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August 8, 2003

Dockets Management Branch (HFA 305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

**RE: DOCKET NO. 96N-0417, GOOD MANUFACTURING PRACTICES**

**FOR DIETARY SUPPLEMENTS**

Pharmavite LLC is a manufacturer of a wide variety of dietary
supplements sold through food, drug and mass merchandise retail outlets
throughout the U.S. Pharmavite recognizes the value of sound Good
Manufacturing Practices (GMP's) for the manufacture of dietary
ingredients and dietary supplements and strongly supports the
development and enforcement of reasonable GMP's that reflect well
controlled manufacturing processes and best practices used by leading
companies in this industry. Pharmavite has also been a strong supporter
of and active participant in the initiative lead by the Council for
Responsible Nutrition to develop the industry draft GMP's that were
submitted to FDA in November 1995 and later published by FDA as the ANPR
on dietary supplement GMP's in 1997. We believe that appropriate GMP's
for this industry will serve a vital role in assuring the safety and
improving the quality of dietary ingredients and dietary supplements.

Although the current proposal captures many elements of best practices
in use today, certain key provisions of the proposal are inconsistent
with standard industry practice and are unreasonable, unnecessary, and
contrary to the statutory mandate. Indeed, some proposed requirements
actually exceed cGMP requirements for drugs. The basic weakness of the
proposal is that it relies too heavily on final product testing as a
means of assuring product quality. Consistent with current best industry
practice, more reliance should instead be placed on a comprehensive
system of process control, augmented by written procedures for all
important aspects of the manufacturing process, to assure consistency in
manufacturing from batch to batch. Excessive testing requirements are
unnecessary overkill and add undue burden on manufacturing operations
that are otherwise adequately controlled. The result of the excessive
testing requirements in the GMP proposal would be to unnecessarily
increase manufacturing costs without significantly improving quality.
This would directly lead to a reduced ability of many companies to
compete in an already highly competitive market that often operates on
very slim profit margins. Higher costs will also be invariable passed on
to consumers, which will limit consumer access to healthful products. We
believe the goal of GMP's should be to provide a reasonable framework
for assuring safe, high quality products, without unnecessarily
burdening industry with redundant and unnecessary requirements.

With this objective in mind, we are providing the following general and
specific comments on the GMP proposal:

[Written Procedures]{.underline}

In the preamble to the proposed GMP's, FDA requested comment on whether
various written procedures should be required to assure the identity,
purity, quality, strength, and composition of components, dietary
ingredients and dietary supplements. We believe that written procedures
are essential for consistent and reliable manufacturing processes. We
also believe that the goal of GMP's for dietary ingredients and dietary
supplements should be to increase the confidence level in production
capability and to reduce the reliance on testing for assuring products
that meet appropriate specifications. It makes no sense for a company to
haphazardly produce products without a consistent, well documented plan
for accomplishing the task. Batch records, as included in the proposal,
provide the basic outline for manufacturing steps, but generally lack
detailed instructions for how individual steps are to be accomplished. A
company that operates without the benefit of written procedures in key
areas is more likely to vary its procedures from batch to batch and
inevitably will produce more batches that do not meet final product
specifications. This is neither a reliable nor an efficient approach to
quality. Written procedures provide greater assurance of consistent
product quality and reduce the overall dependence on testing.

In addition, written procedures provide an important tool for employee
training in basic job functions, as well as GMP principles. We consider
written procedures to be indispensable for training new employees and
providing a reliable reference and reminder for experienced employees
concerning key aspects of critical functions.

For these reasons, we believe that written procedures should be required
for every major aspect of product manufacture, including each of the key
areas previously described in the February 6, 1997 ANPR. In addition, we
believe that several other key functions should be documented in written
procedures, including a written recall plan which would serve an
essential guide in conducting timely and effective recalls. The
following is a list of written procedures that we believe should be
required in GMP regulations for dietary ingredients and dietary
supplements:

1.  Cleaning, sanitizing and maintenance of equipment and utensils used
    in manufacturing operations.

2.  Calibration of instruments and controls used in manufacturing or
    testing operations (as currently proposed in section 111.25 (c)
    (1)).

3.  Procedures used in the receipt, storage, identification,
    examination, handling, sampling and approval or rejection of
    received components.

4.  A description of the laboratory test methods used to assure that
    received components, in process materials and finished product meet
    established specifications.

5.  The method used for reprocessing batches or other materials that do
    not conform to specifications.

6.  Control procedures employed for the receipt, storage, handling,
    sampling, examination, and testing that may be necessary to assure
    the identity of labeling and the appropriate identity, cleanliness
    and quality characteristics of packaging materials used for finished
    dietary ingredients and dietary supplements.

7.  Procedures to assure that correct labels, labeling, and packaging
    materials are issued, used in packaging operations and accounted for
    properly.

8.  Quarantining, examination and, where necessary, testing of returned
    dietary ingredients and dietary supplements.

9.  Complaint handling, investigation and follow up.

10. Product recall.

[Reliance on Certificates of Analysis]{.underline}

The preamble of the GMP proposal states that reliance on a "supplier
certification, guarantee, or certification in lieu of performing testing
on each shipment lot of components, dietary ingredients, or dietary
supplements required in accordance with this section is not appropriate
because it is possible that a supplier\'s certification or guarantee may
not ensure the identity, purity, quality, strength, or composition of a
component, dietary ingredient or dietary supplement." While we would
agree that a certification or guarantee based on typical or expected
results is not adequate verification that a product meets its
specifications, we believe that it is entirely appropriate to rely on a
supplier's certification if it represents bona fide testing using
appropriate methodologies. As discussed below, reliance on a supplier's
certificate of analysis should be conditioned on a qualification program
whereby the recipient independently verifies the supplier's ability to
conduct appropriate tests and verifies test results on a periodic basis
through confirmatory testing. In addition, the recipient of a component
should conduct suitable identification testing to assure the correct
component has been received.

[Expiration Dating and Stability Studies]{.underline}

The vast majority of dietary supplements sold today contain some form of
open-code expiration dating on the product label. Such dates are used
extensively by consumers to assure that products purchased and consumed
conform fully to label claims and other manufacturer's specifications.
Assurance that dietary supplements meet specifications during their
indicated shelf life is an important factor not only in assuring that
consumers are receiving safe and effective products, but also
maintaining consumer's confidence in the products they consume. While we
believe that expiration dating should remain optional for dietary
supplements, we maintain that whenever a dietary supplement bears an
expiration date, such dating should be supported by data and rationale
to reasonably assure that the product meets established specifications
during its indicated shelf life. Appropriate accelerated stability
studies or data from similar product formulations should be acceptable
means of making an initial determination of shelf life. Product shelf
life determined by accelerated stability studies should be confirmed and
may be extended on the basis of real time studies on product stored
under labeled storage conditions. We believe that the GMP should
expressly require records of appropriate justification and/or data to
support any expiration dates assigned by a dietary supplement
manufacturer.

[Plant and Grounds]{.underline}

In the preamble, FDA requested comment on whether the food GMP
requirement found in section 110.20 (a) relating to the condition and
maintenance of physical plants and surrounding grounds should be
included in the final rule for dietary ingredients and dietary
supplements. We believe that this requirement is important to the
assurance of clean, pest-free manufacturing environments and see no
reason why this requirement should differ from food GMP's. We therefore
recommend that this provision be added to the final rule.

[Comments on Specific Sections]{.underline}

§ 111.3 [What definitions apply to this Part?]{.underline}

[Sanitize]{.underline} means to adequately treat equipment, containers,
utensils, or any other dietary product contact surface by applying
cumulative heat or chemicals on cleaned food contact surfaces 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.

Comment: The preamble to the proposal indicates that the proposed
definition is based on the definition in the FDA "Food Code," which also
specifies a 99.999% reduction of disease microorganisms. The preamble
then goes on to state that:

> The proposed requirement mandates that you validate that the control
> measures are both appropriate to their operation and scientifically
> sound. In many cases, processors 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 5-log reduction in the target
> pathogen, to ensure that the process is adequate to destroy
> microorganisms of public health significance or to prevent their
> growth. 68 Fed. Reg. at 12179.

However, the Food Code contains no such requirement for validation in
connection with its definition. Instead, it specifies in Section
4-501.114 conditions under which chemical sanitizers listed in 21 CFR
178.1010 may be used including the requirement that they must be used in
accordance with the EPA-approved manufacturer's label use instructions.
A similar approach should be used here as well rather than imposing a
validation requirement on individual dietary ingredient and dietary
supplement manufacturers.

The proposed requirement for validation is not only inconsistent with
the approach taken in The Food Code but is unreasonable and
unnecessarily burdensome for dietary ingredient and dietary supplement
manufacturers. Any requirement for validation should be limited to
situations in which a manufacturer wishes to sanitize under conditions
contrary to manufacturer's label use instructions or those specified in
Section 4-501.114 of the Food Code.

§ 111.12 [What personnel qualification requirements apply?]{.underline}

\(b\) Each person engaged in manufacturing, packaging, or holding must
have the training and experience to perform the person\'s duties.

Comment: As written, section 111.12 could be interpreted to unreasonably
restrict the hiring of employees who have no prior experience in a
particular job, even if they are adequately trained and supervised to
perform the work. Many jobs on production lines are basically unskilled
labor positions that require little, if any, prior experience to perform
properly when provided with adequate orientation and training. In order
to allow for the reasonable ability to fill manufacturing line
positions, this provision should be modified to require "training and,
if necessary, experience to perform the person's duties."

§ 111.20 [What design and construction requirements apply to your
physical plant?]{.underline}

Any physical plant you use in the manufacture, packaging, or holding of
dietary ingredients or dietary supplements must:

\(d\) Be designed and constructed in a manner that prevents
contamination of components, dietary ingredients, dietary supplements,
or contact surfaces. The design and construction must include, but not
be limited to:

\(5\) Equipment that controls temperature and humidity;

Comment: Section 111.20 (d) states, "The design and construction (of a
physical plant) *must* include...(5) Equipment that controls temperature
and humidity." There may be situations where temperature and humidity
controls are not necessary to prevent contamination, but the proposed
language does not provide for the flexibility to determine whether such
controls are actually necessary. Therefore, for the sake of clarity,
section 111.20 (d) (5) should be modified to read, "Equipment necessary
to adequately control temperature and humidity."

Such modification would also make section 111.20 consistent with
proposed sections 111.80 and 111.82 where flexibility is provided for
holding components, in-process materials, dietary supplements, packaging
and labeling under "appropriate conditions" of temperature and humidity.

§ 111.25 [What requirements apply to the equipment and utensils you
use?]{.underline}

(a)(6) Instruments or controls used in the manufacturing, packaging, or
holding of a dietary ingredient or dietary supplement, including but not
limited to, instruments or controls you use to measure, regulate, or
record temperatures, hydrogen ion concentration (pH), water activity,
other conditions that control or prevent the growth of microorganisms or
other contamination must be:

\(i\) Accurate and precise;

Comment: The requirement in section 111.25 (a) (6) (i) for instruments
and controls to be "accurate and precise" implies a significant
requirement beyond typical calibration that would require full
validation of all instruments and controls. We agree that instruments
and controls should be routinely calibrated for accuracy, but a
determination of *precision* is an unnecessary burden and expense for
most manufacturing applications. We believe that calibration to ensure
the accuracy of instruments and controls would be sufficient to assure
control or prevention of the growth of microorganisms or other
contamination in most situations. For instance, if thermometers are used
to monitor storage conditions in a warehouse where dietary supplement
tablets are stored, a determination of precision for the thermometers is
not generally necessary to assure against contamination of the tablets.
While there may be specific situations where precision would be an
important factor in assuring against product contamination, a
determination of precision should not be a universal requirement for all
instruments and controls. A requirement to determine the precision of
instruments and controls should be limited only to situations where such
determination is necessary to prevent contamination.

§ 111.25 [What requirements apply to the equipment and utensils you
use?]{.underline}

(b)(1) You must calibrate instruments and controls you use in
manufacturing or testing a component, dietary ingredient, or dietary
supplement.

\(2\) You must calibrate before first use; and

(i) As specified in writing by the manufacturer of the instrument and
    control, or

(ii) At routine intervals or as otherwise necessary to ensure the
     accuracy and precision of the instrument and control.

Comment: Section 111.25 (b) (2) (ii) requires calibration of instruments
and controls calibrated to ensure "accuracy and precision." As stated
above, we believe that calibration to ensure accuracy alone is
sufficient for most instruments and controls and a requirement to
determine the precision of instruments and controls should be limited
only to situations where such determination is necessary to prevent
contamination.

§ 111.30 [What requirements apply to automatic, mechanical, or
electronic equipment?]{.underline}

\(a\) When you use automatic, mechanical, or electronic equipment to
manufacture, package, label, and hold a dietary ingredient or dietary
supplement, you must:

\(2\) Determine the suitability of your equipment by ensuring that your
equipment is capable of operating satisfactorily within the operating
limits required by the process.

Comment: The requirement in proposed section 111.30 (a) (2) to
"determine the suitability of your equipment by ensuring that your
equipment is capable of operating satisfactorily within the operating
limits required by the process" is vague and subject to many
interpretations. This situation may cause an uneven playing field among
companies that apply differing standards to this requirement.
Furthermore, the vagueness of this proposed requirement could
potentially cause uneven enforcement, depending on the individual
experience and understanding of FDA investigators. The terms
"suitability" and "capability" might be interpreted to imply validation.
However, Pharmavite submits that validation is unnecessary and overly
burdensome for equipment used in manufacturing dietary ingredients and
dietary supplements. Validation, as currently applied in the drug
industry, is a very costly proposition. For instance, development of a
validation master plan may cost \$15-20,000 or more. "Installation
qualification" and "operational qualification," which are key elements
of equipment validation, may cost roughly 10% of the equipment cost
(including protocol and execution). "Performance qualification" and
revalidation would add further costs, depending on the size of the
company and the amount of equipment involved. Furthermore, additional
personnel would be required to manage and execute a validation program.

Related to this proposed requirement, the preamble states that "systems
need to be installed in a manner that takes in to account the inherent
limitations of the system, tested under conditions that reflect actual
conditions of use." However, this explanation is equally vague and
subject to multiple interpretations.

[]{.mark}

We do not believe that it is FDA's intention to require full validation
of equipment used to process dietary ingredients and dietary supplements
and we ask that the agency confirm this. In any case, the requirements
under section 111.30 (a) (2) need to be clarified further to assure that
the requirements are evenly applied. We also encourage FDA to develop a
separate guidance document with respect to determining the suitability
and capability of equipment used in the manufacture of dietary
supplements.

§ 111.35 [What production and process controls must you
use?]{.underline}

\(d\) Any substance, other than a \`\`dietary ingredient\'\' within the
meaning of section 201(ff) of the Federal Food, Drug, and Cosmetic Act
(the Act), the intended use of which results or may reasonably be
expected to result, directly or indirectly, in its becoming a component
or otherwise affecting the characteristics of the dietary ingredient or
dietary supplement must be:

\(3\) If used as a color additive, subject to a listing that, by the
terms of that listing, includes the use in a dietary supplement;

Comment: Section 111.35 (d) (3) is potentially confusing. This provision
states that a color additive may only be used in a dietary supplement if
it is subject to a color additive listing which "by the terms of that
listing, includes the use in a dietary supplement." This language could
potentially be construed to mean that is not sufficient for a listing to
state that a color additive is permissible for use in foods generally,
but that a color additive listing must expressly state that a color
additive is permissible in dietary supplements. While 21CFR Part 74
lists several certified color additives, such as FD&C Red No. 3, that
"may be safely used for coloring foods generally (including dietary
supplements)," 21CFR Part 73 lists several coloring agents, such as
caramel, that are exempt from certification that do not contain the same
parenthetical mention of dietary supplements. We do not believe that it
is FDA's intention to exclude such color additives from use in dietary
supplements, but feel that this potential misunderstanding should be
clarified in the final GMP regulation.

§ 111.35 [What production and process controls must you
use?]{.underline}

\(g\) You must ensure, through testing or examination, that each
specification that you established under paragraph (e) of this section
is met. Specific testing requirements are as follows:

\(1\) You must test each finished batch of the dietary ingredient or
dietary supplement produced before releasing for distribution to
determine whether established specifications for identity, purity,
quality, strength, and composition are met provided that there are
scientifically valid analytical methods available to conduct such
testing.

\(2\) For any specification for identity, purity, quality, strength, or
composition for which you document cannot be tested on the finished
batch of a dietary ingredient or dietary supplement, because there is no
scientifically valid analytical method available for such testing, then
you must:

\(i\) Perform testing on each shipment lot of components, dietary
ingredients or dietary supplements received to determine whether such
specification is met; and

\(ii\) Perform testing in-process in accordance with the master
manufacturing record where control is necessary to ensure the identity,
purity, quality, strength, and composition of dietary ingredients or
dietary supplements; and

\(3\) Your quality control unit must determine when finished batch
testing cannot be completed for any specification on the identity,
purity, quality, strength, and composition of dietary ingredients or
dietary supplements.

Comment: The requirement in section 111.35 (g) to test each batch of
dietary ingredient or dietary supplement for every established
specification is extremely burdensome and is unnecessary when an
appropriate system of qualifications and controls is employed by the
manufacturer. We believe that the primary means of assuring safe, high
quality products is essentially three-fold:

First, high quality components must be used that meet established
specifications. This requires an understanding of the processes and
controls used by the component manufacturer and pre-qualification of the
component manufacturer's capabilities to help assure that the component
meets all applicable specifications. Such assurance also involves
testing of the component, which may be accomplished by any of the
component manufacturer, the receiving party or a third party laboratory.
In lieu of full testing by the recipient of the component, bona fide
testing, documented on a certificate of analysis from the component
supplier should be sufficient evidence of conformance to specifications.
However, reliance on a supplier's certificate of analysis should be
conditioned on a qualification program whereby the recipient
independently verifies the supplier's ability to perform appropriate
tests and confirms the supplier's test results on a periodic basis. In
all cases, the recipient of the component should also conduct suitable
identification testing to assure the correct component has been
received.

Second, dietary ingredients and dietary supplements should be
manufactured according to a comprehensive system of process controls.
Most of the elements of a comprehensive process control system are
already stated in the proposed GMP. These include requirements for
appropriate employee training, the use of reliable production processes,
the use of suitable and capable equipment, calibration of instruments
and controls, appropriate oversight of critical operations by the
quality control unit, the use of master batch records, and the
application of appropriate in-process controls. In addition, as
described above, we believe that certain written procedures for key
manufacturing operations offer valuable further assurance that
consistency and reliability are maintained in production operations.

The last major element of assuring safe, high quality products is
testing. However, if the first two factors discussed above are
adequately implemented, it is not necessary to test every finished batch
for conformance to every specification. Testing should be strategically
employed to verify that other control procedures have accomplished their
intended result. For this purpose, if other controls are adequate as
discussed above, a statistically-based testing program should be
permitted for finished products instead of the proposed requirement for
testing every batch for every specification.

If complete testing of every batch of finished product is required as
stated in the proposal, testing costs for dietary ingredients and
dietary supplements will increase dramatically. Most firms will not only
need to hire additional chemists and purchase additional testing
equipment to meet this requirement, but additional time will be required
for the production cycle that will add indirect inventory carrying
costs.

We note that the drug GMP's require testing for the identity and
strength of each active ingredient in each batch of finished drug
product. However, this is no basis for requiring similar testing for
dietary supplements. In the case of drugs which are used for therapeutic
purposes, it is critical that the correct active ingredients at the
correct dosage be present every time in each dosage unit. While dietary
supplements also perform important functions, this same critical
importance does not apply. Dietary supplements supplement the diet with
useful dietary ingredients, but they are foods providing nutritional
support and not drugs. We are not aware of any food manufacturing
process in which every batch of food is routinely tested in finished
form as to the identity and amount of their ingredients. This includes
cereals and other conventional foods which are an alternate source of
the nutrients contained in multivitamin and mineral supplements.

With respect to finished product testing, the congressional mandate that
these regulations be based on the food GMP's rather than the drug GMP's
should be followed.

§ 111.35 [What production and process controls must you
use?]{.underline}

\(i\) (4) (iii) You must not reprocess any component, dietary ingredient
or dietary supplement if it is rejected because of contamination with
microorganisms or other contaminants, such as heavy metals;

Comment: The proposed prohibition in section 111.35 (i) (4) (iii)
against reprocessing any component, dietary ingredient or dietary
supplement that is rejected because of contamination with microorganisms
or other contaminants, such as heavy metals, is unnecessarily
restrictive, unjustified and should be eliminated. Manufacturers should
be permitted to use any appropriate means to restore a product to
original specifications if a process can be adequately demonstrated to
be safe, reliable, effective and otherwise permitted by law or
regulation. For instance, irradiation or treatment with ethylene oxide
may be an acceptable means of eliminating microorganism contamination in
certain dietary ingredients. Other suitable technologies for removing
contaminants may also exist or may be developed in the future.
Therefore, GMP requirements should not unnecessarily limit the range of
options available to a manufacturer to reprocess a product to enable it
to meet original specifications.

§ 111.37 [What requirements apply to quality control?]{.underline}

\(b\) Your quality control unit must do the following:

\(6\) Review and approve all processes for calibrating instruments or
controls;

Comment: While it is appropriate for the quality control unit to be
involved in assuring that calibration of instruments and controls occurs
and that results are within specification, the quality control unit is
not necessarily the most qualified party to approve the process used to
calibrate such devices. An option should be provided that would allow
the quality unit to consult with any adequately qualified individual,
including a third party who is qualified by training and/or experience,
to establish and approve the procedures used in the calibration of
instruments and controls. Many modern instruments and controls are
extremely complex devices and are designed such that a typical quality
control person may not have the knowledge to determine the appropriate
means of calibration. The process used to calibrate such devices is
often determined by the manufacturer or qualified service staff of third
party companies that specialize in this type of work. Therefore,
appropriate alternatives should be permitted to assure that appropriate
calibration processes are employed.

§ 111.37 [What requirements apply to quality control?]{.underline}

\(b\) Your quality control unit must do the following:

\(12\) Keep the reserve samples for 3 years from the date of manufacture
for use in appropriate investigations including, but not limited to,
consumer complaint investigations to determine, for example, whether the
dietary ingredient or dietary supplement associated with a consumer
complaint failed to meet any of its specifications for identity, purity,
quality, strength, and composition. The reserve samples must:

\(i\) Be identified with the batch or lot number; and

\(ii\) Consist of at least twice the quantity necessary for tests.

Comment: The proposed GMP is confusing with respect to the types of
reserve samples that must be maintained and this point should be
clarified. For example, section 111.37 (b) (12) states that the quality
control unit must keep "the reserve samples," but does not indicate the
type of reserve samples that must be kept. Confusion is added by the
preceding section 111.37 (b) (11), which refers to the collection of
various types of "representative samples," which includes in-process
samples. Comparing these two provisions might suggest that reserve
samples of in-process materials are be required. However, section 111.50
(h) states that "You must collect representative reserve samples of each
batch of dietary ingredient or dietary supplement...," and requires
collection of reserve samples for received components. Finally, section
111.83 addresses the conditions for *holding* reserve samples of
components, dietary ingredients and dietary supplements, but there is no
reference elsewhere regarding the *collection* of component reserve
samples.

We believe that manufacturers should be required to retain reserve
samples of each lot of each received component used in the manufacture
of a dietary ingredient or dietary supplement, as well as a reserve
sample of each lot of finished dietary ingredient or dietary supplement
produced by the manufacturer's operation. We believe that it would be
unnecessary, impractical and extremely burdensome to maintain reserve
samples of in-process materials. Such samples would be largely
duplicative of retained samples of finished dietary ingredients or
dietary supplements and this practice would require significant
additional documentation, time and space for manufacturers to maintain
such samples.

§ 111.45 [What requirements apply to establishing a master manufacturing
record?]{.underline}

\(b\) The master manufacturing record must include the following
information:

\(8\) Written instructions including, but not limited to, the following:

\(iii\) Specific actions necessary to perform and verify points, steps,
or stages, necessary to meet specifications and otherwise prevent
adulteration, including, but not limited to, one person weighing or
measuring a component and another person verifying the weight or measure
and one person adding the component and another person verifying the
addition;

Comment: The requirement for master batch records to include written
instructions for one person to weigh or measure a component and another
person to verify the weight or measure and for one person to add the
component and another person to verify the addition is overly
prescriptive. Alternate, reliable methods of verifying the weighing and
addition of components should be permitted. For example, many
manufacturers use bar code systems to identify the weight and identity
of components both before and after weighing. In such cases, a computer
generated weigh record and corresponding bar code can be created and
affixed to the container by one individual as reliable verification of
the material's contents and weight. Likewise, the addition of components
to a blender can be adequately controlled and verified by one person
through scanning technology that allows reliable verification of the
identity and weight of components added to a blender without the need
for a second person.

§ 111.45 [What requirements apply to establishing a master manufacturing
record?]{.underline}

\(b\) The master manufacturing record must include the following
information:

\(8\) Written instructions including, but not limited to, the following:

\(v\) Corrective action plans for use when a specification is not met.

Comment: It is not practical to include detailed corrective action plans
in master batch records, because specific defects in a batch and
responsive corrective actions cannot be anticipated with sufficient
specificity to allow for such instructions. As an alternative, it would
be reasonable to include general instructions in the master batch record
that in the event specifications are not met, that the quality control
unit must be notified and must approve any corrective action plan.

§ 111.50 [What requirements apply to establishing a batch production
record?]{.underline}

\(c\) The batch production record must include, but is not limited to,
the following information:

\(4\) The date and time of the maintenance, cleaning, and sanitizing of
the equipment and processing lines used in producing the batch;

Comment: The date and time of cleaning, sanitizing and maintenance of
equipment and processing lines should not have to be recorded in product
batch records. It should be acceptable, and perhaps preferable, to
record and maintain such information in a separate equipment log book,
which offers the advantage of providing a chronological reference to the
sequence of batches processed on a particular piece of equipment. Such
sequential information may be useful in investigating potential
instances of product cross-contamination.

§ 111.50 [What requirements apply to establishing a batch production
record?]{.underline}

\(c\) The batch production record must include, but is not limited to,
the following information:

\(7\) The initials at the time of performance or at the completion of
the batch of the person responsible for verifying the weight or measure
of each component used in the batch;

\(8\) The initials at the time of performance or at the completion of
the batch of the person responsible for verifying the addition of
components to the batch;

Comment: As indicated previously in the comment to section 111.45 (b)
(8) (iii), reliable alternate means of verifying the weight or measure
of components should be permitted in place of a second person witnessing
the weighing or addition of a component to a batch. As discussed,
scanning technology offers an alternate means whereby one person can
reliably verify the weight and identity of components. When such
alternate means of verification are used, a second person should not be
required to verify the weighing, measuring or addition of a component
used in a batch.

§ 111.50 [What requirements apply to establishing a batch production
record?]{.underline}

\(c\) The batch production record must include, but is not limited to,
the following information:

\(12\) Copies of all container labels used and the results of
examinations conducted during the label operation to ensure that the
containers have the correct label;

Comment: Section 111.50 (c) (12) is potentially confusing, because it
does not specify what is meant by "label operation." During the course
of manufacturing operations, containers holding in-process materials are
often labeled. We do not believe that it is FDA's intention to require
the retention of copies of in-process container labels, nor would this
activity add significant value toward the assurance of quality products.
Therefore, we suggest that this section be clarified to indicate that it
refers only to finished or end-stage product container labeling and not
to in-process container labeling operations.

§ 111.50 [What requirements apply to establishing a batch production
record?]{.underline}

\(h\) You must collect representative reserve samples of each batch of
dietary ingredient or dietary supplement and keep the reserve samples
for 3 years from the date of manufacture for use in appropriate
investigations including, but not limited to, consumer complaint
investigations to determine whether, for example, the dietary ingredient
or dietary supplement associated with a consumer complaint failed to
meet any of its specifications for identity, purity, quality, strength,
and composition.

Comment: The requirement in section 111.50 (h) to maintain reserve
samples of each batch of dietary supplement for three years from the
date of manufacture may be insufficient. Some dietary supplements are
labeled with expiration dates of five years or longer. Although most
dietary supplements are consumed within a year or two of manufacture,
situations occur where such products may be in commerce and consumed
several years after manufacture. In these relatively few cases, three
years of reserve retention are not adequate to assure that product
samples would be available for examination or testing if a problem
occurred. Therefore, we believe that reserve samples of dietary
supplements packaged for consumer or retail sale should be maintained
for the longer of three years from the date of manufacture or one year
beyond the expiration date of the batch, if an expiration date is
indicated on the product.

In addition, we believe that a minimum storage period should be required
for reserve samples of received components. Reserve samples of
components should be maintained for a period equivalent to the longer of
three years from the date of manufacture of the last batch of a dietary
ingredient or dietary supplement in which the component is used, or one
year beyond the expiration date of the manufactured batch, if an
expiration date is indicated on the labeling of the batch.

§ 111.70 [What requirements apply to packaging and label
operations?]{.underline}

\(g\) The person that performs the requirements of this section must
document at the time of performance that the requirements are performed
including, but not limited to, documentation in the batch-production
record of:

\(1\) The identity and quantity of the packaging and labels used and
reconciliation of any discrepancies between issuance and use;

Comment: Comprehensive label reconciliation should not be required if
appropriate electronic controls are instituted to assure that correct
labels are used during dietary supplement labeling operations. It should
be noted that 21 CFR 211.125 (c) is worded broadly enough to permit this
alternate for drug labeling operations, which are generally identical or
similar in nature to dietary supplement labeling operations. The same
flexibility for an alternative means of assuring proper labeling should
be afforded to dietary supplement manufacturers as is permitted for
drugs.

§ 111.85 [What requirements apply to returned dietary ingredients or
dietary supplements?]{.underline}

\(b\) You must not salvage returned dietary ingredients and dietary
supplements, unless:

\(2\) Tests demonstrate that the dietary ingredients or dietary
supplements meet all specifications for identity, purity, quality,
strength, and composition.

Comment: The definition of "salvage" is unclear in section 111.85 (b)
(2), but it could be interpreted to include the practice of inspecting
and restocking returned products that do not bear any evidence of
improper storage conditions. If this is the case, the requirement to
test such returned products is unnecessary and overly burdensome.

Frequently dietary ingredients and dietary supplements are returned
simply because they represent excess inventory or were shipped
incorrectly as the result of an ordering error. In such cases, it should
only be necessary for the quality control unit to physically inspect the
returned product to verify that the product is within acceptable shelf
life (if labeled with an expiration date) and that the containers are
sealed, undamaged and otherwise bear no indication that the product was
stored under improper conditions. Testing of returned product should
only be required when there is reason to suspect that the product was
stored under improper conditions, similar to the requirement for drugs
under the drug GMP regulations. The GMP for drug products requires
retesting of returned drug products only if there is a question whether
a drug product has been subjected to improper storage conditions, such
as extremes in temperature, humidity, smoke, fumes, pressure, age, or
radiation due to natural disasters, fires, accidents, or equipment
failures. In contrast, as proposed, the dietary supplement GMP seems to
require testing prior to salvaging (interpreted to include the simple
restocking of) any returned products, regardless of the reason for
return or the conditions in which the product was stored. We believe the
dietary supplement GMP's should be consistent with and no more
burdensome than drug GMP requirements in this respect.

§ 111.90 [What requirements apply to distributing dietary ingredients or
dietary supplements?]{.underline}

Comment: The ability to quickly and efficiently recall a product is an
important safeguard in assuring public health in the event of serious
problem. Therefore, we believe that section 111.90 and related
recordkeeping sections of the proposed GMP's should also include a
requirement for the manufacturer of a dietary ingredient or dietary
supplement to maintain finished product distribution records that
provide the ability to trace the shipment of each product batch in the
event a recall is indicated.

§ 111.125 [What requirements apply to recordkeeping?]{.underline}

\(a\) You must keep written records required by this part for 3 years
beyond the date of manufacture of the last batch of dietary ingredients
or dietary supplements associated with those records.

Comment: Similar to preceding comments about the length of time required
for maintaining reserve samples in section 111.50 (h), written records
associated with the manufacture of a batch of dietary ingredients or
dietary supplements should be maintained for the longer of three years
from the date of manufacture of a batch to which the records pertain, or
one year beyond the expiration date of the batch, if an expiration date
is indicated on the product label.

Clarification is also needed with respect to the definition of the "date
of manufacture." If an expiration date is shown on the label of a
product, we believe the date of manufacture should be considered to be
the date on which the expiration date is based. For tablets and
capsules, this is generally the date the finished dosage form is
released and becomes available for packaging. For instance, if vitamin C
tablets have a two year shelf life and are compressed, tested and
approved for packaging in August 2003, they would generally be assigned
an expiration date of August 2005 regardless of the date of packaging.
If the tablets were held and later packaged in February 2004, records
for this batch should only have to be kept for one year beyond the
expiration date (i.e. August 2005), rather than three years beyond the
packaging date (i.e. February 2006).

[Summary]{.underline}

FDA has a unique opportunity to create a balanced, workable GMP standard
for the manufacture of dietary ingredients and dietary supplements. The
final regulation should reflect the intent of DSHEA that the standard be
modeled after food GMP's, but should also include additional, necessary
elements to assure against adulteration. Consistent with current best
industry practice, this standard should rely on assured ingredient
quality and rigorous process control more than final product testing.
Written procedures should be required for key steps related to the
control of manufacturing equipment, materials and processes. Adequate
flexibility should also be provided throughout the regulation to
accomplish the goal of producing unadulterated products without
requiring practices that are overly prescriptive.

Sincerely,

Paul Bolar

VP, Regulatory & Legal Affairs

Pharmavite LLC