XVI\. Comments on the Production and Process Control System:

Requirements for Manufacturing Operations

(Final Subpart K)

[A. Organization of Final Subpart K]{.underline}

In the 2003 CGMP Proposal, the requirements for manufacturing operations
were set forth in § 111.65. As shown in table 12, we are establishing
the requirements for manufacturing operations in a distinct subpart
(final Subpart K -- Production and Process Control System: Requirements
for Manufacturing Operations). In addition, we are incorporating some
requirements from proposed § 111.74 relating to rejected components,
dietary supplements, and packaging and labels into final subpart K.
Table 12 lists the sections in final subpart K and identifies the
proposed sections that form the basis of the final rule.

Table 12. - Derivation of Sections in Final subpart K

  ------------------------------------------ ----------------------------
  Final Rule                                 2003 CGMP Proposal

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

  § 111.355 What Are the Design Requirements § 111.65(a)
  for Manufacturing Operations?              

  § 111.360 What Are the Requirements for    § 111.65(b)
  Sanitation?                                

  § 111.365 What Precautions Must You Take   § 111.65(c)
  to Prevent Contamination?                  

  § 111.370 What Requirements Apply to       § 111.74
  Rejected Dietary Supplements?              

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

[B. Highlights of Changes to the Proposed Requirements]{.underline}

[for Manufacturing Operations]{.underline}

1\. Revisions

The final rule:

● Applies to persons who manufacture, package, label, or hold dietary
supplements unless subject to an exclusion in § 111.1; and

● Reflects changes relevant to this subpart that we are making to final
subpart C concerning water standards.

2\. Changes Made After Considering Comments

● Requires written procedures for manufacturing operations.

3\. Revisions Associated With the Reorganization

The final rule:

● Sets forth in final § 111.90, rather than in subpart K, the
requirements for in-process adjustments or reprocessing.

[C. General Comments on]{.underline}

[Manufacturing Operations]{.underline}

(Comment 286) Some comments support proposed § 111.65 as a "good model"
for an appropriate level of flexibility, noting that proposed § 111.65
clearly states the requirements and presents relevant factors that must
be considered when determining how to best meet the requirements of the
rule.

(Response) We acknowledge these comments and utilize many elements of
proposed § 111.65 in final § 111.355.

[D. What Are the Requirements Under]{.underline}

[This Subpart for Written Procedures?]{.underline}

[(Final § 111.353)]{.underline}

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, final § 111.353, to require that you
establish and follow written procedures for manufacturing operations.

[E. What Are the Design Requirements]{.underline}

[for Manufacturing Operations?]{.underline}

[(Final § 111.355)]{.underline}

Final § 111.355 requires you to design or select manufacturing processes
to ensure that product specifications are consistently met. Final §
111.355 derives from proposed § 111.65(a) which would require you to
design or select manufacturing processes to ensure that dietary
supplement specifications are consistently achieved. Final § 111.355
refers to "product specifications" rather than "dietary supplement
specifications" to conform with final § 111.70(e). We have substituted
the word "met" for "achieved" to comply with plain language initiatives
and to be consistent with other provisions.

We did not receive comments specific to proposed § 111.65(a).

[F. What Are the Requirements for Sanitation?]{.underline}

[(Final § 111.360)]{.underline}

Final § 111.360 requires you to conduct all manufacturing operations in
accordance with adequate sanitation principles. Final § 111.360 derives
from proposed § 111.65(b). We did not receive comments specific to
proposed § 111.65(b).

[G. What Precautions Must You Take]{.underline}

[to Prevent Contamination?]{.underline}

[(Final § 111.365)]{.underline}

Final § 111.365 requires you to take all necessary precautions during
the manufacture of a dietary supplement to prevent contamination of
components or dietary supplements. Final § 111.365 derives from proposed
§ 111.65(c)(1) through (c) (11).

1\. Final § 111.365(a)

Final § 111.365(a) requires that the necessary precautions include
performing manufacturing operations under conditions and controls that
protect against the potential for growth of microorganisms and the
potential for contamination. Final § 111.365(a) derives from proposed §
111.65(c)(1).

(Comment 287) One comment contends that the requirement in proposed §
111.65(c)(1) to protect "against the potential for growth of
microorganisms," does not take into account processes that have a kill
step. The comment recommends that proposed § 111.65(c)(1) be revised to
be more consistent with § 110.80(b)(2) and state, "performing
manufacturing operations under such conditions and controls as are
necessary to minimize the potential for the growth of undesirable
microorganisms, or for the contamination of the product."

(Response) We decline to modify final § 111.365(a as requested by the
comment. We defined "microorganism" in the 2003 CGMP Proposal similar to
how we describe "undesirable microorganisms" in § 110.3(i). Further, we
decline to use the words "minimize the potential for growth" instead of
"protect against the potential for growth" because the word "minimize"
suggests a lesser standard than "protect against" the potential for
growth of microorganisms.

We would consider that you are not complying with the final rule if you
do not perform manufacturing operations under conditions and controls
that protect against the potential for growth of microorganisms and the
potential for contamination, regardless of whether you use a kill step.
Although a kill step may be necessary in some circumstances, it is not a
substitute for conditions and controls that protect against the
potential for growth of microorganisms and the potential for
contamination. Therefore, we decline to make the change requested by
this comment.

2\. Final § 111.365(b)

Final § 111.365(b) requires that necessary precautions include washing
or cleaning components that contain soil or other contaminants. Final §
111.365(b) is identical to proposed § 111.65(c)(2). We did not receive
comments specific to proposed § 111.65(c)(2).

3\. Final 111.365(c)

Final § 111.365(c) requires that the necessary precautions include using
water that, at a minimum, complies with the applicable Federal, State,
and local requirements and does not contaminate the dietary supplement
when the water may become a component of the finished batch of dietary
supplement.

The proposed requirements would set forth parallel requirements for
water that is used in the manufacture of a dietary supplement for both
your physical plant (proposed § 111.15(d)(2)) and for manufacturing
operations (proposed § 111.65(c)(3)). Thus, proposed § 111.15(d)(2)
would require that water that contacts components, dietary ingredients,
dietary supplements, or any contact surface must, at a minimum, comply
with the NPDW regulations prescribed by the EPA under 40 CFR part 141
and any State and local requirements.

As discussed in subpart C, section VIII (final § 111.15(e)(2)), we are
revising proposed § 111.15(d)(2) to require in the final rule that
water, used in the manufacture of a dietary supplement in a manner such
that the water may become a component of the dietary supplement, *e.g.*,
when such water contacts components, dietary supplements, or any contact
surface, must, at a minimum, comply with applicable Federal, State, and
local requirements and not contaminate the dietary supplement. Given the
parallel nature of proposed § 111.65(c)(3) and proposed § 111.15(d)(2),
we are revising proposed § 111.65(c) to be consistent with the revisions
we are making to proposed § 111.15(d)(2) (final § 111.15(e)(2)).

Final § 111.365(c) also includes grammatical changes consistent with the
structure of final § 111.365.

(Comment 288) One comment asks that the words "or equivalent quality
water" be added to "water that meets the National Primary Drinking Water
regulations" in proposed § 111.65(c)(3) to allow for ingredients
manufactured in facilities outside the United States.

(Response) As stated in response to comment 91, dietary supplements
manufactured in a foreign country would be subject to the requirements
of this final rule. Although EPA NPDW regulations would not apply to a
foreign manufacturer, the foreign manufacturer would need to use water
that is of a standard required in this final rule and that achieves the
same level of performance required of domestic manufacturers. The water
used by the foreign facility must not contaminate the dietary supplement
that is manufactured. We decline to add "or equivalent water quality"
because that would suggest domestic firms would not need to follow
whatever Federal, State, and local requirements are applicable.

(Comment 289) One comment recommends that proposed § 111.65(c)(3) be
revised to be consistent with proposed § 111.15(d)(1), which would
require you to provide water that is safe and of adequate sanitary
quality, at suitable temperatures, and under pressure as needed, in all
areas where water is necessary for: (1) Manufacturing dietary
ingredients or dietary supplements; (2) making ice that comes in contact
with components, dietary ingredients, dietary supplements, or contact
surfaces; (3) cleaning any surface; and (4) employee bathrooms and
hand-washing facilities.

(Response) We do not agree with the comment that we should be consistent
in the water requirement related to proposed § 111.15(d)(1) and the
requirement in proposed § 111.65(c)(3). The requirement in proposed
§ 111.15(d)(1) describes a variety of manufacturing operations where
water is used. For example, water that is safe and of adequate sanitary
quality, as described in the proposed rule, for purposes of
manufacturing dietary supplements or that comes into contact with a
dietary supplement would be water that would have been required to
comply with the requirement in proposed § 111.15(d)(2). Under the
proposed rule and under the final rule, if such water is subject to EPA
NPDW, then the water must meet EPA NPDW requirements at point of use.
Proposed § 111.15(d)(1) has been revised and simplified in final §
111.15(e)(1) to require you to provide water that is safe and sanitary,
at suitable temperatures, and under pressure as needed, for all uses
where water does not become a component of the dietary supplement. Water
that is safe and sanitary for cleaning the floor in a facility would not
need to meet standards for drinking water, but such water could not be a
source of contamination of the dietary supplement. The standard "safe
and sanitary" in final § 111.15(e)(1) allows some flexibility for the
manufacturer in deciding what water it can use in various operations for
which no other requirements in this final rule apply. The requirements
of final § 111.365(c) are consistent with the changes in final §
111.15(e).

4\. Final § 111.365(d)

Final § 111.365(d) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include performing chemical,
microbiological, or other testing, as necessary to prevent the use of
contaminated components. Final § 111.365(d) derives from proposed §
111.65(c)(4).

(Comment 290) One comment asserts that requirements for testing belong
in proposed § 111.25 (proposed requirements for equipment and utensils)
rather than in proposed § 111.65 (proposed requirements for
manufacturing operations).

(Response) In our discussion of proposed § 111.65(c)(4) in the 2003 CGMP
Proposal (68 FR 12157 at 12210), we stated that you consider identifying
those areas in the processing and production areas where chemical,
microbial, or other forms of contamination are most likely to occur. We
also stated that chemical, microbial, or other testing is necessary to
identify areas where sanitation measures have not been adequate or where
products may become adulterated. These remarks reflect that the proposed
requirement in proposed § 111.65(c)(4) is directed to facilities rather
than to equipment and utensils. For example, under proposed §
111.65(c)(4), we encouraged you to establish a testing program that
monitors levels of microorganisms at key places in your physical plant
where you process and produce your products. Thus, we disagree with the
comment that the testing requirements belong in proposed § 111.25 and
are not making any changes in final § 111.365(d).

5\. Final § 111.365(e)

Final § 111.365(e) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include sterilizing, pasteurizing,
freezing, refrigerating, controlling hydrogen-ion concentration (pH),
controlling humidity, controlling water activity (a~w~), or using any
other effective means to remove, destroy, or prevent the growth of
microorganisms, and prevent decomposition. Final § 111.365(e) derives
from proposed § 111.65(c)(5).

(Comment 291) One comment asserts that only sanitary practices are
needed to prevent microbial contamination or decomposition, and,
therefore, requests that we clarify the processes listed in proposed §
111.65(c)(5) are optional.

(Response) We disagree with this comment. Good sanitary practices are
important, but they are not the only precaution to take to prevent a
component or dietary supplement from contamination with microorganisms.
In the preamble to the 2003 CGMP Proposal, we gave the example of bovine
colostrum, which is the lacteal secretion that precedes milk after a cow
gives birth and is a substance that is used in dietary supplements. We
also stated that we consider that bovine colostrum likely presents the
same potential health risks as bovine milk, which can contain pathogenic
organisms capable of causing diseases in man such as tuberculosis,
undulant fever, or gastrointestinal disease and, thus, must be
pasteurized (§ 1240.61). Under final § 111.365(e) you must sterilize or
pasteurize bovine colostrums, or take other steps, to remove or destroy
microorganisms that could be present in bovine colostrum. Under final
§ 111.365(e) we list various ways that, depending upon the particular
situation, would be effective in removing, destroying, or preventing the
growth of microorganisms and preventing decomposition. You must decide
for your given operation what means to use to remove, destroy, or
prevent the growth of microorganisms and prevent deterioration of your
components and dietary supplements so that you ensure the quality of the
dietary supplement.

(Comment 292) Some comments recommend adding "irradiating" to the list
of practices to prevent the growth of microorganisms in proposed §
111.65(c)(5) as in the 1997 ANPRM.

(Response) We decline to revise the provision as suggested by these
comments. We are not adding "irradiating" to the list of practices
because, at this time, irradiation of dietary ingredients and dietary
supplements, as a means to reduce or eliminate microbial loads, is not
permitted. CFSAN is currently reviewing the use of irradiation for the
control of microbial contamination on dietary supplements and
ingredients (including dietary ingredients) used in the manufacture of
dietary supplements (68 FR 25048 May 9, 2003). If we authorize this use
of irradiation you could then use irradiation in compliance with that
rule to comply with final § 111.365(e) as an "other effective means."

6\. Final § 111.365(f)

Final § 111.365(f) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include holding components and
dietary supplements that can support the rapid growth of microorganisms
of public health significance in a manner that prevents the components
and dietary supplements from becoming adulterated. Final § 111.365(f)
derives from proposed § 111.65(c)(6). We did not receive comments
specific to proposed § 111.65(c)(6).

7\. Final § 111.365(g)

Final § 111.365(g) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include identifying and holding any
components or dietary supplements, for which a material review and
disposition decision is required, in a manner that protects components
or dietary supplements that are not under a material review against
contamination and mix-ups with those under a material review. Final §
111.365(g) is substantially similar to proposed § 111.65(c)(7). We did
not receive comments specific to proposed § 111.65(c)(7).

8\. Final § 111.365(h)

Final § 111.365(h) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include performing mechanical
manufacturing steps (such as cutting, sorting, inspecting, shredding,
drying, grinding, blending, and sifting) by any effective means to
protect the dietary supplements against contamination. Final §
111.365(h) derives from proposed § 111.65(c)(8). Such steps must include
consideration of: (1) Cleaning and sanitizing contact surfaces, (2)
using temperature controls, and (3) using time controls.

(Comment 293) One comment suggests that the time controls required in
proposed § 111.65(c)(8)(iii) are not always necessary.

(Response) As written, proposed § 111.65(c)(8) acknowledges that time
controls are not always necessary, because the provision requires that
you consider using time controls, and implement them if they are
necessary to prevent contamination of components or dietary supplements.
Final § 111.65(h) retains this same language.

9\. Final § 111.365(i)

Final § 111.365(i) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include using effective measures to
protect against the inclusion of metal or other foreign material in
components or dietary supplements. Compliance with this requirement must
include consideration of the use of: (1) Filters or strainers, (2)
traps, (3) magnets, or (4) electronic metal detectors. Final §
111.365(i) derives from proposed § 111.65(c)(9).

(Comment 294) One comment contends it is sufficient to require in
proposed § 111.65(c)(9) that manufacturers inspect their equipment
before and after use to determine if any piece is missing, and if so,
the entire batch should be disposed of. The comment states metal
detection devices are not 100 percent effective and that inspection of
equipment before and after use would be preferable.

(Response) We disagree with the comment. As discussed in the 2003 CGMP
Proposal, the purpose behind proposed § 111.65(c)(9) is to ensure that
no metal or foreign material becomes a source of possible contamination
and not to establish mechanisms to be used after contamination has or is
suspected to have occurred (68 FR 12157 at 12211). The source of metal
contamination is not limited to manufacturing equipment. For example,
metal contamination could occur through using utensils such as metal
brushes during processing of natural products. It would be impractical
to determine whether contamination has occurred by examining the brush.

10\. Final § 111.365(j)

Final § 111.365(j) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include segregating and identifying
all containers for a specific batch of dietary supplements to identify
their contents and, when necessary, the phase of manufacturing. Final §
111.365(j) derives from proposed § 111.65(c)(10). We did not receive
comments specific to proposed § 111.65(c)(10).

11\. Final § 111.365(k)

Final § 111.365(k) requires that the necessary precautions you take
during the manufacture of a dietary supplement to prevent contamination
of components or dietary supplements include identifying all processing
lines and major equipment used during manufacturing to indicate their
contents, including the name of the dietary supplement and the specific
batch or lot number and, when necessary, the phase of manufacturing.
Final § 111.365(k) derives from proposed § 111.65(c)(11).

(Comment 295) One comment suggests continuous processes should be
excluded from the requirement in proposed § 111.65(c)(11) to identify
specific batch or lot numbers. The comment explains that in continuous
bulk operations for manufacturing dietary ingredients, the batch or lot
number often is not identified until after the materials have been
blended and moved into a storage bin.

(Response) We are making no changes to proposed § 111.65(c)(11) in final
§ 111.365(k) because the comment describes a situation where the
manufacturer is manufacturing a dietary ingredient, and the final rule
does not apply to the manufacture of a "dietary ingredient" within the
meaning of Section 201(ff) of the act.

[H. What Requirements Apply to]{.underline}

[Rejected Dietary Supplements?]{.underline}

[(Final § 111.370)]{.underline}

Final § 111.370 requires you to clearly identify, hold, and control
under a quarantine system for appropriate disposition any dietary
supplement that is rejected and unsuitable for use in manufacturing,
packaging, or label operations. Final § 111.370 derives from proposed §
111.74 which would require that you clearly identify, hold, and control
under a quarantine system any component, dietary ingredient, dietary
supplement, packaging, and label that is rejected and unsuitable for use
in manufacturing, packaging, or label operations. Because the
requirements regarding components, packaging, and labels that are
rejected and unsuitable for use are already set forth in final §
111.170, final § 111.370 addresses only the requirements for dietary
supplements.

We did not receive comments specific to proposed § 111.74.

[I. Under This Subpart, What]{.underline}

[Records Must You Make and Keep?]{.underline}

[Final § 111.375]{.underline}

In order to ensure that records are maintained as required under subpart
P, we are adding a new § 111.375. This section requires that you make
and keep records of the written procedures you establish for
manufacturing operations. These written procedures are required under
final § 111.353.