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August 11, 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**

**TOPIC: PURPOSE AND SCOPE OF THE RULE**

This is the [second]{.underline} in a series of comments submitted by
the Council for Responsible Nutrition regarding the above-mentioned
proposed rule. These comments will address the purpose and scope of the
proposed rule, as indicated below. The specific topics addressed in this
set of comments are as follows:

[Page Topic]{.underline}

3 Need for the rule

5 Purpose of the rule

8 CRN analysis of recall data

9 FDA analysis of recall data

10 FDA proposes to cover dietary ingredients as well as dietary
supplements

11 CRN proposes that the rule apply only to manufacturers of finished
products

17 DSHEA authorizes FDA to establish dietary supplement GMPs,

not dietary ingredient GMPs

18 Need to define "manufacturer"

19 Limited responsibilities of those who "hold" dietary supplements

19 Conclusion and recommendations

**Attachment A:** List of CRN manufacturer members and their

> products and brands

**Attachment B:** CRN tabulation of recalls, 1990-1999

On this same date, CRN is submitting separate comments on the importance
of process control and on legal aspects of the proposal. In addition, we
will submit a separate comment summarizing our section-by-section
recommendations. At a later date, but before September 9, we will submit
comments on the economic impact of the proposed rule. CRN has requested
and been granted this additional time for submission of economic data
based on new information we have just obtained pursuant to a FOIA
request for underlying data not previously included in the
administrative record, relating to FDA's assumptions and calculations on
the estimated economic impact of the rule. The first comment in this
series (July 8, 2003) provided a four-way comparison of the proposed GMP
with current food GMPs, the industry draft published as the ANPR in
1997, and current drug GMPs.

The Council for Responsible Nutrition (CRN) is one of the leading trade
associations representing the dietary supplement industry. CRN has been
a strong supporter of Good Manufacturing Practices (GMPs) over the
years, and we have an active Regulatory Affairs Committee composed of
industry experts in dietary supplement regulation and in the technical
aspects of production processes, including GMPs. CRN's member company
experts in this arena drafted the guidelines for nutritional supplement
manufacturing practices adopted by USP over a decade ago and also
prepared the industry draft GMPs submitted to FDA in November 1995 by
CRN, joined by other industry trade associations. FDA published the
industry draft verbatim in the ANPR on dietary supplement GMPs in 1997.

CRN member companies currently include 35 manufacturers of finished
dietary supplement products and 31 manufacturers and suppliers of bulk
dietary ingredients or other components of dietary supplements, as well
as a number of associate members that provide services to the industry.
**Attached is a list of our manufacturer and supplier members, together
with examples of the types and brands of products they market.** The
list is designed in such a way that readers of the electronic version
can click on a company name and access its website. CRN's membership
includes some very large companies that manufacture the leading U.S.
brands of dietary supplement products, that manufacture the store brands
marketed by large food and drug chains, and that manufacture and supply
key ingredients used both in conventional foods and in dietary
supplements. Our membership also includes a number of companies that are
"small businesses" as defined by the Small Business Administration but
that also have reputations as leading quality manufacturers of numerous
products or ingredients.

CRN member companies account for a substantial fraction of the dietary
supplement market in the U.S. in terms of sales volume. Using sales data
from *Nutrition Business Journal*, we calculate that nine of the top
fifteen manufacturers and marketers of dietary supplements in the U.S.
are CRN members. These companies, plus a number of smaller CRN member
manufacturers, account for about 40% of the wholesale sales volume of
dietary supplements marketed through supermarkets, natural food stores,
drug stores, and discount department stores. Six of the top twenty
companies in direct sales (called multilevel marketing by *NBJ*) are CRN
member companies, accounting for 26% of the sales volume marketed
through that channel. Eight of the top ten vitamin ingredient suppliers
are CRN member companies, providing 71% of the sales volume for
commercial vitamins used in dietary supplements annually. Another 23
supplier members of CRN provide the industry with other key dietary
ingredients including calcium and other minerals, lutein and other
carotenoids, botanicals, omega-3 fatty acids, and specialty ingredients
such as glucosamine and chondroitin sulfate.

**NEED FOR THE RULE**

CRN and its members support enhanced dietary supplement GMPs because
high quality products will better meet the needs and expectations of
consumers for improved health. Also, stronger GMPs will better reflect
actual current practices employed by responsible companies in the
manufacture of dietary spplement products. FDA, in contrast, argues that
new GMPs are needed because dietary supplement ingredients are different
in kind from conventional food ingredients and are more risky than food
ingredients. We disagree strongly with these assumptions. The fact that
CRN supports enhanced GMPs for dietary supplements is not due to any
difference in their nature, as compared to conventional foods, but is
due to the fact that current manufacturing practices in our industry
typically go beyond current food GMPs, and we believe it makes sense for
GMP regulations for our category to recognize and incorporate current
"best practices."

In the preamble to the proposed rule, FDA asserts that "dietary
supplements have their own set of unique requirements as a result of the
characteristics and hazards due to their 'hybrid' nature, e.g., dietary
supplements can be considered as falling somewhere along the continuum
between conventional foods on the one hand and drugs on the other."
Dietary supplements in fact fall squarely within the food category and
have been treated as a subset of foods for their entire history. In the
1938 Food, Drug and Cosmetic Act, dietary supplements were included in
the category called "foods for special dietary use." Such uses, as
further defined by FDA in 1941, included supplying [vitamins, minerals,
or]{.underline} [other ingredients]{.underline} for use in supplementing
the diet by increasing the total dietary intake. DSHEA in 1994 confirmed
the food status of dietary supplements and provided an expanded
definition of the category.

Dietary supplements and dietary ingredients are currently covered by the
general food GMPs in 21 CFR Part 110. Dietary supplements are foods,
comparable to fortified foods or functional foods. The ingredients used
in them are similar, and the suppliers of key ingredients serve the
conventional food industry as well as the dietary supplement industry.
The vitamins and minerals contained in leading brands of multivitamins
are exactly the same vitamins and minerals that are found in leading
brands of breakfast cereal \-- and the amounts per serving are in many
cases similar. To the extent that potential superpotency or subpotency
exists from errors during manufacturing, that potential exists for
conventional foods as well as for dietary supplements. Indeed, the Upper
Level of Tolerable Intake (UL) for niacin, established in the Dietary
Reference Intakes for B vitamins published by the Institute of Medicine
in 1998, is based in part on an incident involving accidental addition
of excess niacin in the commercial preparation of bagels and the
resultant flushing reaction experienced by some of the people who
consumed the product.

Going beyond vitamin and mineral ingredients, numerous other dietary
supplement ingredients are also identical to or similar to those used in
conventional foods. The soy components in dietary supplements are the
same ones added to cereals and breads and other conventional food
products, and the amounts provided per serving are similar. Botanical
ingredients are derived from unique plant materials, in the same manner
as common spices, and the processing techniques and quality challenges
are similar.

FDA's preamble points out that "plant products that are used to produce
dietary supplements may be ground or in a powder and not easily
recognized compared to conventional food that is readily identifiable
(e.g., one can readily distinguish between white flour and white sugar,
but not between ground plaintain and ground *D. lanata*)." FDA staff
members, in public briefings on the proposed GMP rule, have also
emphasized this presumed distinction, saying that foods contain
recognizable ingredients like peas and beans, while dietary supplements
contain less easily identifiable ingredients, usually in powdered form.
These statements do not fairly characterize the complex nature of the
modern food supply or the types of ingredients utilized in the highly
processed foods that make up a large fraction of today's market.

White flour and white sugar are hardly the only powdered and ground
ingredients used in food production or in the home, and many of the
other highly processed ingredients used in foods are also widely used in
dietary supplements. These include vitamins; soy isoflavones and other
soy components; minerals such as calcium carbonate (used for many
functions in addition to providing the nutrient calcium); antioxidants
such as erythorbate, BHA, and BHT; artificial sweeteners; various food
starches; carboxymethylcellulose and other celluloses; various
silicates; polysorbates; mono and diglycerides; fatty acid salts and
esters; protein ingredients such as casein; and various calcium
phosphates. *Food Chemicals Codex* is an excellent source for a more
complete list of ingredients commonly used both in conventional foods
and in dietary supplements. Many of these ingredients have the physical
form of a "white crystalline powder."

Finally, in attempting to distinguish between conventional food
manufacturers and dietary supplement manufacturers, FDA says "dietary
ingredient and dietary supplement manufacturing requires technical
knowledge and skill (e.g., in research and development, production
equipment and procedures, and analytical equipment and methodology) that
a vast majority of companies in the food processing industry do not
have." This is demonstrably untrue, and FDA's assertion would come as a
shock to the many sophisticated food manufacturers that supply a large
fraction of the food ingredients and conventional foods found in
supermarkets today \-- and that also provide key ingredients to the
dietary supplement industry. Current food GMPs have for many decades
provided an adequate underpinning for the manufacture of both
conventional foods and dietary supplements, even though the current
practices of leading companies in both industries go beyond the
procedures required under the food GMP regulations. CRN supports
enhanced dietary supplement GMPs because we believe the regulations
should better reflect current good manufacturing practices as actually
observed in the industry, in order to raise the bar for those companies
that are not currently producing quality products and to provide an
appropriate model for new companies entering the industry.

**PURPOSE OF THE RULE**

As FDA points out in the preamble to the proposed rule (68 FR 12159),
"Congress enacted DSHEA to ensure consumers' access to safe dietary
supplements."

The agency goes on to note that dietary supplements that are adulterated
or that fail to provide labeled amounts of dietary ingredients may harm
consumers or may fail to provide the expected health benefit. FDA
asserts that regulations on Good Manufacturing Practices (GMPs) "will
help to ensure that the potential health benefits that Congress
identified as the basis for DSHEA are obtained and that consumers
receive the dietary ingredients that are stated on the product label."

CRN agrees that new GMPs for dietary supplements will be beneficial to
consumers and to the industry, provided the regulations are
appropriately modeled after food GMPs and reasonably reflect current
"best practices" and provided they strike the correct balance between
adequate control and necessary flexibility. Responsible manufacturers
and marketers of dietary supplements already produce high quality, safe,
beneficial dietary supplements that are used and valued by more than
half the American population as well as by consumers throughout the
world, and some of these companies have been providing high quality
products for over half a century. New GMP regulations are not required
in order to provide a quality framework for responsible manufacturers.
Rather, their practices [define current GMPs]{.underline} and should
provide the basis for the rule.

CRN disagrees strongly with the implication in the preamble to the
proposed rule that product safety and quality cannot be ensured in the
absence of new GMP regulations. Existing food GMPs and other regulations
combined with the requirements of the Food, Drug, and Cosmetic Act (FD&C
Act) provide a powerful foundation for ensuring product safety and
quality, provided those requirements are enforced. Issuing new GMP
regulations will not eliminate the need for enforcement of existing
regulations or persuade rogue companies to comply with requirements they
currently ignore. Only effective enforcement against outliers can
accomplish that goal. CRN urges effective and consistent enforcement of
current food GMPs applicable to dietary supplements, of other regulatory
and legal requirements, and of any new GMPs once they become effective.

In the preamble, (68 FR 12161-2) the agency notes that "unlike other
major product areas," dietary supplements do not have category-specific
GMPs. The implication is that most other food products do have
category-specific GMPs. However, this is not the case. General food GMPs
(21 CFR, Part 110) apply to all food and food ingredient manufacturers,
including companies producing dietary supplements and dietary
ingredients. Unique GMPs have been developed for only a very few
specific product areas, such as low-acid canned foods, acidified canned
foods, and bottled water. These GMPs address only the requirements
unique to the product category and specify that companies in these
categories must still comply with general food GMPs as set forth in 21
CFR 110. There are quality standards for infant formula, but as yet no
GMPs for this critical food category. Only two FDA-regulated food
categories (juices and seafood) are covered by HACCP rules.

Most food categories are covered [only]{.underline} by general food
GMPs, and these combined with the general provisions of the law have
proven adequate to protect the food supply over the years. Unique GMPs
have been instituted generally in the wake of specific incidents leading
to a call for further action, often at the instigation of the affected
industry. In the case of dietary supplements, industry supported the
inclusion in DSHEA of language granting FDA authority to establish
unique GMPs for this product category, and CRN took the initiative in
preparing the industry draft that FDA published in 1997 in the ANPR.
This effort was undertaken as a positive move toward improved product
quality and as an affirmation of the industry's commitment to good
practices. CRN and its members are concerned by FDA's focus on the
negative, by the implication that problems that may occur cannot be
adequately addressed under existing regulations, and by FDA's erroneous
assertion that GMPs can essentially eliminate human error in
manufacturing. There needs to be full recognition of the fact that
existing regulations cover a great deal of the ground that needs to be
covered, and there needs to be a realistic expectation about what
additional assurance can be provided by new GMPs.

FDA provides nine examples of problems that it says might be avoided by
new GMP regulations. In every case, however, there were and are existing
regulations already in place that could and should have prevented the
problem from occurring and that provided the basis for effective
regulatory action once the problem did occur. One more regulation, added
to those already in place, will not make the critical difference and
will not reduce human error to zero, as predicted in the FDA analysis.
CRN makes this point, not to undermine the importance of new GMP
regulations, but to provide some perspective on what GMPs can and cannot
be expected to accomplish.

1\. FDA's first example of a problem relating to dietary supplements
relates to an occurrence that appears to be driving the direction and
focus of the entire rule. It involves an instance in which an ingredient
that purported to be plantain leaves was contaminated with leaves of
*Digitalis lanata.* Worse, the product went through the hands of
numerous manufacturers apparently without appropriate testing. FDA says
that the proposed GMP regulations "would have required identity and
purity tests" of the ingredient and the finished product and thus would
likely have prevented the mixup. This may be true, but it is also
important to acknowledge that the product was misbranded and adulterated
under current law and under current food GMPs. FDA and industry
responded rapidly as soon as the plantain mixup came to light. FDA
promptly identified the problem and warned consumers, and industry
recalled the products involved.

2\. FDA cites a report by the American Herbal Products Association
(AHPA) listing 43 botanicals that have the potential to be contaminated.
Publication of this report was a responsible educational initiative on
the part of AHPA. The report also suggests methods for testing products
in order to ensure that the potential contaminant is not present. FDA
observes that botanical manufacturers would have to establish
specifications and perform testing under the new GMPs to ensure that
there are no toxic compounds in such products. While this is true, the
need for such testing and specifications is not unique to dietary
supplements. Many basic food commodities are subject to contaminants
such as aflatoxin and mercury, for example, and FDA has established
defect action levels for some contaminants in some commodities.
Environmental chemicals present in air, soil and water are also present
in foods, and microbial contamination is an ever-present hazard in foods
that inherently provide a nutrient-rich growth medium for a wide variety
of micro-organisms. These common hazards are managed in the food
industry through application of general food GMPs. The existence of the
same potential hazards in dietary supplement ingredients does not
constitute a rationale for new GMPs that go beyond food GMP regulations.

3\. FDA says some manufacturers use chemicals that are not food-grade
and cites GBL as an example of this issue. However, the agency fails to
mention that GBL is not a legal dietary supplement ingredient in the
first place. It is available commercially as an industrial and household
solvent. FDA has taken action against GBL and the related product GHB,
which in CRN's view were illegal ingredients "masquerading" as dietary
supplements. These FDA actions have been supported by the responsible
industry. The enforcement actions were not taken on the basis of GMP
violations, but on the grounds that GBL, GHB and related ingredients are
illegal new drugs, not dietary supplements. One company filed a 75-day
notification for GBL as a "new dietary ingredient," and FDA rejected it.
New GMPs would not materially change this picture.

4\. FDA indicates that unsanitary conditions have been found in some
manufacturing facilities and says that the new GMPs would require the
companies to maintain physical plants in sanitary condition. Existing
food GMPs already require companies to maintain sanitary conditions in
their physical plants, and FDA has successfully taken action in cases
where inspections have revealed inadequate attention to sanitation.
Thus, FDA is not reliant on new GMPs for dietary supplements in order to
monitor and correct such problems. Indeed, with respect to sanitation,
the new proposed GMPs are largely identical to the current food GMPs.

5\. FDA cites some recalls of dietary supplements contaminated with
lead, glass, or micro-organisms and says that the new GMPs would require
manufacturers to prevent such adulteration. While this is true of the
new GMPs, it is also true of the existing food GMPs, and it is
inaccurate to imply that these contaminants cannot be adequately
controlled under existing GMP regulations. Adequate enforcement of
existing food GMPs would accomplish a great deal, even in the absence of
new GMPs for dietary supplements.

6\. FDA indicates that some recalls have been necessary for dietary
supplements that contained too much or too little of a labeled
ingredient such as vitamin A, vitamin D, vitamin B-6, selenium, or folic
acid. FDA points out that, under the new GMPs for dietary supplements, a
product will be required to have the amount of a substance indicated on
the label. While this is true, it is already illegal under current law
and regulations for a product not to contain the amounts of ingredients
claimed on the label. Indeed, FDA has taken action against the products
cited in this example, without needing to depend on unique dietary
supplement GMPs. Nutrition labeling regulations applicable to dietary
supplements specifically require that added nutrients (or other
substances) be present at levels that are at least 100% of the amount
claimed on the label. The dietary supplement nutrition labeling
regulations are identical in this respect to the nutrition labeling
regulations applicable to conventional foods. Even if this specific
regulation did not exist, the language of the FD&C Act declares a food
to be misbranded if its labeling is false or misleading. Also, the
Dietary Supplement Health and Education Act of 1994 (DSHEA) specifically
provides that a dietary supplement is misbranded if it "fails to have
the identity and strength" that it is represented to have or if it fails
to meet the quality or specifications it is represented to meet. Thus,
new GMPs would not be breaking new ground in requiring that a product
contain what it claims to contain.

7\. FDA indicates that some recalls of dietary supplements have been
necessary because of undeclared ingredients such as color additives,
lactose, and sulfites. FDA has full authority under the law and under
existing food GMPs to take regulatory action against such products. This
authority will not be enhanced or in any way altered under proposed
dietary supplement GMPs. It should also be noted that there have been
significantly more recalls of conventional foods than of dietary
supplements due to undeclared ingredients such as these. CRN calculated
the number of Class I and Class II recalls of all foods, including
dietary supplements, during the decade of the 1990's (1990 to 1999) from
the weekly recall reports available on the FDA website. We counted 6
recalls of dietary supplements in this period because of undeclared
ingredients, compared to over 600 recalls for conventional foods because
of undeclared ingredients. For dietary supplements, this is about 1
recall per \$3 billion in sales, and for conventional foods this is just
under 1 recall per \$1 billion in sales (based on annual sales of about
\$18 billion and \$500 billion, respectively).

8 and 9. In these two examples, FDA points out that a study of ephedra
supplements found considerable variation in alkaloid content and that
testing by a private company has revealed other instances in which
various products failed to contain the amounts of dietary ingredients
stated on the label. This suggests poor quality control on the part of
some companies in the industry. Responsible manufacturers support
enforcement of GMP regulations and other regulatory requirements in
order to correct this situation, which undermines consumer confidence
and gives the entire industry a black eye. FDA has full authority to
take action against mislabeled products. Vigorous enforcement would
effectively get the attention of the bad actors. CRN supports
appropriate new GMPs, but the new rules will improve compliance only to
the degree that they are enforced.

**CRN ANALYSIS OF RECALL DATA**

CRN analyzed the FDA weekly enforcement reports for the decade of the
1990's. **Attachment B is a table showing CRN's compilation of Class I
and Class II recalls for dietary supplements, conventional foods, and
drugs from 1990 through 1999, based on FDA's weekly enforcement reports
for this period.** For this period, FDA weekly enforcement reports show
a total of 2542 Class I and Class II recalls for conventional foods,
dietary supplements, and drugs. Of this total, dietary supplements
account for only 52. Drugs account for 997, and conventional foods
account for 1493. As a function of sales volume, the rate of recalls for
dietary supplements is comparable to the rate of recalls for
conventional foods. For both categories, there are just under 3 recalls
per billion dollars in sales volume (based on a market size of
approximately \$18 billion for dietary supplements and approximately
\$500 billion for conventional foods). This illustrates that the two
categories have a similar record for product quality and safety, to the
extent that recalls are a reflection of these characteristics.

**FDA ANALYSIS OF RECALL DATA**

FDA's preamble text reports an average of 13 dietary supplement recalls
per year during the 10-year period from 1990 through 1999, or an implied
total of 130. This is more than twice the number identified by CRN, for
the same period. One possible reason for this discrepancy is that FDA
may be counting each separate item covered by a given recall as a
separate event, as discussed below.

In the FDA tabulation of recalls, provided in Table 8 of the *Federal
Register* publication of the proposed rule, FDA lists 41 Class II
recalls relating to EMS. Based on new background information we recently
received from FDA relating to the calculations of economic impact, this
appears to have been an error. It seems that several lines of
information were omitted from Table 8 and that these 41 Class II EMS
recalls actually should have been identified as recalls of various
dietary supplements with excessive lead content. In CRN's analysis of
FDA's weekly enforcement reports, we identified 11 class II recalls of
dietary supplements relating to excessive lead content and 45 class I
and class II recalls of conventional foods due to excessive lead
content. Some of the dietary supplement recalls covered more than one
product distributed by a given manufacturer. Two of the recalls covered
5 products each, one covered 9 products, and one covered 10 products.
Only by counting these as separate recalls can we approach FDA's
reported total of 41 recalls for dietary supplements due to excessive
lead content. If this was the agency's approach to counting dietary
supplement recalls, we question its appropriateness.

Even excluding the 41 EMS recalls apparently included erroneously in
Table 8, FDA's tabulation of dietary supplement recalls still includes 7
recalls of tryptophan products related to the outbreak of EMS. These
should not have been included in the table of "ordinary" recalls, since
the tryptophan case is separately analyzed by the agency as an example
of a "rare catastrophic event," and costs associated with the EMS
outbreak are also calculated separately. Because FDA assumes every
recall is associated with an illness, then multiplies by 100 to
compensate for under-reporting, these recalls represent a number of
presumed illnesses incorrectly included in FDA's analysis of illnesses
associated with ordinary recalls.

Of the recalls tabulated by FDA, 33 are attributed to the recalls
involving dietary supplements that were intended to contain plantain
leaf but that were contaminated with leaves from the plant *Digitalis
lanata.* We have examined the FDA weekly recall reports found on the
agency's website, and we can only identify 13 digitalis recalls during
this period. We believe the agency may have counted each separate item
mentioned in each of the 13 recalls, to reach the total of 33 reported
in the table. For example, one recall for "Chomper" lists five sizes or
varieties of the Chomper product covered by the recall. This item is
listed as one recall in the FDA weekly enforcement report, and we count
it as one recall in our tabulation of recalls. Unless FDA counted this
as five recalls for purposes of its tabulation, we cannot understand how
the agency arrived at a total of 33 recalls relating to
plantain/digitalis. Counting each separate item covered by a given
recall as a separate event does not appear to us to be appropriate.

Logically, we would suggest that the plantain recall, like the
tryptophan recall, should be treated as a single rare event. Only two
adverse events were reported in association with the plantain recall,
including the one that triggered discovery of the problem. There was
very substantial publicity at the time of this recall, and a number of
related FDA consumer warnings. The FDA announcements and media attention
should have led to essentially full reporting of any adverse events
experienced by other consumers using the products. Thus, whatever the
base number of plantain recalls FDA chooses to utilize in this analysis,
it would not be appropriate to apply the 100-fold multiplication because
the assumption of under-reporting in this case is not sound.

In the analysis of economic impacts, FDA assumes that new GMPs will
reduce human error to zero and says there will be no more recalls of
dietary supplements once these regulations are in place. This is
unrealistic. In all FDA-regulated product categories, recalls occur with
regularity for a variety of reasons. GMPs will not totally eliminate
human error. CRN also disagrees with FDA's assumptions that at least one
illness is associated with every recall, and that because of
under-reporting every recall is a proxy for 100 presumed illnesses. We
will be submitting additional data and views on these points in our
comments, in the economic analysis to be submitted at a later date, as
agreed to by the agency in response to our request for additional time
to analyze underlying economic data recently provided by FDA in response
to a FOIA request.

**FDA PROPOSES TO COVER DIETARY INGREDIENTS AS WELL AS DIETARY
SUPPLEMENTS**

The FDA proposed rule on GMPs states in part 111.1: "You are subject to
the regulations in this part if you manufacture, package, or hold a
dietary ingredient or dietary supplement." Thus, FDA intends for the
rule to apply to manufacturers (suppliers) of [dietary
ingredients]{.underline} as well as to manufacturers of finished dietary
supplements.

*Nutrition Business Journal* publishes comprehensive reports on the U.S.
market for dietary supplements. In *NBJ's Supplement Business Report
2002,* the dietary supplement industry value chain is estimated to
include 250 suppliers of dietary ingredients and 925 manufacturers or
processors of finished products. If these data are correct, then
approximately one-fifth of the manufacturers covered by FDA's proposed
rule would be suppliers of dietary ingredients.

The industry draft that was published in the ANPR also was intended to
apply to manufacturers and suppliers of dietary ingredients as well as
to finished product manufacturers. The industry draft was process-based
and principle-oriented and provided enough flexibility to accommodate
the needs of a wide variety of firms with different types of products
and different types of processes. The nature of the FDA proposal has led
to reconsideration of this approach.

More importantly, during the eight years that have elapsed since
submission of the industry draft in 1995, companies and associations
have had ample opportunity to further consider all aspects of the GMP
issue and to give more attention to other GMP models, including
category-specific food GMPs and drug GMPs. These other GMPs apply only
to finished-product manufacturers and not to manufacturers and suppliers
of ingredients used in those finished products. This now seems to CRN to
be a preferable approach to accomplishing the greatest good while
controlling costs and narrowing the range of companies subjected to new
requirements.

There is of course continuing concern in all segments of the industry
regarding the best way to assure the quality of dietary ingredients as
well as finished products. CRN believes sound regulatory policy suggests
focusing the rule are carefully as possible, and we believe the best way
to do this would be to focus it on manufacturers with control over the
selection of ingredients they choose to use in their dietary
supplements, as well as over all aspects of the processing of the
finished product. We are aware that the various industry trade
associations are adopting differing approaches to this matter, as of the
date of this submission. We believe this illustrates the need for
further high-level consideration of this issue by the agency as well as
by the industry, and **we urge FDA to convene a public hearing or
workshop on this and other issues relating to dietary supplement GMPs
before proceeding to a final rule.**

**CRN PROPOSES THAT THE RULE APPLY ONLY TO MANUFACTURERS**

**OF FINISHED PRODUCTS**

The Council for Responsible Nutrition urges FDA to limit the
applicability of the proposed rule to manufacturers of finished dietary
supplements. These manufacturers should be viewed as the companies
primarily responsible for the overall quality of dietary supplements,
including the quality of the ingredients used in their formulation and
the selection of reliable suppliers of those ingredients.

The term "dietary ingredient" is not defined by FDA in the proposed
rule, but CRN will be suggesting that a definition be included. Of
course, the definition should be based on the provisions of the Dietary
Supplement Health and Education Act (DSHEA). Under DSHEA, a dietary
supplement is a product intended to supplement the diet that contains
one of more of the following "dietary ingredients:" a vitamin; a
mineral; an herb or other botanical; an amino acid; a dietary substance
for use by man to supplement the diet by increasing the total dietary
intake; or a concentrate, metabolite, constituent, extract, or
combination of any of these.

These "dietary ingredients" include a large number of ingredients that
are also commonly used in conventional foods, including specialty
products such as functional foods, medical foods and infant formula.
These ingredients are also commonly used in animal feed and pet foods,
as well as in some pharmaceutical products. Calcium carbonate, for
example, is often used as a source of the essential mineral calcium in
dietary supplements, in fortified foods, in infant formula, in medical
foods, and in pet foods and animal feed. It is also used in conventional
foods as well as dietary supplements for functional purposes other than
its nutrient value, for example as a dough conditioner or firming agent
in conventional foods and as a filler or binder in dietary supplements.
In addition, calcium carbonate is used as an active ingredient in OTC
antacid drugs. A similarly wide range of uses can be observed for other
dietary supplement ingredients, including minerals other than calcium,
all of the vitamins, a large number of amino acids, many botanical
ingredients including soy and garlic, and numerous extracts or
constituents of botanical ingredients including isoflavones,
carotenoids, and polyphenols.

In many cases, the use of a particular ingredient in the formulation of
dietary supplements accounts for only a fraction of its total use in
food and feed products in the United States. Taking vitamins as a case
in point, *NBJ's Supplement Business Report 2002* indicates that only
33% of the commercial supply of vitamins in this country is purchased
for use in dietary supplement products. For individual vitamins, the
percent that goes into dietary supplements ranges from 21 percent to 44
percent, as shown in **Table A** below. Fifty-six percent to eighty
percent of the usage for each of the vitamins goes into conventional
foods, animal feed, and cosmetics. The vitamins that go into dietary
supplements are identical to those used for other purposes, are provided
by the same suppliers, and are produced in the same facilities under the
same conditions. The key vitamin suppliers are among the largest and
most expert manufacturers involved in this industry and have a long
history of providing quality materials for use in all the industries
that rely upon them. Indeed, their manufacturing practices **should be
considered to define "good manufacturing practices"** for commercial
vitamin production.

**Table A: Fraction of U.S. Commercial Vitamin Usage by Various
Industries**

+---------------+-----------+---------+---------+----------+---------+
| **U.S.        | **Supp    | *       | *       | **Cos    | **      |
| Vitamin**     | lements** | *Animal | *Food** | metics** | Total** |
|               |           | Feed**  |         |          |         |
| **Usage -     |           |         |         |          |         |
| 2001**        |           |         |         |          |         |
+---------------+-----------+---------+---------+----------+---------+
| Vitamin A     | 41%       | 36%     | 18%     | 5%       | 100%    |
+---------------+-----------+---------+---------+----------+---------+
| B Vitamins    | 31%       | 45%     | 20%     | 4%       | 100%    |
+---------------+-----------+---------+---------+----------+---------+
| Vitamin C     | 34%       | 37%     | 26%     | 3%       | 100%    |
+---------------+-----------+---------+---------+----------+---------+
| Vitamin E     | 44%       | 36%     | 15%     | 5%       | 100%    |
+---------------+-----------+---------+---------+----------+---------+
| Other         | 21%       | 29%     | 45%     | 5%       | 100%    |
| Vitamins      |           |         |         |          |         |
+---------------+-----------+---------+---------+----------+---------+
| **Total       | **33%**   | **36%** | **27%** | **4%**   | *       |
| Vitamins**    |           |         |         |          | *100%** |
+---------------+-----------+---------+---------+----------+---------+

Source: *NBJ's Supplement Business Report 2002*

Worldwide, the share of the commercial vitamin supply that is used in
the U.S. dietary supplement market is relatively small. **Table B**,
below, shows that only 14% of the worldwide commercial supply of
vitamins goes into the U.S. supplement market. For individual vitamins,
the share of the world supply that goes into the U.S. dietary supplement
market ranges from 12 to 18 percent.

**Table B: Share of Worldwide Commercial Vitamin Supply**

**Used in U.S. Dietary Supplement Market, 2001 (\$mil)**

+-------------+-------------+-------------+-------------+-------------+
| **VITAMIN** | **          | **U.S.      | **U.S.      | **U.S.      |
|             | WORLDWIDE** | TOTAL**     | SUPPS**     | SUPPS**     |
|             |             |             |             |             |
|             |             |             |             | **% OF      |
|             |             |             |             | TOTAL**     |
+-------------+-------------+-------------+-------------+-------------+
| Vitamin C   | \$1,960     | \$700       | \$240       | 12%         |
+-------------+-------------+-------------+-------------+-------------+
| Vitamin E   | 1,330       | 550         | 240         | 18%         |
+-------------+-------------+-------------+-------------+-------------+
| B Vitamins  | 1,180       | 490         | 150         | 13%         |
+-------------+-------------+-------------+-------------+-------------+
| Vitamin A   | 700         | 220         | 90          | 13%         |
+-------------+-------------+-------------+-------------+-------------+
| Other       | 1,160       | 750         | 160         | 14%         |
+-------------+-------------+-------------+-------------+-------------+
| **TOTAL**   | **\$6,330** | **\$2,710** | **\$880**   | **14%**     |
+-------------+-------------+-------------+-------------+-------------+

Source: *NBJ's Supplement Business Report 2002*

A potential outcome of requiring suppliers of dietary ingredients to
comply with new dietary supplement GMPs could be to significantly raise
costs in order to cover new and extensive testing beyond what many
responsible companies consider to be necessary for a high level of
quality assurance. Another potential impact could be to reduce the
supply of dietary ingredients, if suppliers find it too costly to supply
the dietary supplement segment of the market and withdraw from that
segment rather than change their basic procedures to comply with new
provisions that are considered to exceed what is necessary or reasonable
for the manufacture of quality products. The potential for some key
suppliers to withdraw from the U.S. dietary supplement market may seem
more real when it is recognized that a large fraction of the supply for
many ingredients is from foreign sources.

The top 10 vitamin manufacturers in 2000 accounted for 77% of worldwide
production. As indicated by data in **Table C,** for the two largest
suppliers (Roche and BASF), only 13% of their vitamin production volume
went into the U.S. dietary supplement market. Among the other eight top
suppliers, 12 to 47% of their total vitamin production went into the
U.S. dietary supplement market. Only one of the top ten vitamin
manufacturers (ADM) is headquartered in the U.S., although all of the
top ten have large U.S. facilities. Of the other nine that were market
leaders in 2000, three were headquartered in Germany, two in
Switzerland, one in France, and three in Japan. Two of the Japanese
firms (Takeda and Eisai) have since withdrawn from the U.S. vitamin
market, although they still have a U.S. presence in other markets,
including pharmaceuticals. Market share for Chinese suppliers is growing
and is undoubtedly much greater today than it was in 2000.

**Table C: Top Vitamin Suppliers Worldwide, 2000**

  ----------------- ----------------- ----------------- -----------------
  **COMPANY**       **GLOBAL VITAMIN  **U.S. SALES FOR  **% OF COMPANY
                    SALES (\$mil)**   SUPPLEMENT USE    SALES IN U.S.
                                      (\$mil)**         SUPPLEMENTS**

  Roche             2,100-2,200       250-300           13%

  BASF              1,000-1,100       120-150           13%

  Takeda            100-200           50-60             37%

  Lonza             100-200           30-40             23%

  Eisai             100-200           20-30             17%

  Rhone Poulenc     100-200           15-20             12%

  Daiichi Fine      50-100            20-30             33%
  Chem.                                                 

  ADM               50-100            40-50             60%

  Cognis            50-100            20-30             33%

  Degussa           50-100            30-40             47%

  Chinese and       1,000             200               20%
  others                                                

  **TOTAL**         **\$5,100**       **\$850**         **17%**
  ----------------- ----------------- ----------------- -----------------

Source: *NBJ's Supplement Business Report 2002*

On the botanical side of the business, eleven of the top 26 suppliers
are headquartered outside the U.S. and account for 36% of the current
supply of botanical ingredients, as shown in **Table D**, below.

**Table D: Top U.S. Herbal/Botanical Ingredient Suppliers, 2000**

+----+---------------------+-------------+----------------+-----------+
| ** | **Company**         | #### HQ     | **2000 US      | **Cum     |
| Ra |                     |             | Herb/Bot Raw   | Share of  |
| nk |                     |             | Matl Sales     | Market    |
| ** |                     |             | (\$mil)**      | \***      |
+----+---------------------+-------------+----------------+-----------+
| 1  | Martin Bauer Group  | Germany     | 60-70          | 10%       |
+----+---------------------+-------------+----------------+-----------+
| 2  | Hauser Inc.         | United      | 60-65          | 20%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 3  | Indena              | Italy       | 35-40          | 25%       |
+----+---------------------+-------------+----------------+-----------+
| 4  | Degussa AG          | Germany     | 30-40          | 30%       |
+----+---------------------+-------------+----------------+-----------+
| 5  | A.M. Todd           | United      | 25-30          | 34%       |
|    | Botanicals          | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 6  | Frutarom Ltd.       | United      | 25-30          | 38%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 7  | Pharmachem          | United      | 25-30          | 42%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 8  | Arkopharma          | France      | 20-25          | 46%       |
+----+---------------------+-------------+----------------+-----------+
| 9  | Technical Sourcing  | United      | 20-25          | 49%       |
|    | Intl (Inabata)      | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 10 | Cognis (Henkel)     | Germany     | 20-25          | 52%       |
+----+---------------------+-------------+----------------+-----------+
| 11 | Triarco Industries  | United      | 20-25          | 55%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 12 | Pure World          | United      | 20-25          | 58%       |
|    | Botanicals          | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 13 | Sabinsa             | United      | 15-20          | 61%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 14 | Maypro              | United      | 15-20          | 64%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 15 | Trout Lake Farm     | United      | 15-20          | 67%       |
|    | (Amway)             | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 16 | Mafco Worldwide     | United      | 10-15          | 69%       |
|    | Corp.               | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 17 | Schwabe             | Germany     | 10-15          | 71%       |
+----+---------------------+-------------+----------------+-----------+
| 18 | Schweizerhall       | Switzerland | 10-15          | 73%       |
|    | (Aceto Corp.)       |             |                |           |
+----+---------------------+-------------+----------------+-----------+
| 19 | InterHealth         | United      | 10-15          | 75%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 20 | Euromed (Madaus)    | Spain       | 10-15          | 77%       |
+----+---------------------+-------------+----------------+-----------+
| 21 | Quality Botanical   | United      | 10-15          | 79%       |
|    | Ingredients         | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 22 | Pharmline           | United      | 10-15          | 81%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 23 | Bio-Botanica        | United      | 10-15          | 83%       |
|    |                     | States      |                |           |
+----+---------------------+-------------+----------------+-----------+
| 24 | Chai-Na-Ta          | Canada      | 5-10           | 84%       |
+----+---------------------+-------------+----------------+-----------+
| 25 | Flachsmann          | Germany     | 5-10           | 85%       |
+----+---------------------+-------------+----------------+-----------+
| 26 | Linnea              | Switzerland | 5-10           | 86%       |
+----+---------------------+-------------+----------------+-----------+

Source: *NBJ's Supplement Business Report 2002*

**Table E**, below, shows that 89% of the botanical suppliers have less
than \$20 million in sales, so an increase in compliance costs could
have an especially severe impact. Increases in costs and regulation have
the potential to seriously reduce supplies of botanical ingredients. To
the extent that such an impact "weeds out" poor quality suppliers, it
may actually prove beneficial. However, the impact would be negative if
it caused responsible and reliable botanical suppliers such as those
listed above to withdraw from the U.S. market. Obviously, the quality of
botanicals used in dietary supplements must be assured, and CRN is
suggesting that burden be placed on finished product manufacturers to
select reliable suppliers, to take responsibility for assuring overall
product quality, and to negotiate an appropriate division of labor with
their individual suppliers with respect to necessary testing of the
ingredient.

**Table E: Revenue for Suppliers of Botanical Ingredients Used In**

**U.S. Dietary Supplements, 2000**

+-----------------+-----------------+-----------------+-----------------+
| **REVENUE**     | **COMPANIES**   | **TOTAL REVS.** | **SHARE OF      |
|                 |                 |                 | REVS.**         |
|                 | **(NUMBER)**    | **(\$mil)**     |                 |
+-----------------+-----------------+-----------------+-----------------+
| More than \$20  | 12              | \$397           | 59%             |
| mil             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| \$5 to \$20 mil | 14              | 167             | 25%             |
+-----------------+-----------------+-----------------+-----------------+
| Less than \$5   | 79              | 106             | 16%             |
| mil             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **TOTAL         | **105**         | **\$670**       | **100%**        |
| WHOLESALE       |                 |                 |                 |
| (\$mil)**       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

Source: *NBJ's Supplement Business Report 2002*

The agency cites as an example of the need to regulate dietary
ingredients the case in which an ingredient marketed as plantain leaf
was contaminated with *Digitalis lanata* and was sold to consumers as a
dietary supplement to be used for the purpose of "cleansing" the body.
This contamination is an example of an egregious error that could and
should have been detected by multiple players in the supply chain, but
it was not in fact detected prior to the occurrence of an adverse event.
This incident, however, must be recognized as rare and does not justify
invoking a rule that is broader than it needs to be in order to ensure
the quality of products in the future. Careful observance of existing
food GMPs should have prevented this event. New and stronger GMPs
applicable to finished product manufacturers would clearly place the
responsibility for ensuring identity of the ingredient on the
manufacturer of the finished product and would provide for adequate
controls to prevent such an occurrence.

Many dietary ingredients are manufactured by large agricultural or
chemical firms in a continuous process. Many of these firms have a long
history of supplying reliable quality ingredients for the food, feed,
and pharmaceutical industries in the U.S. and worldwide. For such
companies, an incoming "lot" may be the soybeans produced by an entire
farm, and a dietary ingredient may be produced as a sidestream of the
processing of the core commodity. The notion of quarantining incoming
lots or analyzing individual batches has little practical application in
such a production system. In some cases, lots and batches may be
identified only as the amount of material produced during a certain
period of time.

Many dietary ingredients and food ingredients are derived from
non-food-grade materials, and become food-grade only after appropriate
processing. Calcium carbonate, for example, is quarried as stone and is
transformed into a "white microcrystalline powder" (*Food Chemicals
Codex*) only after extensive processing in a sophisticated manufacturing
plant. Thus, the proposed GMP requirement that only food-grade bulk
ingredients be used as raw materials is not appropriate to the supplier
environment, since by definition some suppliers begin with cruder
materials and create from them new ingredients of food or pharmaceutical
grade. Our member companies have informed us that there are not food
grade specifications for some ingredients, including some of the
essential trace minerals.

**An ingredient does not become a "dietary ingredient" until it is
purchased by a dietary supplement manufacturer specifically for the
purpose of being included in the formulation of a dietary supplement
product.** Thus, CRN believes it is the manufacturer of the finished
dietary supplement product who bears the responsibility for selecting
ingredients appropriate for their intended use and for verifying the
reliability of the supplier as well as the quality of the ingredients
purchased for that use. Thus, the manufacturer of the finished product
should be subject to the new GMP rule. The manufacturer of the bulk
dietary ingredient should, as heretofore, be covered by general food
GMPs.

CRN will be making specific recommendations regarding areas in which
special provisions need to be drafted for suppliers, if FDA decides to
apply the final GMP rule to suppliers, but we believe the more rational
approach would be to apply the GMP rule only to finished product
manufacturers. The proposed GMP regulations include a substantial number
of provisions intended to control the quality of dietary ingredients
used in the manufacturing of finished dietary supplements. Thus, the
ingredients will be subject to specific quality controls under the
requirements applicable to manufacturers of finished products.

**DSHEA AUTHORIZES FDA TO ESTABLISH DIETARY SUPPLEMENT GMPs, NOT DIETARY
INGREDIENT GMPs**

The specific language of the Dietary Supplement Health and Education Act
says that the Secretary (or by delegation FDA) "may by regulation
prescribe good manufacturing practices for dietary supplements." The
language in this section of DSHEA does not include any reference to
dietary ingredients. Accordingly, CRN questions whether FDA has
authority to establish new GMPs for dietary ingredients, as opposed to
finished dietary supplement products.

**NEED TO DEFINE "MANUFACTURER"**

It is clear that a company that formulates and produces finished dietary
supplement products is a "manufacturer" of such products. However, it is
not entirely clear from the text of the regulation what other types of
companies may also be considered "manufacturers" for purposes of the
rule. For example, some companies may not actually manufacture specific
products but may purchase the bulk tablets or capsules from another
company and then package or label the finished products. The infant
formula proposed GMPs provide a definition of "manufacturer" that may be
useful in defining the types of companies that will be covered. Proposed
21 CFR 106.3(j) would define an infant formula manufacturer as follows:

> "Manufacturer means a person who prepares, reconstitutes, or otherwise
> changes the physical or chemical characteristics of an infant formula
> or packages or labels the product in a container for distribution."

The FDA preamble to the infant formula proposed GMP explains at 62 FR
36156: "In the past there has been some confusion about who is and who
is not a manufacturer of infant formula. This definition makes clear
that a manufacturer is not only a person who combines raw ingredients
together to produce an infant formula but also is a person who
reconstitutes or otherwise [changes the physical or chemical
characteristics of an infant formula or who packages or labels the
product in a container for distribution]{.underline}." (emphasis added)

Adoption of a specific definition such as this would eliminate confusion
over the responsibilities of product handlers such as contract
packagers, repackers and relabelers. For dietary supplement GMPs, we
would suggest a definition such as the following:

> "Manufacturer means a person who formulates or changes the composition
> or physical characteristics of a dietary supplement or who packages or
> labels the product in a container for distribution."

CRN agrees with FDA that foreign manufacturers should be subject to the
same requirements as domestic manufacturers, and that importers of
foreign products share the responsibility for assuring that imports of
dietary supplements are accurately labeled and have the appropriate
identity, purity, quality, strength and composition they are represented
to have. FDA discusses this issue in the preamble to the proposed rule
at 68 FR 12216, saying: "We recognize that the safety of dietary
supplements cannot be adequately ensured if the imports are not subject
to the same controls as domestic products. In addition, we believe that
the importer who distributes a foreign product should share the
responsibility with the foreign manufacture for safety. More often than
not, it is a U.S. importer, rather than the foreign manufacturer, who
actually distributes imported dietary supplements for sale in the United
States."

**LIMITED RESPONSIBILITIES OF THOSE WHO "HOLD"**

**DIETARY SUPPLEMENTS**

There are many types of companies or individuals in the supply chain who
may "hold" a dietary supplement after final production, packaging and
labeling is complete, as the product makes its way to the retail or
consumer level. They may be described as brokers, distributors, or
wholesalers. They would typically be receiving the finished product from
manufacturers who are subject to this regulation, and that manufacturer
would bear the responsibility for the content for the product and for
its packaging and labeling.

As CRN reads the proposed rule, those who receive and distribute
finished dietary supplements in the final packaged form would be subject
only to part 111.95 of the regulation, which says: "Distribution of
dietary supplements must be under conditions that will protect the
dietary supplements against contamination and deterioration." CRN
believes this is the appropriate extent of responsibility that should
apply to those whose sole function in the supply chain is to "hold"
dietary supplements for distribution.

The agency states that even these requirements for those who "hold"
dietary supplements do not extend to retail establishments. FDA
indicates at 68 FR 12214 that it will defer to State and local
governments regarding any requirements that may be applicable to
retailers. CRN agrees that this is an appropriate determination and that
retailers should not be covered by any of the provisions of the GMP rule
for dietary supplements. As we have noted in comments submitted on
various aspects of the FDA regulations implementing the Bioterrorism
Act, independent distributors of direct selling companies should be
included in the definition of "retailers" and thus excluded from
coverage by the rule.

**CONCLUSION AND RECOMMENDATIONS**

CRN believes careful consideration needs to be given to the purpose of
the rule and to what can realistically be expected of new GMPs, over and
above the protections already provided by existing food GMPs and other
FDA policies and authorities. CRN and its member companies support
enhanced dietary supplement GMPs, but we do not believe they are
essential as a prerequisite to FDA action against misbranded or
adulterated products, and we do not believe they will reduce recalls to
zero, as FDA's economic analysis predicts.

CRN also recommends that FDA limit the applicability of any new GMP rule
to finished product manufacturers, who will not only be able to control
their own processes but who also have the ability to control the quality
of the ingredients they purchase for use in dietary supplements and to
evaluate the reliability of the firms that supply dietary ingredients.
We also believe applicability to "dietary supplements" as opposed to
"dietary ingredients" is the scope permitted by the language of DSHEA.

Because of the importance of issues such as these, we urge the agency to
hold a public hearing or perhaps a series of public workshops on key
aspects of the proposed rule, in order to help craft an appropriate and
workable final rule.

Sincerely,

![](media/image2.png){width="2.2569444444444446in" height="0.6in"}

Annette Dickinson, Ph.D.

President

  ----------------------------------------------------------------------------------------- ------------------------------------
  **Manufacturers of Finished Products**                                                    

  **Member Company**                                                                        **Products**

  [Access Business                                                                          Nutrilite®, Trim Advantage®
  Group/Nutrilite](http://www.alticor.com/products/nutritional_supplements.html)            

  [Accucaps Industries Limited](http://www.accucaps.com/defaultframe.htm)                   Private Label Manufacturer of
                                                                                            Vitamins and Minerals, Oils,
                                                                                            Specialty Supplements, and Herbals

  [Arkopharma, LLC](http://www.arkopharma.com/english/index.html)                           Sokoja®, Azinc®, Potensium®,
                                                                                            Arkocaps®, Memoboost®, Turbodiet®

  [B&C Nutritional Products, Inc.](http://www.bcnutritional.com/product_offerings.htm)      Private Label Manufacturer of
                                                                                            Vitamins and Minerals, Specialty
                                                                                            Supplements, and Herbals

  [Bayer HealthCare LLC](http://www.bayer.com/en/index.php)                                 One-A-Day®, Flintstones®

  [Bio San Laboratories Inc.](http://www.biosan.net/)                                       Private Label Manufacturer of
                                                                                            Vitamins and Minerals, MegaFood®,
                                                                                            DailyFoods®, Essentials®

  [Enzo Nutraceuticals](http://www.enzo.co.nz/)                                             Enzogenol®

  [Experimental and Applied Sciences, Inc. (EAS)](http://www.eas.com/)                      AdvantEdge®, BetaGen®, CytoVol®,
                                                                                            EcdyMax®, Lean DynamX®, Mass
                                                                                            Factor®, Muscle Drive®, Myoplex®,
                                                                                            Precision Protein®, Simply
                                                                                            Creatine®, SimplyProtein®, Synthe
                                                                                            Vol®, Thermo DynamX®, ZMA®

  [GNC Incorporated](http://www.gnc.com/)                                                   GNC ProPerformance®, Preventive
                                                                                            Nutrition®, Herb Plus®, GNC Natural
                                                                                            Brand®, Total Lean®, Mega Men®,
                                                                                            Womens Ultra Mega®, Herbal Plus®

  [GNLD International](http://www.gnld.com/)                                                Carotenoid Complex®, GR^2^ Control®

  [Herbalife International](http://www.herbalife.com/uk/)                                   Herbalife, Thermo Complete®,
                                                                                            Thermojetics®,

  [Jamieson Laboratories Ltd.](http://www.jamiesonvitamins.com/)                            Mega Cal®, Vita Vim®

  [Kemin Consumer Care, L.L.C.](http://www.kemin.com/)                                      Satise®

  [Mannatech, Inc.](http://www.mannatech.com/default.asp)                                   Glycentials®, Ambrotose®,
                                                                                            Phyt•Aloe®, CardioBALANCE®,
                                                                                            ImmunoStart®, Glyco•Bears®,
                                                                                            Phyto•Bears®, EM•Pact®, GlycoLEAN®,
                                                                                            Plus®, Ambrostart®, Sport®,
                                                                                            Emprizone®

  [Mary Kay, Inc.](http://www.marykay.com/)                                                 Daily Benefits for Women®, Daily
                                                                                            Benefits for Men®

  [Natural Alternatives International Inc.](http://www.nai-online.com/)                     Pathway to Healing®, Jennifer
                                                                                            O'Neill Essentials®, Private Label
                                                                                            Manufacturer

  [NBTY,                                                                                    Nature\'s Bounty®, Vitamin World®,
  Inc.](http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=NBTY&script=2100&layout=8)   Puritan\'s Pride®, Holland &
                                                                                            Barrett®, Nutrition Headquarters®,
                                                                                            American Health® and Nutrition
                                                                                            Warehouse®, Private Label
                                                                                            Manufacturer

  [Nu Skin International                                                                    LifePAK®, Phamanex Solutions®,
  Inc.](http://www.nuskinenterprises.com/corp/index.shtml)/[Pharmanex                       Pharmanex Bodydesign®
  LLC](http://www.pharmanex.com/)                                                           
  ----------------------------------------------------------------------------------------- ------------------------------------

+----------------------------------+-----------------------------------+
| ######## Ma                      |                                   |
| nufacturers of Finished Products |                                   |
+----------------------------------+-----------------------------------+
| **Member Company**               | **Products**                      |
+----------------------------------+-----------------------------------+
| [Nutraceutical                   | Solaray®, KAL®, NaturalMax®,      |
| Corporation                      | VegLife®, Premier One®, Sunny     |
| ](http://www.nutraceutical.com/) | Green®, Natural Sport®, ActiPet®, |
|                                  | Action Labs®, Miztique®, Ultimate |
|                                  | Nutrition® and Thompson®, Private |
|                                  | Label Manufacturer                |
+----------------------------------+-----------------------------------+
| [Nutramax Laboratories,          | Senior Moment®, Cosamin® DS       |
| Inc                              |                                   |
| .](http://www.nutramaxlabs.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Perrigo                         | Private Label Manufacturer and    |
| Company](http://                 | Branded Contract Manufacturer     |
| www.perrigo.com/index_flash.htm) |                                   |
+----------------------------------+-----------------------------------+
| [Pharmaton Natural Health        | Ginsana®, Ginkoba®, Flexium®,     |
| Products](http://ww              | Kyolic®, Venastat®, Supplifem®,   |
| w.pharmaton.com/us/homepage.jsp) | Prostatonin®                      |
+----------------------------------+-----------------------------------+
| [Pharmavite                      | Nature Made®, Nature's Resource®, |
| LLC](http://www.pharmavite.com/) | Private Label Manufacturer, Olay™ |
|                                  | Vitamins                          |
+----------------------------------+-----------------------------------+
| [Proper Nutrition,               | SeaCure®, SeaVive®                |
| Inc.](                           |                                   |
| http://www.propernutrition.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Pulse                           | Pulse® Water + Nutrients          |
| Nutrition](http://www.pul        | (Vitamins and Minerals)           |
| senutrition.com/html/index.html) |                                   |
+----------------------------------+-----------------------------------+
| [Rainbow Light Nutritional       | Active Health®, Complete          |
| System                           | Nutritional System®, Complete     |
| s](http://www.rainbowlight.com/) | Prenatal System®, Nutristars®,    |
|                                  | Performance Energy®, Women's      |
|                                  | Answer® and other Single          |
|                                  | Nutrient, Herbal, and Specialty   |
|                                  | Supplements                       |
+----------------------------------+-----------------------------------+
| [Rexall Sundown,                 | Sundown®, Osteo Bi-Flex®,         |
| Inc.                             | Pokemon®, Private Label           |
| ](http://www.rexallsundown.com/) | Manufacturer                      |
|                                  |                                   |
| (now part of NBTY, Inc.)         |                                   |
+----------------------------------+-----------------------------------+
| [Ross                            | Glucerna®, Ensure®, Infant        |
| Products](http://www.ross.com/)  | Formula                           |
+----------------------------------+-----------------------------------+
| [Shaklee                         | CorEnergy®, Mood-Lift®,           |
| Corpo                            | Vita-Lea®, CoQHeart®, Immunity    |
| ration](http://www.shaklee.com/) | Formula I®, Herb-Lax®,            |
|                                  | Optiflora®, EZ-Gest®, Shaklee     |
|                                  | Fitness®, Performance®,           |
|                                  | Physique®, Liver DTX®, Fiber      |
|                                  | Plan®                             |
+----------------------------------+-----------------------------------+
| [Sigma Tau Health                | ## Pro                            |
| Sciences](http:/                 | Xeed®, Megasol®, Megasol Q10®, Ph |
| /www.sigmatau-hs.it/default.htm) | ototrop®, Avant®, Biorecord Plus® |
+----------------------------------+-----------------------------------+
| [Tom's of                        | Botanicals                        |
| Mai                              |                                   |
| ne](http://www.tomsofmaine.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Vitamin Shoppe Industries,      | Vitamins and Minerals, Specialty  |
| Inc.                             | Supplements, and Botanicals       |
| ](http://www.vitaminshoppe.com/) | distributed under the Vitamin     |
|                                  | Shoppe® name                      |
+----------------------------------+-----------------------------------+
| [VitaTech International,         | Private Label Manufacturer        |
| Inc.](http://www.vitatech.com/)  |                                   |
+----------------------------------+-----------------------------------+
| [Warner Lambert Consumer Group   | Finished Product Manufacturer     |
| of                               |                                   |
| Pfizer](                         |                                   |
| http://www.pfizer.com/main.html) |                                   |
+----------------------------------+-----------------------------------+
| [Weider Nutrition International, | Schiff®, Schiff® Move Free®,      |
| Inc.](http                       | Tiger's Milk®, Weider®, Fi Bar®   |
| ://www.weidernutrition.biz/weide |                                   |
| r_interior.asp?strLink=investor) |                                   |
+----------------------------------+-----------------------------------+
| [Wyeth](http://www.wyeth.com/)   | Centrum®, Centrum Silver®,        |
|                                  | Centrum Performance®, Centrum     |
|                                  | Kids®, Caltrate®                  |
+----------------------------------+-----------------------------------+

+---------------------------------+------------------------------------+
| **Suppliers**                   |                                    |
+---------------------------------+------------------------------------+
| **Member Company**              | **Products/Ingredients/Services**  |
+---------------------------------+------------------------------------+
| [Access Business Group - Trout  | Grower and Processor of Botanical  |
| Lake                            | Ingredients, Ocean Essentials®     |
| Farms](http://www.acces         |                                    |
| sbusinessgroup.com/default.asp) |                                    |
+---------------------------------+------------------------------------+
| [Albion Laboratories,           | Bulk Minerals                      |
| I                               |                                    |
| nc.](http://www.albion-an.com/) |                                    |
+---------------------------------+------------------------------------+
| [American Laboratories,         | Processor and Supplier of Enzymes, |
| Inc.](http:/                    | Peptones, Liver Products and       |
| /www.americanlaboratories.com/) | Glandulars                         |
+---------------------------------+------------------------------------+
| [Archer Daniels Midland         | Vitamin E, Soy Isoflavones,        |
| Com                             | Lecithin                           |
| pany](http://www.admworld.com/) |                                    |
+---------------------------------+------------------------------------+
| [B&D Nutritional Ingredients,   | Supplier of Vitamin E, Lecithin,   |
| Inc.](http://www.bndni.com/)    | Lutein, Phytosterols, Grape Seed   |
+---------------------------------+------------------------------------+
| [BASF                           | Vitamins A, C, D & E, B Vitamins,  |
| Cor                             | Carotenoids, Excipients,           |
| poration](http://www.basf.com/) | Clarifying Agents, Aroma Chemicals |
+---------------------------------+------------------------------------+
| [Biotron Laboratories,          | Supplier of Various Mineral Amino  |
| Inc                             | Acid Chelates                      |
| .](http://www.biotronlabs.com/) |                                    |
+---------------------------------+------------------------------------+
| [Caps                           | Encapsulated Products and Capsules |
| ugel](http://www.capsugel.com/) |                                    |
+---------------------------------+------------------------------------+
| [Cargill Health & Food          | Soy Isoflavones, Chondroitin,      |
| Technol                         | Vitamin E                          |
| ogies](http://www.cargill.com/) |                                    |
+---------------------------------+------------------------------------+
| [Cognis Nutrition &             | Natural Vitamin E, Tonalin® CLA,   |
| Health](htt                     | Vegapure®, Sterols/Sterol Esters,  |
| p://www.cognis.com/cognis.html) | Lutein Esters, Natural Mixed       |
|                                 | Carotenoids, ALA, Botanicals,      |
|                                 | Emulsifiers, Food Technology       |
|                                 | Ingredients                        |
+---------------------------------+------------------------------------+
| [Colo                           | Excipients, Colors, Coating        |
| rcon](http://www.colorcon.com/) | Systems, Printing Inks             |
+---------------------------------+------------------------------------+
| [Daiichi Fine Chemicals,        | B Vitamins, Vitamin D, Carotenoids |
| Inc.](http://www.               |                                    |
| daiichi-fcj.co.jp/en/home.html) |                                    |
+---------------------------------+------------------------------------+
| [E.T. Horn                      | Bulk Ingredients Including:        |
| C                               | Calcium Carbonate, Glucosamine,    |
| ompany](http://www.ethorn.com/) | Cellulose                          |
+---------------------------------+------------------------------------+
| [Generichem                     | Bulk Supplier of Minerals          |
| Corporati                       |                                    |
| on](http://www.generichem.com/) |                                    |
+---------------------------------+------------------------------------+
| [Indena USA,                    | Botanicals Supplier                |
| Inc.](http://www.indena.com/)   |                                    |
+---------------------------------+------------------------------------+
| [Kaneka America                 | ## Supplier of Co-Enzyme Q10       |
| Corporation](htt                |                                    |
| p://www.kaneka.com/kacfine.htm) |                                    |
+---------------------------------+------------------------------------+
| [Kemin Foods,                   | Lutein - FloraGLO®, Antioxidants   |
| L.C.](http://www.kemin.com/)    |                                    |
+---------------------------------+------------------------------------+
| [Linnea,                        | Botanicals Supplier                |
| Inc.](http://www.               |                                    |
| linnea-worldwide.com/home1.asp) |                                    |
+---------------------------------+------------------------------------+
| [Loders-Crok                    | Supplier of Oils Including:        |
| laan](http://www.croklaan.com/) | Clarinol®, Marinol®, Membranol®,   |
|                                 | Safflorin®                         |
+---------------------------------+------------------------------------+
| [Lonza,                         | Supplier of L-Carnitine and B      |
| Inc.](http://ww                 | Vitamins                           |
| w.lonzagroup.com/group/en.html) |                                    |
+---------------------------------+------------------------------------+
| Mingtai Chemical, LLC           | ## Micr                            |
|                                 | ocrystalline Cellulose, Comprecal® |
+---------------------------------+------------------------------------+
| [Nashai Biotech                 | Supplier of Ingredients Including  |
| LLC](http://www.nashai.com/)    | TeaFlavin®                         |
+---------------------------------+------------------------------------+
| [Nutrinova](http://www.nutr     | DHActive®, Fiber - Caromax®,       |
| inova.com/easy2web/internet.nsf | Nutrinova® Sorbates                |
| /directframe/home?OpenDocument) |                                    |
+---------------------------------+------------------------------------+
| [Nutrition 21,                  | Chromax® Chromium Picolinate,      |
| Inc                             | Zinmax® Zinc Picolinate,           |
| .](http://www.nutrition21.com/) | Selenomax® High Selenium Yeast,    |
|                                 | Selenopure® l-selenomethionine,    |
|                                 |                                    |
|                                 | Zenergen™ Chromium Picolinate plus |
|                                 | CLA                                |
+---------------------------------+------------------------------------+
| [Ocean Nutrition Canada         | Omega-3 Fatty Acids                |
| Ltd.](h                         |                                    |
| ttp://www.ocean-nutrition.com/) |                                    |
+---------------------------------+------------------------------------+
| [Omya,                          | Supplier of Calcium Carbonate      |
| Inc.](http://www.omya-na.com/)  |                                    |
+---------------------------------+------------------------------------+
| **Suppliers**                   |                                    |
+---------------------------------+------------------------------------+
| **Member Company**              | **Products/Ingredients/Services**  |
+---------------------------------+------------------------------------+
| [Polyphenolics]                 | MegaNatural® Gold Grape Seed       |
| (http://www.polyphenolics.com/) | Extract, MegaNatural® Grape Skin   |
|                                 | Extracts, MegaNatural® Rubired     |
|                                 | Grape Juice Extract, MegaNatural®  |
|                                 | Red Wine Extract                   |
+---------------------------------+------------------------------------+
| [Pronova Biocare,               | Omega-3 Fatty Acids - EPAX®,       |
| a.s.](http://ww                 | Triomega®, Pikasol®, Omacor®       |
| w.pronovabiocare.com/index.php) |                                    |
+---------------------------------+------------------------------------+
| [Rhodia,                        | Antioxidants - Embanox®, Calcium   |
| I                               | Phosphate, Probiotics              |
| nc.](http://www.us.rhodia.com/) |                                    |
+---------------------------------+------------------------------------+
| [Roche Vitamins,                | Vitamins A, C, D, & E, B Vitamins, |
| Inc.](                          | Carotenoids, Omega-3 Fatty Acids   |
| http://www.roche.com/home.html) |                                    |
+---------------------------------+------------------------------------+
| [Seven Seas                     | Fish Oils, Multivitamins, Evening  |
| Limited]                        | Primrose Oil, Herbals,             |
| (http://www.seven-seas.ltd.uk/) | ActionPlan50+®                     |
+---------------------------------+------------------------------------+

**Class I and Class II Recalls for**

**Dietary Supplements, Foods and Drugs**

**1990-1999**

+----------------------+------+-------+------+-------+-------+-------+
|                      | ##   |       |      | **    |       |       |
|                      |  Cla |       |      | Class |       |       |
|                      | ss I |       |      | II    |       |       |
|                      |  Rec |       |      | Reca  |       |       |
|                      | alls |       |      | lls** |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| **Reason for         | **   | **F   | **Dr | *     | **F   | **D   |
| Recall**             | DS** | ood** | ug** | *DS** | ood** | rug** |
+----------------------+------+-------+------+-------+-------+-------+
| Undeclared           | 1    | 229   | 1    | 5     | 381   | 6     |
| Ingredient/Color     |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Unapproved           | \--  | \--   | \--  | 1     | 39    | 12    |
| Ingredient/Color     |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant          | 3    | 310   | 15   | 2     | 34    | 27    |
| --Microorg.          |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant --       | 13   | \--   | \--  | \--   | \--   | \--   |
| Digitalis            |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant -- Lead  | \--  | 2     | \--  | 11    | 43    | \--   |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant --       | \--  | \--   | \--  | \--   | 4     | 4     |
| Mercury              |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant --       | \--  | \--   | \--  | \--   | 16    | \--   |
| Pesticide            |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Contaminant -- Misc. | 1    | 33    | 2    | \--   | 193   | 65    |
+----------------------+------+-------+------+-------+-------+-------+
| Super-Potent         | 2    | 1     | \--  | 3     | 6     | 17    |
+----------------------+------+-------+------+-------+-------+-------+
| Sub-Potent           | \--  | \--   | 8    | 1     | 2     | 123   |
+----------------------+------+-------+------+-------+-------+-------+
| L-Tryptophan         | 5    | \--   | \--  | \--   | \--   | \--   |
+----------------------+------+-------+------+-------+-------+-------+
| Mi                   | \--  | 10    | 14   | 4     | 44    | 181   |
| spackaged/Mislabeled |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Processing/GMP       | \--  | 4     | 10   | \--   | 23    | 228   |
| Violation            |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Physical             | \--  | 2     | \--  | \--   | 15    | 159   |
| Characteristics      |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Regulatory Issue     | \--  | 1     | 1    | \--   | 1     | 42    |
+----------------------+------+-------+------+-------+-------+-------+
| Defective Packaging  | \--  | \--   | \--  | \--   | 8     | 4     |
+----------------------+------+-------+------+-------+-------+-------+
| Toxins/Poisons       | \--  | \--   | \--  | \--   | 14    | 2     |
+----------------------+------+-------+------+-------+-------+-------+
| Illness Related      | \--  | \--   | \--  | \--   | 58    | 2     |
+----------------------+------+-------+------+-------+-------+-------+
| Histamine            | \--  | \--   | \--  | \--   | 14    | \--   |
+----------------------+------+-------+------+-------+-------+-------+
| Unapproved           | \--  | \--   | 11   | \--   | 2     | 22    |
| Drug/Claim           |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| Non-Sterile          | \--  | \--   | 4    | \--   | \--   | 33    |
+----------------------+------+-------+------+-------+-------+-------+
| Other/Misc.          | \--  | \--   | \--  | \--   | \--   | 4     |
+----------------------+------+-------+------+-------+-------+-------+
|                      |      |       |      |       |       |       |
+----------------------+------+-------+------+-------+-------+-------+
| # Total Recalls      | **   | **    | **   | *     | **    | **    |
|                      | 25** | 592** | 66** | *27** | 901** | 931** |
+----------------------+------+-------+------+-------+-------+-------+