Document ID: FDA-1996-N-0028-0060
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-01T04:00Z

XII.  Comments on the Production and Process Control System: 

Requirements for Components, Packaging, and Labels, and 

for Product that You Receive for

Packaging or Labeling as a Dietary Supplement

(Final Subpart G)

A.  Organization of Final Subpart G

     In the 2003 CGMP Proposal, the requirements for production and
process controls related to components, packaging, dietary ingredients,
labels, and dietary supplements that you receive were set forth in
proposed § 111.40.  As shown in table 8, we are reorganizing the
requirements related to components, packaging, labels, and product that
you receive for packaging and labeling as a dietary supplement, into a
distinct subpart (final Subpart G - Production and Process Control
System: Requirements for Components, Packaging, and Labels, and for
Product that You Receive for Packaging or Labeling as a Dietary
Supplement).  Table 8 lists the sections in final subpart G and
identifies the sections in the 2003 CGMP Proposal that form the basis of
the final rule.

Table 8. - Derivation of Sections in Final Subpart G

Final Rule 	2003 CGMP Proposal

§ 111.153  What Are the Requirements Under this Subpart for Written
Procedures?	N/A

§ 111.155 What Requirements Apply to Components of Dietary Supplements?
§ 111.40(a)(1) through (a)(5)

§ 111.35(d)(1)-(5)

§ 111.160 What Requirements Apply to Packaging and Labels Received?	§
111.35(e)(4)

§ 111.40(a)(2)

§ 111.40(b)

§ 111.165 What Requirements Apply to a Product Received for Packaging
or Labeling as a Dietary Supplement (and for Distribution Rather Than
for Return to the Supplier)? 	§ 111.40(a)

§ 111.170 What Requirements Apply to Rejected Components, Packaging,
and Labels, and to Rejected Products That are Received for Packaging or
Labeling as a Dietary Supplement?	§ 111.74

§ 111.180 Under this Subpart, What Records Must You Make and Keep?	§
111.40(c)(1)(i) through (c)(1)(iv)

§ 111.40(c)(2) 

§ 111.35(d)(4)

B.  Highlights of Changes to the Proposed Requirements for 

Components, Packaging, and Labels, and 

Product That You Receive 

for Packaging or Labeling as a Dietary Supplement

1.   Revisions

	The final rule:

●	Applies to persons who manufacture, package, label, or hold a
dietary supplement unless subject to an exclusion in § 111.1.

●	Includes requirements that apply to components, including components
that are dietary ingredients, regardless of whether you receive the
components or manufacture them yourself (final §§ 111.70(b) and
111.75(a)).  

●	Separates the requirements for product you receive from a supplier
for packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier)(final § 111.165) from the
requirements for components (final § 111.155).

	2. Changes After Considering Comments

	The final rule:

•	Incorporates a new requirement to establish and follow written
procedures for fulfilling the requirements for components, packaging,
labels, and product you receive from a supplier for packaging or
labeling as a dietary supplement for distribution rather than for return
to the supplier.

C.  General Comments on Proposed § 111.40

(Final Subpart G)

	(Comment 236) One comment states that many companies use an electronic
material resource planning system to control the status of inventory,
and assert this type of system provides suitable controls to ensure only
materials that are approved by the quality control unit are used.  The
comment notes only the quality control unit has the authority to release
any material on quarantine and asks whether such a system would comply
with the requirements of the proposed regulation.

     (Response) Based on the limited information provided by the
comment, it appears the electronic inventory system that the comment
describes would comply with the requirements of final § 111.155(c)(3)
to quarantine components until the quality control personnelunit
releases them for use in manufacture, provided that appropriate controls
are established and used to ensure the system functions in accordance
with its intended use as required by final § 111.30(e).  We are making
no changes based on this comment.

D.  What Are the Requirements Under This Subpart for Written Procedures?

 (Final § 111.153)

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.

	Final § 111.153 requires you to establish and follow written
procedures for fulfilling the requirements of Subpart G.  Under final §
111.180(b)(1), as a conforming requirement, we require you to make and
keep records of such written procedures.  Such records would be
available to us under the requirements in subpart P, Records and
Recordkeeping. 

E.  What Requirements Apply to Components 

of Dietary Supplements?

(Final § 111.155)

     The final rule applies only to persons who manufacture, package,
label, or hold dietary supplements unless subject to an exclusion under
final § 111.1.  The effect of this revision is that the requirements
that derive from proposed § 111.40(a) for components you receive now
apply to all components, whether you receive them or manufacture them
yourself.  

	The final rule separates the requirements for product you receive from
a supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier)(final § 111.165)
from the analogous requirements for components, packaging, and labels
(final § 111.155).  

1. Proposed § 111.35(d)

	In proposed § 111.35(d), we would require that any substance, other
than a “dietary ingredient” within the meaning of section 201(ff) of
the act, that is subject to section 409 of the act, be: (1) Authorized
for use as a food additive under section 409 of the act; or (2)
authorized by a prior sanction consistent with § 170.3(l); or (3) if
used as a color additive, subject to a listing that, by the terms of
that listing (including a listing for use in coloring foods generally),
includes the use in a dietary supplement; or (4) GRAS for use in a
dietary supplement.  We also proposed that any claim that a substance is
GRAS must be supported by a citation to the agency’s regulations or by
an explanation for why there is general recognition of safety of the use
of the substance in a dietary supplement.  Further, under
§ 111.35(d)(5), we proposed to require that you comply with all other
applicable statutory and regulatory requirements under the act.  

     We received several comments objecting to one or more of the
provisions of proposed § 111.35(d) and to our statement in the preamble
to the 2003 CGMP Proposal regarding how we would apply the provisions of
proposed § 111.35(d)(4).  After considering these comments, we have
deleted the requirements in § 111.35(d) in this final rule. 

(Comment 237)  Several comments recommend proposed § 111.35(d) be
deleted because the statute already requires that ingredients, other
than “dietary ingredients,” be approved as a food additive or a
color additive, or be GRAS.  Some comments assert that proposed
§ 111.35(d) and proposed § 111.5 already require compliance with all
other applicable statutory and regulatory requirements under the act,
and therefore, there is no need to refer to food additive, color
additive, and GRAS requirements.  Some comments assert that proposed
§ 111.35(d) is unnecessary because there is no such requirement in the
food CGMPs.  Other comments assert this proposed requirement should be
deleted because it is only tangentially related to the manufacturing
process, and CGMP should be focused on setting minimum standards for
manufacturing systems and steps in the production and distribution of
dietary supplements that are required to produce safe and accurately
labeled products.  Other comments assert that because the drug CGMPs do
not have such a requirement, dietary supplement CGMPs should not have
such a requirement.

Other comments did not object to the principle underlying proposed
§ 111.35(d), i.e., that we need to ensure GRAS substances used in
dietary supplements are GRAS under the manufacturer's specified use. 
However many comments disagreed, for various reasons, with the proposed
requirement in § 111.35(d)(4) that a claim that a substance is GRAS
must be supported by a citation to our regulations or by an explanation
for why there is general recognition of safety of the use of the
substance in a dietary supplement.  

	(Response)  We agree that proposed § 111.35(d) is unnecessary because
there are already existing statutory and regulatory requirements related
to the lawful use of ingredients used in dietary supplements.  We do not
have to repeat those requirements in this final rule.  Ensuring the
ingredients you use to manufacture a dietary supplement are lawful under
the applicable statutory and regulatory requirements is the
responsibility of the dietary supplement manufacturer.  

For the reasons set forth above, we are deleting proposed
§ 111.35(d)(4) from the final rule.  Because we are deleting this
provision, it is unnecessary to respond to the various comments related
to the documentation that proposed § 111.35(d)(4) would have required,
or whether we could not have included such requirements in the dietary
supplement CGMP final rule because the requirements are not in food or
drug CGMP regulations.  

We also agree that proposed § 111.35(d)(5) is redundant with § 111.5
and are therefore deleting § 111.35(d)(5) from the final rule. 

	Although we are deleting § 111.35(d) from the final rule, there were
several comments that we received, and respond to below, that seemed to
question whether existing statutory and regulatory requirements apply to
the use of ingredients in a dietary supplement.  

	(Comment 238) One comment suggests components not found in finished
goods in a material amount should not be subject to the same GRAS
requirements as those found in a material amount.  Another comment
states dietary supplements are excluded from the food additive
definition in section 201(s) of the act, and that components that
constitute the dietary supplement are also excluded from the food
additive definition.  The comment suggests that, under proposed
§ 111.35(d), we are erroneously trying to maintain food additive
authority for dietary supplements.  

(Response) The assertion that dietary supplements and all of their
components are not subject to the food additive provisions of the
act’s definition is incorrect.  We do maintain authority over the use
of certain substances, as color additives, food additives, or GRAS
substances that may be used in manufacturing dietary supplements.

	The food additive definition in section 201(s) of the act excludes
“an ingredient described in paragraph (ff) in, or intended for use in,
a dietary supplement.”  Thus, a “dietary ingredient” described in
section 201(ff)(1) of the act is not a “food additive.”  Nor can the
use of a dietary ingredient be considered to be GRAS, since the GRAS
status itself is an exception to the definition of a food additive. 
However, ingredients that may be used in a dietary supplement, other
than those excepted in section 201(s), are subject to our regulatory
authority as a food additive, unless their use is GRAS or authorized by
a prior sanction.  Thus, it is incorrect to say, as the comment asserts,
that dietary supplements and all of their components are not subject to
the food additive definition.  

	We also disagree that components not found in finished goods in a
material amount should not be subject to the same GRAS requirements as
those found in a material amount.  It is not clear what the comment
meant by “material amount.”  A substance that is subject to FDA’s
authority as a food additive is one the intended use of which results or
may reasonably be expected to result, directly or indirectly, in its
becoming a component of a food or that otherwise affects the
characteristics of any food, if the use of such substance is not GRAS. 
We have discretion to determine whether an ingredient is one where the
agency would find the presence to be “de minimis” (Monsanto v.
Kennedy, 613 F.2d 947, 956 (D.C. Cir. 1979).  However, whether the
agency would find it appropriate to exercise such discretion with
respect to the use of a particular ingredient is beyond the scope of
this final rule.  

 (Comment 239)  Several comments questioned whether certain ingredients
would be considered GRAS.  One comment stated excipients regularly used
in pharmaceuticals for many years and safely used in dietary supplements
may not be considered GRAS for use in foods, approved for use as a food
additive, or considered a dietary ingredient.  An example provided was
“croscarmellose sodium” used for disintegration.  The comment asks
permission to use any recognized excipient, an excipient that is
monographed in a recognized compendium, used in drug products, or shown
to be in use prior to the implementation of the final rule.  Other
comments stated proposed § 111.35(d) would be overly burdensome since
many ingredients are GRAS for broad food use, have been used in dietary
supplements without specific recognition as a GRAS use, and should be
permitted.  Other comments state substances listed in the USP National
Formulary, Food Chemical Codex, the American Pharmaceutical Associations
Handbook of Pharmaceutical Excipients, and FDA’s inactive ingredient
guide are considered GRAS based on a history of common use even though
there is no listing of these substances as GRAS.  

(Response)  The GRAS status of specific uses of excipients cannot be
treated as a general class and is beyond the scope of this final rule. 
It is possible that the data needed to support safe uses as an excipient
in a drug may be widely known among experts and form a basis for a
consensus that use in a dietary supplement is safe.  However, use of
drugs containing the excipient may be short term or may be intermittent,
leading to far less exposure than routine use in some dietary
supplements.  As human exposure increases, not only does the safety
profile of the intended excipient become more important, but the purity
specifications also become more critical.  We advise persons who need
more information about the basis for concluding that a use of a
substance is GRAS to consult § 170.30 and our 2003 CGMP GRAS Proposal
to establish a notification program for the use of GRAS substances (62
FR 18937, April 17, 1997).  

(Comment 240)  Some comments assert it is not feasible to require that
starting materials used by bulk ingredient manufacturers be GRAS or
approved food additives.  The comments state many ingredients are not
food grade substances or approved for use in food until after
processing.  One comment states raw materials may become dietary
ingredients after processing, but the materials from which the dietary
ingredient is derived are not considered to be a GRAS ingredient, a
dietary ingredient, or a dietary supplement.  The comment gives examples
of Ginkgo biloba leaves or Saw palmetto or cartilage.  The comment asks
us to consider natural products (from animal, mineral, or vegetable
origin) to be included in the rule as potential raw materials for
nutritional supplements.  Another comment expresses concern that a soy
isolate, from which natural vitamin E is derived, would not be
considered a GRAS substance.  

(Response)  These comments seem to be concerned about the regulatory
status of substances used as raw materials in the manufacture of a
dietary ingredient or dietary supplement.  An important consideration,
however, is whether such materials become a component of the dietary
ingredient or dietary supplement.  

Dietary ingredient manufacturers who manufacture dietary ingredients for
further processing by another person into a dietary supplement are
outside the scope of this final rule.  However, such manufacturers are
still subject to other applicable statutory and regulatory provisions. 
For example, if you are a dietary ingredient manufacturer that uses a
material in the manufacture of a dietary ingredient, and the material
becomes part of the dietary ingredient, we would consider it to be part
of the dietary ingredient and subject to the exception to the food
additive definition in section 201(s)(6) of the act.  However, because
the material becomes a component of the dietary ingredient, you are
subject to the applicable statutory and regulatory requirements that
would apply to the dietary ingredient, including the safety of the
dietary ingredient.  

	If you use a material, other than a dietary ingredient, in the
manufacture of a dietary supplement, that becomes a part of the dietary
supplement, you are subject to the applicable statutory and regulatory
requirements that apply to the use of such material, including its
safety for such use.  In this case, the use of the material would be
subject to regulation as a  food additive (unless it is GRAS or
prior-sanctioned).  

Alternatively, if you use material in the manufacture of a dietary
ingredient or a dietary supplement that does not become part of the
dietary ingredient or dietary supplement, then we would not consider the
material to be a food. 

     (Comment 241) Several comments state the color additive provision
would be too restrictive if it only allowed colors listed for use in a
dietary supplement, rather than colors listed for use in foods
generally.  Some comments note none of the color additives currently
approved generally for “food” use is approved specifically for
dietary supplements within the food category.  Another comment argues we
gave no rationale for requiring a categorical listing under specific
color additives for dietary supplements.  The comment states color
additives are not used in any greater amount in supplements than in
foods and, if anything, are probably used less because supplements are
consumed in smaller amounts than foods and less color additive must be
used to achieve the desired effect.  One comment notes it was not
familiar with any evidence to indicate that a color additive (whether it
is certified or exempt) found by us to be safe for use in foods is not
safe in dietary supplements. 

     (Response) We acknowledge that the combination of proposed §
111.35(d)(3) and several color additive listings is confusing and could
lead to incorrect conclusions about whether specific color additives may
lawfully be used in a dietary supplement.  As the comments point out,
some listings for color additives (such as for the certified colors FD&C
Blue No. 1 (§ 74.101) and FD&C Red No. 40 (§ 74.340)) list the color
additive “for coloring foods (including dietary supplements)
generally” - i.e., the listings specifically identify dietary
supplements as a food category in which the color additive may be used. 
In contrast, some listings for color additives (such as for annatto
extract (§ 73.30) and for beta-carotene (§ 73.95)) list the color
additive “for coloring foods generally” - i.e., without specifically
identifying dietary supplements as a food category in which the color
additive may be used.  In general, the terms of either of these two
kinds of listings (i.e., “for coloring foods (including dietary
supplements) generally” and “for coloring foods generally” mean we
saw no need for restriction of the use of the color additive when FDA
approved the listing of that color additive.  Thus, a color additive
listed for use in food generally may be used in a dietary supplement. 

     Although most listings of color additives provide for the use of
the color additive in food generally, some listings for color additives
restrict the use of the color additive in terms of the food category in
which it may be used.  For example, under § 73.125 sodium copper
chlorophyllin may be safely used to color citrus-based dry beverage
mixes in an amount not exceeding 0.2 percent in the dry mix, and the
terms of this listing would not include the use in a dietary supplement.
 We list a color additive with restrictions such as these when for
example, the person who submits a petition for us to approve the listing
of a color additive only requests a specific use, or when the available
data and information only support the safety of a limited consumption of
the color additive.

2.  Final § 111.155(a)

     Final § 111.155(a) (proposed § 111.40(a)(1)) requires you to
visually examine each immediate container or grouping of immediate
containers in a shipment you receive for appropriate content label,
container damage, or broken seals to determine whether the container
condition may have resulted in contamination or deterioration of the
components.  Final § 111.155(a) is substantially similar to proposed §
111.40(a)(1) which would require you, for components you receive, to
visually examine each container or grouping of containers in a shipment
for appropriate content label, container damage, or broken seals to
determine whether the container condition has resulted in contamination
or deterioration of the components.  Because you do not receive
shipments for components you make, we are revising proposed § 111.40(a)
so that it applies only to shipments of components you receive.  We have
added the word “immediate” to identify the container as the one in
contact with the dietary supplement or component.  We also have changed
“has resulted” to “may have resulted” since in some cases you
may not be able to make a final determination from a visual inspection
alone whether the container condition has resulted in contamination or
deterioration of the components. 

     (Comment 242) One comment supports the proposed requirements of
proposed § 111.40(a) as an effective guideline for the inspection of
purchased ingredients.  

     (Response)  The provisions of final § 111.155(a) are
requirements, not guidelines, as stated by the comment.

3.  Final § 111.155(b)

     Final § 111.155(b) (proposed § 111.40(a)(2)) requires you to
visually examine the supplier’s invoice, guarantee, or certification
in a shipment you receive to ensure that the components are consistent
with your purchase order.  Final § 111.155(b) is substantially similar
to proposed § 111.40(a)(2) which would require you to visually examine
the supplier’s invoice, guarantee, or certification to ensure the
components are consistent with your purchase order and perform testing,
as needed, to determine whether specifications are met.  As with final
§ 111.155(a), final § 111.155(b) clarifies that the invoice,
guarantee, or certification comes in the shipment you receive.

	Final § 111.155(b) does not include any requirements related to
testing components.  Final § 111.75(a) sets forth the requirements to
test or examine components; final §§ 111.110 and 111.120 set forth
requirements for the quality control personnelunit to ensure that
appropriate tests or examinations are conducted; review the results of
any tests or examination;, determine whether components conform to
specifications; and approve the components before they are used in the
manufacture of a dietary supplement.  Given this set of requirements, it
would be redundant to set forth requirements regarding testing for
components in final subpart G.

     We did not receive comments specific to the requirements of
proposed § 111.40(a)(2).   

4.  Final § 111.155(c)

     Final § 111.155(c) (proposed § 111.40(a)(3)) requires you to
quarantine components before you use them in the manufacture of a
dietary supplement until: 

(1) You collect representative samples of each unique lot of components
(and, for components that you receive, of each unique shipment, and of
each unique lot within each unique shipment); 

(2) The qQuality control personnelunit reviews and approves the results
of any test or examinations conducted on components; and 

(3) The qQuality control personnelunit approves the components for use
in the manufacture of a dietary supplement, including approval of any
treatment (including in-process adjustments) of components to make them
suitable for use in the manufacture of a dietary supplement, and
releases them from quarantine.  

     Final § 111.155 modifies proposed § 111.40(a)(3) which would
require: 

•	You to quarantine components until your quality control unit reviews
the supplier’s invoice, guarantee, or certification;

• 	The quality control unit to perform testing, as needed, of a
representative sample to determine that specifications are met; 

• 	You to conduct a material review and make a disposition decision if
specifications are not met; and

• 	The quality control unit to approve and release the components from
quarantine before you use them.

     Final § 111.155(c) includes revisions related to the following
changes to other provisions already discussed. 

•	Under final § 111.110 the quality control personnelunit ensures
that all appropriate tests and examinations are conducted, and reviews
and approves the results of tests and examinations conducted on
components, but the quality control personnelunit is are not required to
conduct the tests or examinations; 

•	Under final § 111.80(a) we establish the convention in this final
rule of referring to “each unique lot within each unique shipment”
rather than “each shipment lot.” 

•	The requirements to conduct a material review and make a disposition
decision are already set forth in final §§ 111.87, 111.113, and
111.120 and, therefore, are not repeated in final § 111.155; and

•	Under final § 111.90(c) any batch of dietary supplement that is
reprocessed, that contains components that you have treated, or to which
you have made in-process adjustments to make them suitable for use in
the manufacture of the dietary supplement, must meet all product
specifications for the dietary supplement and be approved by the quality
control personnelunit before being released for distribution.

	(Comment 243) Some comments address the requirement to quarantine
components before you use them and assert that it is not feasible to
quarantine incoming materials in a continuous extraction and
purification operation, such as one built adjacent to a soy crushing or
vegetable oil refinery to receive a continuous side stream flow from
that operation.  One comment explains that in such operations,
quarantine and quality control approval occurs later in the process
after the material has been isolated and concentrated in a stable matrix
suitable for holding.  One comment suggests proposed § 111.40(a)(3)
state “quarantine components or dietary supplements as
applicable...”.  

     (Response) We decline to revise proposed § 111.40(a)(3) as
suggested by the comments.  The comment describes a situation where a
manufacturer of a dietary supplement is also manufacturing a dietary
ingredient or other component but only provides limited information.  It
appears that, however, the procedures described for quarantine of the
isolated, stable matrix, with subsequent evaluation by the quality
control personnelunit before release for use in the manufacture of the
dietary supplement, would satisfy the requirements of final §
111.155(c), provided the quality control personnelunit is are able to
determine that all specifications for the component are met.

     (Comment 244) One comment states that plant personnel who are not
formally part of the manufacturer’s quality control unit can conduct
the quality control functions required for the release of materials from
quarantine before use.  

     (Response) As already discussed with respect to the definition of
the quality control personnel unit (see section VI), these comments may
have misunderstood the role of the quality control unit (now quality
control personnel).  To clarify that role, final § 111.12(b) states you
must identify a qualified person who is responsible for your quality
control operations.  

	(Comment 245) One comment suggests components that cannot be used in a
short time should be retested at least yearly. 

     (Response) We are making no changes to the provision after
considering this comment.  Whether any tests or examinations must be
repeated over time, or whether the information in a certificate of
analysis remains valid over time, is a matter to be decided by the
manufacturer based on the established characteristics and shelf life of
the component.

5.  Final § 111.155(d)

     Final § 111.155(d)(1) (proposed § 111.40(a)(4)) requires you to
identify each unique lot within each unique shipment of components you
receive and any lot of components that you produce in a manner that
allows you to trace the lot to the supplier, the date received, the name
of the component, the status of the component (e.g., quarantined,
approved, or rejected), and to the dietary supplement you manufactured
and distributed.  Final § 111.155(d)(2) requires you to use this unique
identifier whenever you record the disposition of each unique lot within
each unique shipment of components that you receive and any lot of
components that you produce.

     Final § 111.155(d)(1) and (2) are substantially similar to
proposed § 111.40(a)(4) which would require you to identify each lot of
components in a shipment in a manner that allows you to trace the
shipment to the supplier, the date received, the name of the component,
and the status (e.g., quarantined, approved, or rejected), and to trace
the shipment lot to the dietary supplement you manufactured and
distributed.  Proposed § 111.40(a)(4) also would require you to use
this unique identifier whenever you record the disposition of each
shipment lot received. 

     Final § 111.155(d)(1) and (2) include revisions associated with
final § 111.80(a). 

     We did not receive comments specific to proposed § 111.40(a)(4).

6.  Final § 111.155(e)

     Final § 111.155(e)(proposed § 111.40(a)(5)) requires you to hold
components under conditions that will protect against contamination and
deterioration and avoid mixups.  

	We did not receive comments specific to proposed § 111.40(a)(5).

F.  What Requirements Apply to Packaging and Labels Received?

(Final § 111.160)

1.  Final § 111.160(a)

     Final § 111.160(a) (proposed § 111.40(b)(1)) requires you to
visually examine each immediate container or grouping of immediate
containers in a shipment for appropriate content label, container
damage, or broken seals to determine whether the container condition may
have resulted in contamination or deterioration of the packaging and
labels.  Final § 111.160(a) is similar to proposed § 111.40(b)(1) with
the addition of the word “immediate” to identify the container as
the container that is in contact with the packaging or labels and
substituting “may have” for “has” before the word “resulted”
as discussed in this section. 

      We did not receive comments specific to proposed § 111.40(b)(1).

2.  Final § 111.160(b) 

     Final § 111.160(b) requires you to visually examine the
supplier’s invoice, guarantee, or certification in a shipment to
ensure the packaging or labels are consistent with your purchase order. 
Final § 111.160(b) is a new requirement that is analogous to proposed
§ 111.40(a)(2).  We are requiring in final § 111.160(b), that, as
part of your visual identification, you compare what was received, based
on the supplier’s invoice, guarantee, or certification, with your
purchase order so you can ensure your specifications for packaging and
labels are met.  This is consistent with what you would do with respect
to components and dietary supplements you receive.  Without final §
111.160(b), the review by the quality control personnelunit under final
§ 111.120(a) would be a matter of performing receiving operations
rather than performing quality control operations; as already discussed
in this section, some comments asserted the quality control unit should
focus on reviewing the work of others rather than conducting the
operations themselves.  Thus, final § 111.160 is consistent with these
comments.

3.  Final § 111.160(c)

     Final § 111.160(c) requires you to quarantine packaging and labels
before you use them in the manufacture of a dietary supplement until: 

(1) You collect representative samples of each unique shipment, and of
each unique lot within each unique shipment, of packaging and labels
and, at a minimum, conduct a visual identification of the immediate
containers and closures; 

(2) The qQuality control personnelunit reviews and approves the results
of any tests or examinations conducted on the packaging and labels; and 

(3) The qQuality control personnelunit approves the packaging and labels
for use in the manufacture of a dietary supplement and releases them
from quarantine.

     Final § 111.160(c) is similar to proposed § 111.40(b)(2)which
would require that:

• 	You quarantine packaging and labels until your quality control unit
tests or examines a representative sample to determine that
specifications are met; 

• 	You conduct at least a visual identification of the containers and
closures; 

• 	If specifications are not met, you conduct a material review and
make a disposition decision; and

•  	Your quality control unit approve and release packaging and labels
from quarantine before you use them.

     Final § 111.160(c) includes revisions that reflect the following
change already discussed in this final rule: 

•    Referring to “each unique lot within each unique shipment”
rather than “each shipment lot;”

     We did not receive comments specific to proposed § 111.40(b)(2).

4.  Final  § 111.160(d)

     Final § 111.160(d)(1) requires you to identify each unique lot
within each unique shipment of packaging and labels in a manner that
allows you to trace the lot to the supplier, the date received, the name
of the packaging and label, the status of the packaging and label (e.g.,
quarantined, approved, or rejected), and to the dietary supplement you
distributed.  Final § 111.160(d)(2) requires you to use this unique
identifier whenever you record the disposition of each unique lot within
each unique shipment of packaging and labels.  Final § 111.160(d)
derives from proposed § 111.40(b)(3) which would require you to
identify each shipment lot of packaging and labels in a manner that
allows you to trace the shipment lot to the supplier, the date received,
the name of the packaging and label and the status (e.g., quarantined,
approved, or rejected) and to trace the shipment lot to the dietary
supplement manufactured and distributed.  Proposed § 111.40(b)(3) also
would require that you use this unique identifier whenever you record
the disposition of each shipment lot received.

     Final § 111.160(d) includes revisions that reflect the following
changes already discussed in this final rule:  

•    Reference to “each unique lot within each unique shipment”
rather than “each shipment lot.” 

•    As a clarification, final § 111.160(d)(2) refers to the
“dietary supplement that you distributed” rather than to the
“dietary supplement manufactured and distributed” to avoid a narrow
- and incorrect - interpretation of “manufactured.”  Under proposed
§ 111.40(b)(3) we used the term “manufactured” in a broad sense
that includes any aspect of the manufacturing process rather than a
narrow sense that applied to manufacturing operations for producing a
batch of dietary supplement.  Both proposed § 111.40(b)(3) and final §
111.160(e) address the need to trace the packaging and labels that you
use to the product that you distribute, regardless of whether your role
in the manufacturing process includes the production of the batch or
includes only packaging a dietary supplement you receive from a
supplier.

	(Comment 246) One comment believes packaging and labels are rarely the
source of quality problems.  This comment suggests proposed §
111.40(b)(3) allow the use of packaging approved by the quality control
unit without the need to use a specific lot identification number.  The
comment explains that this type of flexibility is needed when they have
dozens of short run lots each day and use less than a carton of
packaging supplies for each run.

     (Response) This comment may have misinterpreted proposed §
111.40(b)(3).  Under proposed § 111.40(b)(3) (final § 111.160(d)) you
must assign the identifier to each unique lot within each unique
shipment of packaging and labels when you receive them rather than each
time that you use them.  This number would stay the same for each of the
short runs described by the comment.  We are making no changes to the
requirement.

5.  Final § 111.160(e)

     Final § 111.160(e) requires you to hold packaging and labels under
conditions that will protect against contamination and deterioration,
and avoid mixups.  Final § 111.160(e) is identical to proposed §
111.40(b)(4).  

     We did not receive comments specific to proposed § 111.40(b)(4).

 G.  What Requirements Apply to Product That You Receive for

Packaging or Labeling as a Dietary Supplement(and for distribution
rather than for return to the supplier)?

(Final § 111.165)

 	Final § 111.165 (proposed § 111.40(a)) sets out actions you must
take when you receive a product for packaging and labeling and for
distribution.  Final § 111.165 includes editorial changes associated
with the reorganization and revisions that reflect changes we are making
to other sections of the final rule. 

     Final § 111.165 sets forth requirements for “product that you
receive from a supplier for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier)” rather than for “dietary supplements that you receive.”

     The final rule separates the requirements in proposed § 111.40(a)
for product that you receive from a supplier for packaging or labeling
as a dietary supplement (and for distribution rather than for return to
the supplier) (final § 111.165) from the analogous requirements for
components, packaging, and labels (final § 111.155).  

1.  Final § 111.165(a)

     Final § 111.165(a) requires you to visually examine each immediate
container or grouping of immediate containers in a shipment of product
you receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) for appropriate
content label, container damage, or broken seals to determine whether
the container condition may have resulted in contamination or
deterioration of the received product.  Final § 111.165(a) is
substantially similar to proposed § 111.40(a)(1) which, in part, would
impose this requirement for dietary supplements you receive.  We have
added the word “immediate” to identify the container as the
container that is in contact with the product you receive for packaging
or labeling as a dietary supplement and substituted “may have” for
“has” before the word “resulted” as explained in this section.

2.  Final § 111.165(b)

     Final § 111.165(b) requires you to visually examine the
supplier’s invoice, guarantee, or certification in a shipment of the
received product to ensure the received product is consistent with your
purchase order.  Final § 111.165(b) is substantially similar to
proposed § 111.40(a)(2) which, in part, would establish a similar
requirement for dietary supplements that you receive.

3.  Final § 111.165(c)

     Final § 111.165(c) requires you to quarantine the received product
until:

(1) You collect representative samples of each unique shipment, and of
each unique lot within each unique shipment, of received product;

(2) The Qquality control personnelunit reviews and approves the
documentation to determine whether the received product meets the
specifications you established under § 111.70(f); and

(3) The Qquality control personnelunit approves the received product for
packaging or labeling as a dietary supplement and releases the received
product from quarantine.

     Final § 111.165(c) is similar to proposed § 111.40(a)(3) which,
in part, would require that: 

•	You quarantine dietary supplements that you receive until your
quality control unit reviews the suppliers invoice, guarantee, or
certification;

• 	The quality control unit performs testing, as needed, of a
representative sample to determine that specifications are met; 

• 	You conduct a material review and make a disposition decision if
specifications are not met; and

• 	The quality control unit approves and releases the dietary
supplements that you receive from quarantine before you use them. 

	Final § 111.165(c) includes revisions that reflect that under final §
111.75(e) before you package or label a product you received for
packaging or labeling as a dietary supplement, you must visually examine
the product and have documentation to determine whether the
specifications you established under § 111.70(f) are met, but not
otherwise examine or conduct tests.

4.  Final § 111.165(d)

     Final § 111.165(d)(1) requires that you identify each unique lot
within each unique shipment of received product in a manner that allows
you to trace the lot to the supplier, the date received, the name of the
received product, the status of the received product (e.g., quarantined,
approved, or rejected), and to the product you packaged or labeled and
distributed as a dietary supplement.  Final § 111.165(d)(2) requires
you to use this unique identifier whenever you record the disposition of
each unique lot within each unique shipment of the received product. 
Final § 111.165(d) derives from proposed § 111.40(a)(4) which would
require you, in part, to identify each lot of dietary supplements in a
shipment in a manner that allows you to trace the shipment to the
supplier, the date received, the name of the dietary supplement, and the
status (e.g., quarantined, approved, or rejected) and to trace the
shipment lot to the dietary supplement manufactured and distributed. 
Proposed § 111.40(a)(4) also would require you to use this identifier
whenever you record the disposition of each shipment lot received.  

     Final § 111.165(d) includes a revision associated with final §
111.80 referring to “each unique lot within each unique shipment”
rather than “each shipment lot.” 

5.  Final § 111.165(e)

     Final § 111.165(e) requires you to hold the received product under
conditions that will protect against contamination and deterioration,
and avoid mixups.  Final § 111.165(e) derives from proposed §
111.40(a)(5) with editorial changes associated with the reorganization.

 

H.  What Requirements Apply to Rejected Components, 

Packaging, and Labels, and to Rejected Products That AreYou Received for
Packaging or Labeling as a Dietary Supplement?

(Final § 111.170)

     Final § 111.170 requires you to clearly identify, hold, and
control under a quarantine system for appropriate disposition any
component, packaging, and label, and any product you receive for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier), that is rejected and unsuitable
for use in manufacturing, packaging, or labeling operations.  Final §
111.170 is substantially similar to proposed § 111.74 which would
require you to clearly identify, hold, and control under a quarantine
system any component, dietary supplement, packaging, and label that is
rejected and unsuitable for use in manufacturing, packaging, or labeling
operations.

     We did not receive comments specific to proposed § 111.74.  Final
§ 111.170 includes revisions associated with the series of provisions
that distinguish a product you receive for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier) from a dietary supplement you manufacture.

 

I.  Under this Subpart, What Records Must You Make and Keep?

(Final § 111.180)

     Final § 111.180 sets forth the requirements to make and keep
records associated with components, packaging, labels, and product you
receive for packaging and labeling as a dietary supplement.  Final §
111.180 derives from proposed § 111.40(c). 

1.  Final § 111.180(a)

     Final § 111.180(a) requires you to make and keep records required
under subpart G in accordance with subpart P.  Final § 111.180(a)
derives from proposed § 111.40(c)(2), with editorial changes associated
with the reorganization.

     We did not receive comments specific to the requirements set forth
in final § 111.180(a).

2.  Final § 111.180(b)(1)

     Final § 111.153 requires you to establish and follow written
procedures to fulfill the requirements of subpart G.  These written
procedures are records.  Therefore, final § 111.180(b)(1) requires you
to make and keep a record of the written procedures for fulfilling the
requirements of subpart G.

3.  Final § 111.180(b)(2)

     Final § 111.180(b)(2) requires you to make and keep receiving
records (including records such as certificates of analysis,
suppliers’ invoices, and suppliers’ guarantees) for components,
packaging, and labels, and for products you receive for packaging or
labeling as dietary supplements (and for distribution rather than for
return to the supplier).  Final § 111.180(b)(2) derives from proposed
§ 111.40(c)(2) with editorial changes associated with the
reorganization.  Final § 111.180(b)(2) also includes revisions
associated with the series of provisions that distinguish a product you
receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) from a dietary
supplement you manufacture.  Because the final rule provides that you
may rely, under certain circumstances, on a certificate of analysis to
ensure that some component specifications are met (final §
111.75(a)(2)(ii)) and that you may rely, in part, on documentation to
determine whether specifications for received products are met, we
specifically identify a certificate of analysis and common forms of
documentation as being “receiving records” for purposes of this
rule. 

	(Comment 247)  One comment on proposed § 111.40(c)(2) points out the
recordkeeping requirements of any final rule will be a costly burden for
a company that produces multiple ingredient products in several
packaging configurations and will be much greater than the burden for a
company that produces batches of single ingredient products in one
packaging configuration. 

     (Response) We acknowledge that companies that produce multiple
ingredient products in several packaging configurations will have more
records to keep than companies that produce single ingredient products
in one packaging configuration.  However, these records are necessary to
be able to determine the source of the component, packaging, and labels,
so that if adulteration of the dietary supplement occurs, the records
will show the source of the material so that its use can be stopped. 

4.  Final § 111.180(b)(3)

     Final § 111.180(b)(3) requires you to make and keep documentation
that the requirements of Subpart G were met. Under final §
111.180(b)(3)(i) the person who performs the required activity must
document, at the time of performance, that the required operation was
performed.  Under final § 111.180(b)(3)(ii), the documentation must
include: 

(A) the date that the components, packaging, labels, or products you
receive for packaging or labeling as a dietary supplement were received;

(B) the initials of the person performing the required operation; 

(C) the results of any tests or examinations conducted on components,
packaging or labels, and of any visual examination of product you
receive for packaging or labeling as a dietary supplement; and 

(D) any material review and disposition decision conducted on
components, packaging, labels, or products received for packaging or
labeling as a dietary supplement. 

     Final § 111.180(b)(3) differs from proposed § 111.40(c)(1)(i)
through (iv), by referring to “required operation” rather than
“requirement.”  Additionally as conforming revision associated with
final § 111.75(a) which requires appropriate tests and examinations,
final § 111.180(b)(3) requires you to include in the documentation the
results of any examinations as well as tests.  Final § 111.180(b)(3)
also includes revisions associated with the series of changes that
distinguish a product that you receive for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier) from a dietary supplement that you manufacture.

	(Comment 248) A few comments note proposed § 111.40(c) requires the
signature of the person performing the requirement, whereas other
sections of the 2003 CGMP Proposal, such as proposed § 111.50(c)(2),
only require the initials of the person performing the requirement.  One
comment requests the format for the requirement to document the person
performing the step be made consistent throughout the regulations.

     (Response) We agree that the identity of the person performing a
requirement should be required throughout the final rule and that this
can be accomplished through initials except for operations that are
performed by the quality control personnelunit.  Therefore, we are
revising the requirements so that a signature (and not initials) is
required for any operation performed by the quality control
personnelunit (see final § 111.140).  Because § 111.40(c)(1)(ii) is
not a quality control operation, we also revised proposed §
111.40(c)(1)(ii) (final § 111.180(b)(3)) to require the initials,
rather than the signature, of the person performing the required
operation.  Initials are required for other circumstances that do not
involve quality control operations, including final § 111.180(b)(3). 
However, whenever this final rule requires initials, a signature is also
acceptable, because a signature would achieve the goal of identifying
the person who performed the requirement. 

 Although we refer to the term “food additive” in the preamble, the
reader should also consider color additives and substances prior
sanctioned for such use as being relevant to the discussion.

-

!

"

I

L

p

û

ü

ý

@

p

v

w

¢

£

Á

Ó

ú

û

ý

 

!

"

#

2

3

?

@

H

I

V

W

]

^

d

h`?

Ĩ脈䠄栅틷⚦栖㽠

Ĩ脈䠄栅틶⚦栖㽠

̀d

e

…

‘

’

¡

¢

¨

®

¯

¹

º

Á

Â

È

É

Î

Ï

Û

Ü

é

ê

ñ

ò

0g

v

…

‘

h

Ĩ脈䠄栅틷⚦栖㽠

@

@

@

h

ሀā㄀$摧桂Û฀ It is important to note that it is the use of
the substance, not the substance itself that must be GRAS.  The amount
of a substance in the food is a critical factor in determining whether
the use would be GRAS.

FDA-Internal-Confidential-Deliberative

Final Subpart G 9-28-05, 6-26-06, 3-30-07, 5-04-07

page   PAGE  711