requirements persons who engage solely
in activities related to the harvesting, storage, or distribution of raw
agricultural commodities that would be incorporated into a dietary
supplement by other persons.  However, as we explained in our response
to comment 27[x] in this section, we decided that the exclusion was not
necessary, given the changes that we made to final § 111.1(a).

	Nevertheless, we received several comments on proposed § 111.6, and we
address those comments here.

	(Comment 65) One comment would revise the rule to exclude or use
different requirements for small businesses.  The comment suggested we
categorize small businesses by employment levels or dollar sales and
adopt a tiered enforcement strategy similar that used in other
government programs, such as those under the Occupational Safety and
Health Act, the Americans with Disabilities Act, and the Family Leave
Act.  Another comment would exempt small businesses from the specific
requirements for testing if those businesses produce annual batch runs
of 25,000 capsules and tablets.

	(Response) We decline to exclude small businesses from the final rule
or to have different criteria for such businesses.  As we stated in our
response to comments 1,3 and 16 x, there is no reason to assume that
Congress meant to apply different or lesser CGMP requirements, or no
CGMP requirements at all, to dietary supplements made by small
businesses.  Dietary supplement CGMP requirements help to ensure the
quality of the dietary supplement and, among other things, that a
dietary supplement meets its specifications, that it contains the
ingredients specified in its master manufacturing record, and that it is
not contaminated.  Consumers should be able to expect that the dietary
supplements they purchase meet CGMP requirements regardless of the
manufacturer’s size.  However, to help businesses comply with dietary
supplement CGMPs, we are giving businesses with fewer than 500 employees
but 20 or more employees a compliance date of 24 months after the date
of publication of this final rule, and we are giving businesses with
fewer than 20 employees a compliance date of 36 months after the date of
publication of this final rule.

	We carefully considered the size of a business when developing these
regulations.  The most common SBA size standard applicable to
manufacturers covered by this final rule is 500 employees.  Based on
comments and our knowledge of the dietary supplement industry, we know
that there are a number of dietary supplement manufacturers who fall
significantly below the standard of 500 employees.  To accommodate these
manufacturers, we have established different compliance dates as noted.

	(Comment 66)  One comment would exempt “consolidators” (whom it
described as individuals who purchase raw agricultural commodities for
sale to raw ingredient manufacturers) from the rule.  Some comments
suggest expanding the exclusion pertaining to harvesting, storage, and
distribution of raw agricultural commodities to include other common and
basic raw botanical processing activities, such as drying, chopping,
cutting, size reduction, sifting, grinding, and storage.  One comment
would delete the word  “solely” to make the rule more flexible and
make it possible to exclude producers, who do not manufacture a distinct
product, from the CGMP rule.  Another comment expresses concern about
potential safety issues that can arise from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration; the comment says businesses
involved in producing or distributing raw agricultural commodities
should be subject to some requirements under the rule.  A few comments
ask us to draft guidance documents to address activities such as
wildcrafting, plant identification, good agricultural practices, and
good hygienic practices for wildcrafters (persons who harvest plants
grown in the wild), and growers and brokers and specific service
providers (millers, extractors).  Some comments would exempt individual
wildcrafters because wildcrafters deal in relatively small amounts of
material at a time and sell their material to larger brokers who combine
materials from different pickers together.

	(Response) As explained in our responses to comments 29 and 30, [x],
persons who only manufacture or supply a component that will be further
processed as a dietary supplement by another person are not within the
scope of this final rule.  Thus, a “consolidator” who simply buys
raw agricultural commodities and then sells them to dietary ingredient
manufacturers would not be subject to this final rule.  Similarly,
persons engaged in drying, chopping, cutting, size reduction, sifting,
and grinding of raw agricultural commodities which they then sell to
others for processing into a dietary supplement would not be subject to
this final rule.  We note, however, that such persons are not exempt
from other regulatory requirements.  We remind readers that a dietary
ingredient is a food under section 201(f)(3) of the act.  Consequently,
a raw agricultural commodity that is a dietary ingredient is still
subject to the umbrella food CGMP requirements in part 110, and
activities such as drying, chopping, and cutting are what we have long
considered to be types of food processing.

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rvesting, sorting, packing, and distribution of fresh produce, and
contains principles that would apply to raw agricultural commodities,
such as herbs and botanicals.

	 As for the comment that would delete the word “solely” from
proposed § 111.6, we note that such a change is no longer necessary
since we are deleting § 111.6.  However, we caution that only those
persons or entities that manufacture or supply components that will be
further processed as a dietary supplement by others are not subject to
the final rule.  If you manufacture and sell dietary supplements, in
addition to supplying components to others, you would be subject to this
final rule under § 111.1(a).

	As for potential safety issues arising from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration, the final rule, at § 111.75,
describes criteria that enable a manufacturer of a dietary supplement to
rely on a certificate of analysis.  One criterion is that the
manufacturer must first qualify the firm providing the component by
establishing the reliability of the firm’s certificate of analysis
through confirmation of the results of the firm’s tests or
examinations.  Firms that improperly handle raw agricultural
commodities, such that the commodities that they provide are
adulterated, are not likely to be qualified as suppliers of those
commodities.

     In the future, we will consider the requests to develop guidance
for subsets of agricultural and post-harvest activities (such as for
hygienic practice for wildcrafters, identifying botanicals) associated
with dietary supplement manufacturing, along with other guidance we may
find useful as they relate to certain CGMP requirements for dietary
supplements.

 Throughout this final rule, we refer to the “manufacture” or
“manufacturing process” of dietary supplements.  We use these terms
in the broad sense, i.e., the terms refer to those activities that may
be done from receipt of raw ingredients through the distribution of a
finished dietary supplement, including labeling, packaging, and holding
activities.  We discuss the various roles and responsibilities of those
who “manufacture” dietary supplements in the context of final
§ 111.1 “Who is subject to these regulations?”  We also sometimes
use the terms to apply to only part of the process, i.e., those
operations other than labeling, packaging, and holding.

 Under section 402(f) of the act, a dietary supplement is deemed to be
adulterated if it is or contains a dietary ingredient that presents a
significant or unreasonable risk of illness or injury under conditions
of use recommended or suggested in labeling or, if no such conditions,
under ordinary conditions of use.

 Mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the “Dietary Supplement and
Non-Prescription Drug Consumer Protection Act” (Pub. L. 109-462)
signed into law on December 22, 2006. (See discussion in section XX).

 The Senate Report on DSHEA states that Congress inserted section 402(g)
because it recognized that “dietary supplements may require different
manufacturing and quality controls” when compared to food CGMP (S.
Rep. No. 140, 103rd Cong., 2d Sess., at 31 (1994)). However, the report
is not considered legislative history.  Congress issued a Statement of
Agreement (140 Cong. Rec. S14801 (Oct. 7, 1994), reprinted in 1994
U.S.C.C.A.N. 3523) that stated “it is the intent of the chief sponsors
of the bill . . . that no other reports or statements be considered as
legislative history for the bill”).

 Although the act does not define “current good manufacturing
practice,” the term is used elsewhere in the statute (see, e.g.,
sections 501(a)(2)(B) (drug CGMP) and 520(f)(1)(A) of the act (device
CGMP).  Case law supports the agency’s view that “current” does
not mean “actually prevailing manufacturing practice” in an industry
and that such a practice need not be accepted by a majority of
manufacturers (National Ass’n of Pharmaceutical Mfr’s v. Department
of Health and Human Services, 586 F. Supp. 740, 752 (S.D.N.Y. 1984)).
Nevertheless, the requirements of this final rule embody current
practices of many food and dietary supplement manufacturers, as
reflected in the comments supporting the provisions of the proposed
rule.

  It is also worth noting that standard references used in many
industries establish clear expectations for documentation and record
keeping practices for assuring quality control in manufacturing
operations. (Ref. 130);(Ref. 9).

 In discussing section 306 of the Bioterrorism Act (Maintenance and
Inspection of Records for Foods), Congress stated, “The managers did
not adopt a Senate proposal to authorize the Secretary to require the
maintenance and retention of other records for inspection relating to
food safety, because the Secretary has authority under section 701(a) of
the [act] to issue regulations for the ‘efficient enforcement of this
Act’ and this authority, in combination with other provisions (such as
section 402 [of the act]), gives the Secretary the authority to require
appropriate record keeping in food safety regulations.” (H.R. Conf.
Rep. No. 107-481, at 135 (2002), (Ref. 141))

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