XVIII.  Comments on Holding and Distributing

(Final Subpart M)

A.  Organization of Final Subpart M

    In the 2003 CGMP Proposal, the requirements for holding operations
were set forth in §§ 111.80, 111.82, and 111.83 in subpart F; the
requirements for distribution operations were set forth in proposed
§ 111.90 in subpart F.  As shown in table 14, the final rule moves the
requirements related to holding and distributing operations to a new
subpart (Final Subpart M - Holding and Distributing).  Table 14 lists
the sections in the final rule and identifies the sections that form the
basis of the final rule. 

Table 14. - Derivation of Sections in Final Subpart M

Final Rule	2003 CGMP Proposal

§ 111.453 What Are the Requirements Under this Subpart for Written
Procedures?

	N/A

§ 111.455  What Requirements Apply to Holding Components, Dietary
Supplements, Packaging, and Labels?	§ 111.80

§ 111.460 What Requirements Apply to Holding In-process Material?

	§ 111.82

§ 111.465 What Requirements Apply to Holding Reserve Samples of
Dietary Supplements?

	§ 111.83(b)(1) and (b)(2)

§ 111.470 What Requirements Apply to Distributing Dietary Supplements?
§ 111.90

§ 111.475 Under this Subpart, What Records Must You Make and Keep?	N/A



B.  Highlights of Changes to the Proposed Requirements 

for Holding and Distributing

1.   Revisions

	The final rule includes changes that reflect that the scope of the
final rule applies to persons who manufacture, package, label or hold
dietary supplements, unless subject to an exclusion in § 111.1.

2.  Changes Associated With the Reorganization

     Final § 111.465 in subpart M duplicates the requirement of final
§ 111.83(b)(3) to retain reserve samples of dietary supplements for
one year past the shelf life date (if shelf life dating is used) or for
three years from the date of distribution of the last batch of dietary
supplements associated with the reserve samples.  We are duplicating
this requirement in this subpart because we believe that it will be
useful to include the length of time that you must hold reserve samples
in each place of the codified where it is logical to look for this
information.

3.  Changes After Considering Comments

	The final rule:

●	Does not require that you collect reserve samples of components; 

●    Provides flexibility as to the container-closure system used to
hold reserve samples of dietary supplements;

●	Includes a new requirement for written procedures; and

●	Includes a new requirement to make and keep records of product
distribution and written procedures.

C.  General Comments on Proposed §§ 11.80, 111.82,

 111.83, and 111.85

     (Comment 306) One comment requests that factory sealed finished
products, which have been specifically manufactured to be held and
transported in a variety of conditions, be excluded from the
requirements for holding.  Another comment states that there are many
types of companies or individuals in the supply chain who may “hold”
a dietary supplement after final production, packaging, and labeling is
complete.  This comment seeks clarification that brokers, distributors,
or wholesalers would be subject only to the proposed requirements for
holding in proposed § 111.90.

     (Response) If you hold a dietary supplement, you are subject to all
applicable requirements of these CGMP regulations related to your
operation.  For example, if you are a wholesaler, you would be subject
to the requirements in final § 111.470 for the dietary supplements you
are holding for distribution as well as other applicable requirements,
such as those related to personnel, physical plant and grounds,
equipment and utensils, quality control, returned dietary supplements,
and product complaints.  We decline to list all of the requirements that
would be applicable because individual operations may vary.  However, we
provide the following examples of requirements that would, or would not,
apply in some specific circumstances.  For example, if the dietary
supplements that you hold require refrigeration, your refrigeration
equipment must comply with the requirements to be fitted with an
indicating thermometer, temperature-measuring device, or
temperature-recording device that shows the temperature accurately
within the compartment, and have an automated device for regulating
temperature or an automatic alarm system to indicate a significant
temperature change in a manual operation.  However, you would not be
required to establish specifications for the finished batch of the
dietary supplement, for product that is received for packaging or
labeling, or for packaged and labeled dietary supplements or to
determine whether such specifications are met if you only hold the
product and do not perform any other functions. 

_D. What Are the Requirements Under

This Subpart for Written Procedures?

 (Final § 111.453)

We received many comments that recommended written procedures for
various provisions.  We address the need for written procedures
generally in section IV.  We also respond to individual comments on
specific provisions in the same section.

We are including a new provision § 111.453 “What are the requirements
under this subpart for written procedures?” which requires you to
establish and follow written procedures for holding and distribution
operations. 

E.  What Requirements Apply to Holding Components, Dietary Supplements,
Packaging, and Labels? 

(Final § 111.455)

1.  Final § 111.455(a)

     Final § 111.455(a) requires you to hold components and dietary
supplements under appropriate conditions of temperature, humidity, and
light so that the identity, purity, strength, and composition of the
components and dietary supplements are not affected.  Final
§ 111.455(a) derives from proposed § 111.80(a) which would require
that you hold components, dietary ingredients, and dietary supplements
under appropriate conditions of temperature, humidity, and light so that
the identity, purity, quality, strength, and composition of the
components, dietary ingredients, and dietary supplements are not
affected. 

	We did not receive comments specific to proposed § 111.80(a).

2.  Final § 111.455(b)

     Final § 111.455(b) requires you to hold packaging and labels
under appropriate conditions so that the packaging and labels are not
adversely affected.  Final § 111.455(b) derives from proposed
§ 111.80(b) with modifications for consistency with other provisions
addressing packaging and labels.  

     We did not receive comments specific to proposed § 111.80(b).

3.  Final § 111.455(c)

     Final § 111.455(c) requires you to hold components, dietary
supplements, packaging, and labels under conditions that do not lead to
the mixup, contamination, or deterioration of components, dietary
supplements, packaging, and labels.  Final § 111.455(c) derives from
proposed § 111.80(c).

     We did not receive comments specific to proposed § 111.80(c).

F.  What Requirements Apply to Holding In-process Material?   (Final
§ 111.460)

1.  Final § 111.460(a)

     Final § 111.460(a) requires you to identify and hold in-process
material under conditions that protect against mix-ups, contamination,
and deterioration.  Final § 111.460(a) is similar to § 111.82(a)
with a grammatical change (i.e., a change from “that will protect
them” to “that protect”).

     We did not receive comments specific to proposed § 111.82(a).

2.  Final § 111.460(b)

     Final § 111.460(b) requires you to hold in-process material under
appropriate conditions of temperature, humidity, and light.  Final
§ 111.460(b) is identical to proposed § 111.82(b).

	(Comment 307)  One comment asserts it would be impractical,
unnecessary, and extremely burdensome to maintain reserve samples of
in-process materials.  The comment asserts that collecting and holding
samples of in-process materials would duplicate the requirement to
collect and hold reserve samples of finished dietary supplements and
require significant additional documentation, time, and storage space.

     (Response) This comment may have misinterpreted proposed
§ 111.37(b)(11) (final §111.80(g)) which included requirements for
collecting representative, rather than reserve, samples of in-process
materials.  The representative sample is used for those tests or
examinations conducted to determine whether the batch meets
specifications.  A representative sample is held for only a short period
of time - i.e., the time between the collection and the test or
examination.  Neither the 2003 CGMP Proposal nor this final rule
includes a requirement to maintain a reserve sample of in-process
materials. 

G.  Proposed Requirement for Holding 

Reserve Samples of Components 

(Proposed § 111.83(a))

     Proposed § 111.83(a) would require you to hold any collected
reserve samples of components or dietary ingredients in a manner that
protects against contamination and deterioration. 

     (Comment 308)  One comment requests the final rule not require that
manufacturers of dietary supplements collect and hold reserve samples of
components.  The comment asserts that all components can be traced back
to their source (i.e, the vendor or manufacturer of the material) for a
more in-depth investigation if a dietary supplement comes under
investigation due to a product complaint.

     (Response)  We agree with this comment.  Therefore, the final rule
contains no requirement for holding reserve samples of components, only
finished dietary supplements, and, thus, proposed § 111.83(a) has no
counterpart in the final rule.

H.  What Requirements Apply to Holding Reserve Samples of Dietary
Supplements? 

 (Final § 111.465)

1.  Final § 111.465(a)

     Final § 111.465(a) requires you to hold reserve samples of
dietary supplements in a manner that protects against contamination and
deterioration.  Under final § 111.465(a)(1) this includes holding the
reserve sample under conditions consistent with product labels or, if no
storage conditions are recommended on the label, under ordinary storage
conditions.  Final § 111.465(a)(1) derives from proposed
§ 111.83(b)(1) which would require you to hold reserve samples under
conditions of use recommended or suggested in the label of the dietary
supplement and, if no conditions of use are recommended or suggested in
the label, then under ordinary conditions of use.

     Final § 111.465(a)(1) refers to “conditions consistent with
product labels” rather than to “conditions of use recommended or
suggested in the label of the dietary supplement” and refers to
“storage conditions” rather than “conditions of use.”  This
change is to reflect that the “conditions of use” referenced in the
2003 CGMP Proposal referred to the typical storage of the dietary
supplement and not the consumption of the product by the consumer.

     We did not receive comments specific to proposed § 111.83(b)(1).

     Under final § 111.465(a)(2) the manner in which you hold reserve
samples of dietary supplements includes using the same container-closure
system in which the packaged and labeled dietary supplement is
distributed, or if distributing dietary supplements to be packaged and
labeled, using a container-closure system that provides essentially the
same characteristics to protect against contamination or deterioration
as the one in which you distribute the dietary supplement for packaging
and labeling elsewhere.  Final § 111.465(a)(2) derives from proposed
§ 111.83(b)(2) which would require that the manner in which you hold
reserve samples of dietary supplements include using the same
container-closure system in which the dietary supplement is marketed or
in one that provides the same level of protection against contamination
or deterioration.  

       (Comment  309) One comment states a substantial amount of its
product is shipped in bulk for packaging elsewhere.  As a result, one
often does not know the packaging being used to market the dietary
supplement or how the packaged product is being stored.  This comment
recommends we revise the proposed regulation to require using the same
container-closure system in which the dietary supplement is marketed
“if known and if not in a typical market container-closure system.”

     (Response) We acknowledge that some manufacturers of dietary
supplements will distribute product in bulk and will not know the
packaging used to market the dietary supplement.  In addition, if you
ship products in bulk, any commitment you make to your customer about
the quality of the product you shipped would relate to the container you
used to ship the bulk product.  To address these points we provide in
final § 111.465(a)(2) that you have the flexibility to use a
container-closure system that provides essentially the same
characteristics to protect against contamination or deterioration as the
one in which it is distributed for packaging and labeling elsewhere. 
For example, if you distribute product in bulk using a polyethylene
bottle that can hold 50 kilograms (kg) of the product, and there is an
air space above the product, you would hold the reserve samples in a
polyethylene bottle with an air space.  However, you would use a bottle
that is sized to fit the amount that you are holding in reserve.

2.  Final § 111.465(b)

     Final § 111.465(b) requires you to retain reserve samples for one
year past the shelf life date (if shelf life dating is used), or for 3
years from the date of distribution of the last batch of dietary
supplements associated with the reserve samples, for use in appropriate
investigations.  Final § 111.465(b) derives from proposed
§ 111.37(b)(12), which proposed, in part, that you must keep reserve
samples for three years from the date of manufacture.  Proposed
§ 111.37(b)(12) is now final § 111.83(b)(3) with changes that we are
making consistent with comments that requested that the time frame for
retaining reserve samples be linked to a shelf life date (or other form
of expiration dating) when such a date is established.  We discuss the
reasons for the change from “date of manufacture” to “the date of
distribution” in section XXI.  In essence, final § 111.465(b)
duplicates final § 111.83(b)(3) because we believe it will be useful
to include the length of time you must hold reserve samples in each
place in the codified where it is logical to look for this information.

I.  What Requirements Apply to Distributing Dietary Supplements?  (Final
§ 111.470)

     Final § 111.470 requires you to distribute dietary supplements
under conditions that will protect the dietary supplements against
contamination and deterioration.  Final § 111.470 derives from
proposed § 111.90. 

     We did not receive comments specific to proposed § 111.90.

J.  Under this Subpart, What Records Must You Make and Keep? (Final
§ 111.475)

     In the 2003 CGMP Proposal, we invited comment on whether we should
require you to make and keep records on the distribution of dietary
supplements that you manufacture, package, or hold.  

     (Comment  310) Some comments assert that written records of product
distribution would provide the ability to trace the shipment of each
finished batch in the event of a product recall.  One comment expresses
the view that the ability to quickly and efficiently recall a product is
an important safeguard in ensuring public health in the event of a
serious problem.  Another comment points out that the scope of recall
would likely be much broader if records of product distribution were not
available to pinpoint distribution.

     (Response) We agree with these comments.  Therefore, final §
111.475 requires you to make and keep records of product distribution in
accordance with subpart P.  In addition, we are adding a provision to
complement final § 111.453 to ensure that records are maintained of the
written procedures you establish for holding and distributing
operations.  As discussed, comments stressed that such procedures must
be available to us during the course of an inspection.

     (Comment 311) One comment asserts that the final rule should not
include a requirement for records of product distribution, because such
records are already common industry practice.  This comment also points
out that neither the food CGMPs in part 110 nor the agency’s 1997
ANPRM have requirements for records of product distribution.

     (Response ) To the extent that the comment asserts that a practice
that is a common industry practice should not be a requirement in the
final rule, we disagree.  CGMP includes those practices that may be
commonly used in industry.  In fact, the reason that such practices may
be common in industry is because they are already considered to be CGMP.
 As we noted in the preamble to the 2003 CGMP Proposal (68 FR 12157 at
12221), however, not all dietary supplement establishments follow CGMP
and, therefore, may not be keeping records of product distribution. 
Thus, in this final rule we do not exclude practices we consider to be
CGMP and already may be used by some in industry.  

 

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Therefore, we disagree that the 1997 ANPRM did not suggest a requirement
to make and retain records of product distribution.

HHS/FDA-Internal-Confidential-Deliberative

Final Subpart M 9-28-05

Page   PAGE  877 

