Pharmaton Natural Health Products, a division of Boehringer Ingelheim
Pharmaceuticals, Inc. (Pharmaton) markets Ginsana®, Ginkoba® and other
leading branded herbal products in the dietary supplement industry.
Pharmaton has been a strong supporter of Good Manufacturing Practices
(GMPs) over the years, and was part of the coalition of experts that
prepared, through our Trade Associations, the industry draft GMPs that
were submitted to FDA in November 1995. This submission was published as
the ANPR on dietary supplement GMPs in 1997.

Although we support GMPs for dietary supplements, we believe the
proposal needs substantial amendment in order to achieve its stated
objectives. We have the following general comments on these proposed
rules.

Congress enacted a provision of the Dietary Supplement Health and
Education Act authorizing FDA to adopt dietary supplement GMPs "modeled
after" food GMP regulations. Pharmaton is concerned that the proposed
rules are not sufficiently modeled after food GMPs. We understand that
the GMPs required of dietary supplement manufacturers are not intended
to be identical to food GMPs, it is nevertheless relevant during this
comment period to consider the origins of each component of the FDA
proposal and to consider whether the total document is sufficiently
modeled after food GMPs.

In comparing the GMPs for drugs, foods, the dietary supplement ANPR and
this proposal, the origins of several components of the rule are
evident. The comparison clearly identifies some areas in which the drug
GMPs or other provisions appear to have served as the model. We do not
believe that these proposed rules are sufficiently modeled after the
food GMPs and therefore do not meet the statutory requirements for GMP
regulations for dietary supplements. Pharmaton continues to support GMP
regulations for dietary supplements provided that they strike the proper
balance between effective control and necessary flexibility.

The proposed rules attempt to encompass manufacturers of dietary
ingredients as well as manufacturers of dietary supplement products.
Clearly this expansion of authority is unwarranted by the act and
unworkable in practice. Many of the ingredients used in dietary
supplements are identical to those used in drugs or foods. It would be
unnecessary and prohibitively expensive to require major agricultural
and chemical product manufacturers to have different GMPs for
ingredients sold to the dietary supplement industry as opposed to the
very same ingredients sold to the conventional food industry.

The proposed anticipates that establishing dietary supplement GMPs will
totally eliminate product recalls and other similar errors. It is
impossible to eliminate human error, as is seen with the number of
recalls and medication errors seen even with pharmaceutical GMPs. The
effect of these rules should be associated with reasonable potential
benefits.

Additionally, these proposed rules do not allow for any level of trust
and cooperation among manufacturers and suppliers. For example, a
dietary supplement manufacturer is not allowed to rely upon a supplier's
certificate of analyses to accept incoming materials. This is permitted
in the drug industry and is a current custom in both the drug and food
industries. However, these rules would prohibit the practice in the
dietary supplement industry. This type of inequity must be eliminated
from the rules. The final regulation should describe only those rules
that are minimally necessary to assure the product's identity, purity,
quality, strength and composition.

These proposed rules rely more on exhaustive testing of final product
than describing the elements of a well-controlled manufacturing process.
The long-standing Agency policy was that quality cannot be "tested into"
a product, but that quality is "built in" as a result of a
well-controlled production process. The final rules should revert to the
established policy of building in quality rather than requiring
detailed, extensive and unnecessary testing of the final product.

We also believe that written procedures are an integral component of the
process of assuring a well-controlled production process. We are unsure
why the Agency eliminated this proposal from the ANPR, but would request
that it be restored. It is impossible to assure the adequacy of a
process in the absence of written procedures for key operations.

Also eliminated from the ANPR was the requirement for expiration dating.
This is an essential element of quality product labeling and is being
demanded by consumers and retail establishments. The final rules should
describe an appropriate model for establishing expiration dating on
dietary supplements based on current practices in shelf-life dating for
foods.

Furthermore, the economic impact on large manufacturers as well as small
companies is vastly underestimated, by at least an order of magnitude.
Production volume of large companies is immense, and the increased
testing burden proposed under these rules would be both enormous and
unjustified, particularly when a well-controlled process for quality
assurance is in place.

Finally, the ability of GMP regulations to improve quality in dietary
supplement manufacturing will be directly related to the degree of
enforcement the Agency gives to these regulations. As we know, the
Agency has had ample authority to bring actions against dietary
supplement manufactures that make products that contain the wrong
ingredients, do not contain the amount of ingredients identified on the
label, contain prescription drugs, or make outrageous claims for their
product. However, the Agency has chosen not to use their authority to
stop these practices. If the Agency chooses to enforce these rules with
the same vigor they have applied to existing regulations, the industry
will see no level of improvement.

We wish to thank the Agency for this opportunity of comment on the
proposed GMP regulation for dietary supplements. We continue to support
GMPs for dietary supplements and hope that these comments will assist
the Agency in crafting GMP regulations for dietary supplements that
strike the proper balance between effective control and necessary
flexibility.

Sincerely,

David R. Morrison

The key areas of concern will be those proposed requirements concerning
the scope of record keeping and FDA access to those records, the
imposition of essentially a "Hazard Analysis Critical Control Point"
(HACCP) system on manufacturing, the burdens involved in utilizing
non-dietary ingredients as "GRAS," and the requirement for a
centralized, omnipotent quality control unit.

> The proposal would apply to a broad range of activities connected with
> dietary ingredients and dietary supplements. It would cover entities
> that manufacture, package, or hold dietary ingredients or dietary
> supplements in the United States, including those involved in testing,
> quality control, packaging, labeling, and distribution. It would also
> cover foreign entities that manufacture, package or hold these
> products for distribution into the United States.[^1] \[Hereinafter,
> entities covered by the proposed rule will be referred to as
> "companies."\]

## Proposed Requirements by Segment

To accomplish the twin, broad goals of reducing adulteration and
mislabeling of dietary ingredients and dietary supplements, the proposal
sets forth specific requirements and guidance in seven categories. For
certain categories, including personnel, physical plant, and equipment
and utensils, the requirements proposed parallel those rules that
already regulate "food" generally under the FDCA. In these areas,
however, FDA proceeds in much greater detail than in food GMPs. Other
requirements are peculiar to dietary ingredients and dietary
supplements. In general, FDA is proposing to regulate the manufacturing
*process,* as opposed to its results. This proposed rule entails an
extraordinarily high degree of specificity, in contrast to the brief,
principle-based CGMPs for conventional food or drugs under existing FDA
rules. This memorandum will convey the types of requirements proposed in
each of the seven categories but will not attempt to swallow the sea of
detail.

1.  Personnel

    Companies would have to maintain a staff of qualified employees. FDA
    leaves the number of staff up to each company's discretion but
    recommends a minimum of two. Employees would need sufficient
    training and experience to perform their assigned duties.
    Supervisors would also need to be qualified and adequate in number.
    Companies would be required to clearly impress upon them their
    responsibility to ensure that all proposed CGMPs are met.

Companies would be required to develop procedures for excluding from
operations those personnel who might cause microbial contamination. The
requirement would exclude from operations any person while he or she (by
medical exam or a supervisor's observation) at least appears to have an
illness, open lesion, or other condition which may be expected to result
in microbial contagion of components,[^2] dietary ingredients, dietary
supplements, or contact surfaces. A company would need to instruct
employees to notify their supervisors of any reasonable possibility that
they have a health condition that could cause such contamination.

The proposal mandates hygienic practices for personnel to the extent
necessary to protect against contamination. Required practices would
include wearing outer garments, maintaining personal cleanliness,
washing hands adequately, and securing or removing jewelry.

2.  Physical Plant Environment

A company's physical plant would need to be designed and constructed in
a matter that protects against product adulteration during
manufacturing, packaging, and holding. The proposed provisions are
similar to existing GMPs for facilities associated with conventional
food, except that this proposal's requirements do not extend to upkeep
of the grounds that border a physical plant. They would require that the
plant's interior facilitate maintenance, cleansing, and sanitizing
operations. Walls, floors, and ceiling would need to be hard, smooth
surfaces. Facility design would need to permit adequate segregation of
those materials being received, stored, and rejected. The proposal also
specifies requirements for ventilation, lighting, and climate control
systems.

The proposed rules would require a company to maintain its facilities in
a clean and sanitary condition. Cleaning and sanitizing agents would
need to be free of microorganisms of public health significance. To
minimize the risk of contamination, the use or storage of toxic
materials would be permitted only under limited circumstances. The
physical plant would also need to be kept in sufficient repair to avoid
contamination of components and contact surfaces involved in the
production of dietary ingredients and dietary supplements. Holes in
walls or windows would need repair to block the entry of pests or
contaminants. Requirements regarding water supplies would be modeled
after the CGMPs for food. In any operation where water contacts
components, dietary ingredients, dietary supplements, or contact
surfaces, the water must comply with EPA's National Primary Drinking
Water regulations. Other requirements would regulate bathrooms,
hand-washing facilities, paper towels, trash bins, and sewage systems.

3.  Equipment and Utensils

Equipment and utensils would need the proper design, construction, and
workmanship for their intended use. Their use could not result in
contamination of components or output from lubricants, metal or glass
fragments, fuel, etc. Proposed specifications would limit the materials
from which equipment and utensils could be made in order to minimize
seams, breaks, pits, cuts, or grooves that can harbor microorganisms.
Equipment that uses compressed air or gas may need filtration to prevent
contamination.

Instruments and controls such as thermometers would have to be
maintained and calibrated for accuracy and precision. Companies would
have a choice: develop written procedures for calibration and then
document that those procedures were followed each time a calibration is
performed, or document at the time of performance that the calibration
was performed in accordance with this section.

Companies would have to perform specified steps to ensure that
automatic, mechanical, and electronic equipment operates as intended and
remains suitable for its task. The current proposal would not impose a
verification system, i.e. ensuring that the processes that this
equipment performs consistently produce results that meet preset
specifications and quality traits.

All equipment, utensils, and contact surfaces used to manufacture,
package, or hold dietary ingredients or dietary supplements would have
to be maintained, cleaned, and sanitized. All other surfaces would need
to be cleaned regularly too. The requirements would also govern the
storage and disposal of single-use and disposable items.

4.  Production and Process Controls

This section of the proposal, draft 21 C.F.R. 111.35, and the following
sections that elaborate on elements of production and process controls,
such as quality control, component controls, and master and batch
production records, are the core of the major new requirements for
dietary supplement manufacturing. These sections impose requirements
from product conception through delivery to customers, and require the
creation of a quality control unit with authority to oversee and
document all the new requirements. These new requirements include the
following:

-   Companies would have to establish and utilize a quality control
    unit[^3] in manufacturing, packaging, and labeling operations. The
    proposal lists sixteen duties of the quality control unit.

-   Companies would have to evaluate and document the basis for the use
    of every component that is not a dietary ingredient, including the
    basis for GRAS status of any such component.[^4]

-   Companies would have to develop and use master manufacturing records
    and batch[^5] records to ensure consistency of output among batches,
    which records must be specific to a stock-keeping unit, because they
    are tied to specific labels.

-   Companies would have to develop and monitor specifications at every
    step in the manufacturing process where control is necessary to
    assure the identity, purity, quality, strength, and composition
    claimed on the label. Through appropriate testing,[^6] companies
    would have to monitor each such step to detect any deviations that
    could cause adulteration. Each finished batch of the dietary
    ingredient or dietary supplement would need testing before it is
    released for distribution. Any results that deviate from that
    specification would indicate possible adulteration and thus require
    investigation and a disposition decision approved by the quality
    control unit.[^7]

-   Companies would have to develop and implement procedures for dealing
    with rework, returned goods, and acceptance or rejection of
    out-of-specification components or finished product, which must be
    accepted by the quality control unit.[^8]

-   Companies would have to document the entire control process: the
    specifications established, the actual results of monitoring, any
    deviations, any corrective action taken, the disposition decision
    and follow-up, and the identities of the investigator and the
    quality control reviewer.

-   To ensure that companies receive the inputs they ordered, they would
    be required to conduct (1) a visual examination of incoming
    containers and the supplier's invoice and (2) testing where needed.
    Companies would have to quarantine incoming material until the
    quality control unit conducts the proper inspection and testing of a
    representative sample, uniquely identify each lot of arriving
    inputs, and hold them in a manner that avoids contamination,
    deterioration, and mix-ups.

-   Companies would have to develop and follow a written master
    manufacturing record (akin to a recipe) for each kind of dietary
    ingredient or dietary supplement produced. The proposal describes
    eight items that the master manufacturing record would need to
    contain.

-   Companies would also have to use batch[^9] production records to
    ensure consistency of output among batches. Batch records,
    containing fourteen items specified in the proposal, would track the
    master manufacturing record and ensure that each step is taken when
    creating the batch.

-   Companies would have to ensure that the laboratories that conduct
    their testing meet certain requirements. Laboratory control
    processes would need to use sampling plans to retain representative
    samples of inputs received, in-process materials, each batch of
    dietary ingredient or dietary supplement produced, packaging and
    labels, and each batch of finished product. For use in later
    testing, these reserve samples would be held in the same container
    and conditions as would a consumer.

-   Companies would have to take certain other precautions: chemical,
    microbiological, or other testing to prevent contamination; climate
    control to eliminate microorganisms and prevent decompositions; and
    mandatory measures to guard against the inclusion of metal slivers
    or foreign objects.

-   Companies would have to take precautions against contamination or
    deterioration from packaging or labeling operations. In filling,
    assembling, and packaging products, companies would have to guard
    effectively against adulteration and misbranding, and the proposal
    lists eight possible methods.

-   To prevent companies from mistakenly using materials that have been
    rejected by the quality control unit, companies would have to
    implement a mandatory system of identification, control, and
    quarantine that would segregate any component, dietary ingredient,
    dietary supplement, packaging and label that is deemed not suitable
    for use, i.e., not even reprocessing.

5.  Holding and Distributing

The requirements regarding holding and distributing would protect
components, dietary ingredients, dietary supplements, packaging, and
labels against contamination and deterioration. Companies holding any of
these materials would have to do so in the right conditions of
temperature, humidity, and light so that the quality of those materials
is unaffected by the holding period. The holding of these materials
would have to be organized to avoid mix-ups, contamination, or
deterioration.

The proposals would require segregation of any in-process material that
failed to meet specifications, was awaiting additional processing, or
required further study by the quality control unit. They also establish
requirements for handling dietary ingredient or dietary supplement
products that are returned by entities downstream in the distribution
channels. These returned products would only be salvageable if they had
been properly stored and tests reveal they meet all specifications.
Otherwise, they would have to be destroyed.

Proposed requirements for distribution would prevent contamination and
deterioration. They would apply equally to distributors of domestic
products and to importers who distribute foreign products.

6.  Consumer Complaints Related to CGMPs

Companies would be required to keep a written record of each consumer
complaint[^10] that was related to CGMPs. A company's quality control
unit would have to review these complaints to discern whether the
consumer complaint involves a possible deficiency in a dietary
ingredients or dietary supplements with regard to its specifications or
any other requirements of the proposed rule, including those that carry
a possible risk of illness or injury.

Companies would be required to investigate a consumer complaint when
there is a "reasonable possibility" of a relationship between the
consumption of dietary supplements and the adverse event. The proposal
describes what such an investigation would entail. FDA would not require
a company to report such complaints. But the agency strongly suggests
reporting such complaints within 15 days to the FDA's MedWatch program.

7.  Records and Record-Keeping

Companies would be required to keep records to document their compliance
with the many requirements of CGMPs. Those records would need to be
retained for three years beyond the date of manufacture of the last
batch of dietary ingredients or dietary supplements tied to those
records.

For the duration of the three-year retention period, companies would
have to keep all required records (or copies) readily available for
inspection and copying at FDA's request. Archival procedures --
microfiche and electronic -- are acceptable means of retaining records,
subject to Part 11 of FDA's regulations dealing with electronic records.

II\. Part II \-- Issues of Potential Concern

-   [Records Maintenance and Inspection]{.underline}

FDA requires significant records maintenance requirements throughout the
CGMP regulations, applicable to every element for which there is a
requirement or specification to be met. FDA justifies these requirements
by stating that the documentation is necessary to establish compliance
with the very detailed requirements of the proposed regulations.
"Records, therefore, enable you to show, and for us to determine, how
you complied with the CGMP requirements." Preamble discussion of
111.125, 68 Federal Register 12218. Not only does FDA establish a three
year records retention rule, but FDA also grants itself access to the
records, and instructs companies to make copies of the records available
to FDA. Proposed 21 C.F.R. 111.125(c).

Records access of this nature is unprecedented in the food industry.
While there are certain limited circumstances where FDA has records
access (low acid canned foods and one-up/one-down shipment records
specifically authorized under the Bioterrorism Act), FDA has generally
been denied records access to food facilities. With these proposed
regulations, FDA is making clear that it is attempting to treat dietary
supplements much more like drugs than foods, despite clear statutory
instructions to model the dietary supplement GMP regulations after the
requirements for foods. FDCA § 402(g)(2).

The precedent with respect to drugs is instructive. While FDA was given
statutory GMP authority in 1962 for all drugs, it was only given record
inspection authority with respect to new drugs and prescription drugs;
from 1962 until record inspection authority was expanded to OTC drugs in
1997 (FDAMA), FDA had to determine OTC drug manufacturer compliance with
drug GMPs without authorized access to their records. In the case of
devices, two statutory provisions -- one dealing with GMPs and the other
with mandatory record keeping -- were used by FDA to craft the device
quality system regulation. FDA has in the past accepted that the
revision of section 704 of the Act to mandate physical access to
facilities did not, absent other statutory authority which exists for
drugs and devices, authorize access to records.

FDA estimates the annual record-keeping burden of the proposed
regulation at an astounding **500,587** hours. 68 Federal Register
12219, Table 1 (emphasis added). That is the [annual]{.underline}
burden. This is an incredible amount of time and effort -- and probably
underestimated -- that will be spent creating records that then must be
maintained for at least three years, and must always be available for
FDA inspection and copying.

-   [HACCP-like Requirements]{.underline}

Proposed 21 C.F.R. 111.35 requires that dietary supplement companies
"must establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration" and then goes on to name required specifications. 21
C.F.R. 111.35(e) In FDA's Hazard Analysis and Critical Control Point
(HACCP) regulations for juice manufacturers, FDA states that the HACCP
plan shall, among other things, "list the critical control points for
each of the identified food hazards that is reasonably likely to occur."
21 C.F.R. 120.8(b)(2). "Critical control point" is defined as "a point,
step, or procedure in a food process at which a control measure can be
applied and at which control is essential to reduce an identified food
hazard to an acceptable level." 21 C.F.R. 120.3(d). The HACCP plan must
also list the critical limits (specifications) that shall be met at each
of the critical control points. These HACCP requirements sound very
similar to the requirements proposed in 21 C.F.R. 111.35(e), (f), (g),
(h), and (i). These subsequent provisions require monitoring of the
specifications to ensure they are met, testing to ensure each
specification is met, ensuring that tests are appropriate, and
establishing corrective actions if the specifications are not met. These
are the classic elements of a HACCP plan.

The statutory mandate to FDA to develop GMP regulations for dietary
supplements instructed that they be modeled on the GMP requirements for
foods. The juice HACCP regulation is not the appropriate model for FDA
to be using in establishing "food-like" GMP requirements for dietary
supplements. The requirements of a HACCP plan go well beyond the food
GMP requirements, and impose record-keeping burdens far in excess of
what Congress envisioned for dietary supplements. Again, FDA is showing
a clear intent to impose a very high regulatory burden on the supplement
industry, and a departure from treating supplements like foods, despite
the fact that they are statutorily defined as such. Separate comments to
OMB, which are due by April 14, 2003, may be appropriate, as OMB has
separate oversight of record-keeping burdens.

An alternative interpretation is that FDA is firing a warning shot at
the entire food industry that HACCP-like regulations may be on the
horizon for conventional foods, as there is nothing in the principles
embodied in proposed 111.35 that could not also be applied to
conventional foods. This could include records maintenance and
inspection authority, as FDA is already on record, from the seafood
HACCP process, that records inspection is essential to maintain a HACCP
system. The conventional food industry would be well advised to monitor
this process.

-   [Nullification of GRAS Notifications]{.underline}

Proposed 21 C.F.R. 111.35(d) requires that all non-dietary ingredient
components of dietary supplements be (1) authorized for use as a food
additive, (2) authorized by a prior sanction, (3) if used as a color
additive, used in accordance with a listing that includes use in dietary
supplements, or (4) GRAS. FDA goes on to state 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 ingredient or a dietary
supplement." FDA clarifies in the preamble discussion of this section
what is meant with respect to an explanation that the substance is GRAS.
This can be documentation supporting a determination that the substance
satisfies the requirements of a scientific procedures GRAS determination
under 21 C.F.R. 170.30(b). If relying on common use in food under 21
C.F.R. 170.30(c)(1), a manufacturer must be able to support that it was
commonly used [in a dietary ingredient or dietary
supplement]{.underline} prior to January 1, 1958. If the GRAS substance
cannot meet these standards, FDA will consider it a food additive, and
inclusion of an unapproved food additive subjects the product to
regulatory action.

FDA also discusses its GRAS Notification process, which is still
operating under a draft regulation proposed in 1997. The GRAS
Notification process is the only means currently available to receive
agency feedback on a GRAS determination. FDA responds to the
notification with a letter stating that the agency has no questions
regarding the notifier's determination that the substance is GRAS for
the proposed use. Generally, the notification process had been used in
the food industry to provide evidence to others in the industry that a
GRAS determination they had made for a substance was unlikely to be
challenged by FDA, and thus could be relied upon. In the preamble to the
dietary supplement GMP proposal, however, FDA states:

> If you submit a GRAS notification to us under the April 17, 1997
> proposed rule, our failure to object to your determination that an
> ingredient is GRAS in a dietary ingredient or a dietary supplement
> will not constitute a GRAS affirmation by us. Further, if we know of
> no reason to question the safety and lawfulness of the ingredient that
> is the subject of a GRAS notification and that is used in the
> manufacture of a dietary ingredient or dietary supplement, we would
> not object to your reliance on **your** determination that the use of
> the substance is GRAS. **You could not use our response to your GRAS
> notification as your basis for asserting compliance with the
> requirements under proposed § 111.35(d) because an FDA response letter
> to a GRAS notification is not the same as your explanation, e.g., a
> response letter does not provide an explanation for why an ingredient
> is GRAS.** 68 Federal Register at 12196. (emphasis added)

From this language, it is clear that FDA would not allow a customer to
rely on someone else's (e.g., their supplier's) determination that a
substance was GRAS, even if that determination was the subject of a GRAS
notification to which FDA did not object. Each manufacturer must have
its own determination in its files for every GRAS ingredient in a
supplement.

Because this position from FDA completely removes the utility of a GRAS
notification for purposes of customer assurance, it is likely to have a
serious impact on GRAS notifications. FDA suggests that manufacturers
should contact the agency to determine if these substances should more
properly be considered food additives. It was this position of FDA,
restricting access to supplements by regulating dietary ingredients as
food additives, that led to the push for DSHEA. While FDA must still
adhere to the statutory exemption from the definition of food additive
for dietary ingredients, few supplements consist solely of dietary
ingredients, and this provision could therefore subject many formulation
ingredients in supplements to the food additive process.

Further, as dietary supplements are foods, there is no reason that FDA
could not expand this treatment of GRAS notified substance to
conventional foods as well. If the logic holds for dietary supplements,
why would conventional foods be any different? If it is not appropriate
in FDA's view to rely on GRAS notifications as establishing GRAS status,
what is the purpose of notifications? And because notifications are the
only means to submit GRAS substances to the Agency, is this an attempt
by FDA to remove, or at least severely curtail, the GRAS option for food
ingredients? The answers to these questions will reveal much about FDA's
agenda toward GRAS substances.

-   [Centralized Quality Control]{.underline}

Proposed 21 C.F.R. 111.37 requires the establishment of "a quality
control unit to ensure that your manufacturing, packaging, labeling, and
holding operations in the production of dietary ingredients and dietary
supplements are performed in a manner that prevents adulteration and
misbranding." This means that one unit within the company must have
oversight of all these operations. Many companies are not currently set
up in this fashion. It is common for a company to have each separate
section perform its function and it own quality control. Now, the
quality control function must be centralized into one unit, and that
unit must establish very detailed requirements and documentation. The
regulation invests the quality control unit with oversight of all
operations within the facility, and requires that all aspects be tested,
approved or rejected, and that the quality control unit document all
aspects of each decision. This requirement could be cause for a major
overhaul of how dietary supplement companies operate, as their will now
be this over-arching level of approval inserted into the process. The
burden this could impose on companies that are not already set up in
this manner could be immense.

\* \* \* \* \*

Manufacturers, packagers, and holders of dietary ingredients and dietary
supplements should become familiar with the requirements of the proposed
rule regarding CGMP standards, and should make FDA aware of issues the
agency has either not addressed or has approached inadequately or
improperly. The text of the proposed rule and prior notice form
published in today's Federal Register can be found on FDA's website and
can be reached by clicking
[**here**](http://a257.g.akamaitech.net/7/257/2422/14mar20010800/edocket.access.gpo.gov/2003/pdf/03-2444.pdf).

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[^1]: Despite its breadth, the proposal would not apply to a person
    engaged only in activities associated with the harvesting, storage,
    or distribution of raw agricultural commodities that will be
    incorporated into a dietary ingredient or dietary supplements by
    other persons. This parallels the exclusion in conventional food
    CGMP for raw agricultural commodities. 21 C.F.R. 110.19.

[^2]: Component is defined as "any substance intended for use in the
    manufacture of a dietary ingredient or dietary supplement including
    those that may not appear in the finished dietary ingredient or
    dietary supplement." Proposed 21 C.F.R. 111.3.

[^3]: Quality control unit is defined as "any person or group that
    \[companies\] designate to be responsible for quality control
    operations." Proposed 21 C.F.R. 111.3.

[^4]: If a substance intended for use in a dietary ingredient or dietary
    supplement would not qualify as a "dietary ingredient" within the
    meaning of § 201 (ff) of the FDCA, then it could be used only if it
    (1) is authorized for use as a food additive under § 409, (2) if
    used as a color additive, is subject to a listing that includes use
    in a dietary supplement, (3) is authorized by a prior sanction
    consistent with 21 C.F.R. 170.3(1), or (4) is generally recognized
    as safe (GRAS) for use in a dietary ingredient or dietary
    supplement, where any GRAS claim would need to be supported by
    citation to FDA regulations or by an explanation for why the safe
    use of the substance in a dietary ingredient or dietary supplement
    is generally recognized. In this last scenario, an FDA response to
    GRAS notification would not suffice as a surrogate for the
    explanation of why an ingredient is GRAS.

[^5]: Batch is defined as "a specific quantity of a dietary ingredient
    or dietary supplement that is intended to meet specifications for
    identity, purity, quality, strength, and composition, and is
    produced during a specified time period according to a single
    manufacturing record during the same cycle of manufacture." Proposed
    21 C.F.R. 111.3.

[^6]: The testing requirements would be flexible. They would require a
    company to test final products against specifications, unless no
    scientifically valid method of analysis exits. If no such method
    exits, then companies would be required to test arriving shipment
    lots of components and to test in-process any such specification
    according to the master manufacturing record where control is needed
    to ensure the identity, purity, quality, strength, and composition
    of the product.

[^7]: The proposal identifies stages where a regulatory specification
    would be required: for materials received, for the in-process stage,
    for the finished product stage, and for packaging that could contact
    the dietary ingredient or dietary supplement.

[^8]: For those batches that fail to meet specifications, companies
    would have to follow a corrective action plan; review the monitoring
    results; and conduct a well-documented material review and render a
    material disposition decision approved by the quality control unit.
    Deviations would require rejection of the component, dietary
    ingredient, dietary supplement, packaging, or label unless the
    quality control unit decides that in-process corrections can fix the
    deviation. (However, contamination by microorganisms or heavy metals
    would preclude reprocessing.)

[^9]: Batch is defined as "a specific quantity of a dietary ingredient
    or dietary supplement that is intended to meet specifications for
    identity, purity, quality, strength, and composition, and is
    produced during a specified time period according to a single
    manufacturing record during the same cycle of manufacture." Proposed
    21 C.F.R. 111.3.

[^10]: Defined as "communication that contains any allegation, written
    or oral, expressing dissatisfaction with the quality of dietary
    ingredients or dietary supplements related to good manufacturing
    practices. Examples of product quality related to good manufacturing
    practices are: foul odor, off taste, superpotent, subpotent, wrong
    ingredient, drug contaminant, other contaminant (e.g. bacteria,
    pesticide, mycotoxin, glass, lead), disintegration time, color
    variation, table size or size variation, under-filled container,
    foreign material in a dietary supplement container, improper
    packaging, or mislabeling. For the purposes of this regulation, a
    consumer complaint about product quality may or may not include
    concerns about a possible hazard to health. However, a consumer
    complaint does not include an adverse event, illness, or injury
    related to the safety of a particular dietary ingredient independent
    of whether the product is produced under good manufacturing
    practices."