Toxicology 221 (2006) 9–16

The impact of cGMP compliance on consumer confidencein dietary supplement products

Richard Crowley a,∗, Libby Harvey FitzGerald b

a Covance Laboratories, 3301 Kinsman Blvd, Madison, WI 53704, United Statesb FitzGerald Consultants, P.O. Box 750694, Petaluma, CA 94975-0694, United States

Received 16 June 2005; received in revised form 19 December 2005; accepted 3 January 2006

Abstract

The FDA estimates that US citizens spend more than $ 8.5 billion a year on dietary supplements and world wide the market isestimated at more than $ 60 billion. However, although a majority of consumers express confidence in the safety of these products,74% believe the government should be more involved in ensuring that these products are safe and efficacious. Recent regulatoryinitiatives such as the imminent adoption of cGMPs for dietary supplements in the US, implementation of cGMPs in Canada andthe recent EU dietary supplement initiative represent legislative and industry response to public clamor for more comprehensiveoversight of dietary supplements. Regardless of mandated practices, the majority of dietary supplement manufacturers have done anexcellent job of protecting the safety and quality of their products. The promulgation of these cGMPs will help ensure consumersthat equal standards are followed throughout the industry. For some companies with established processes based on existing food orpharmaceutical cGMP regulations, the transition will be relatively painless while, for many, it will represent a significant increaseiqptS©

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n the level of documentation and testing. However, consumers deserve and demand that products meet standards for safety anduality and the implementation of cGMPs for these products are an important first step. Although the cGMPs are designed to ensureroducts are safe from a standpoint of identity, purity, quality, strength and composition, they do not address preclinical or clinicalesting of ingredients for safety or efficacy. This would involve ingredients meeting the requirements of Generally Recognized asafe (GRAS) status or going through the New Dietary Ingredient (NDI) process.2006 Elsevier Ireland Ltd. All rights reserved.

eywords: Current Good Manufacturing Practices (GMP); cGMP; Dietary supplements; Regulations; Quality control; Purity; Testing requirements

. Introduction

Consumer reliance on regulatory initiatives to ensureood safety dates back to landmark legislation such asngland’s Adulteration of Food Acts of 1860 and 1872hich for the first time, mandated the hiring of ana-

ysts and inspectors. In the US, President Lincoln first

∗ Corresponding author. Tel.: +1 608.242.2712x2531.E-mail addresses: rick.Crowley@covance.com (R. Crowley),

ibfitz@sbcglobal.net (L.H. FitzGerald).

appointed a chemist to the USDA in 1862 signaling whatwas to be the beginning of the Bureau of Chemistryand the eventual passage of the Food and Drug Act in1906. Current Good Manufacturing Practices (cGMP),whether they be for drugs, food products or dietary sup-plements are a key to consumer confidence, productsafety, and recognized standards.

The potential physiological benefits of ingredientssuch as the antioxidant properties of polyphenolic com-pounds (e.g., catechins, trans-resveratrol, gallic acid)have accelerated the interest of consumers and healthprofessionals in the role of these compounds in disease

300-483X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.tox.2006.01.011

10 R. Crowley, L.H. FitzGerald / Toxicology 221 (2006) 9–16

prevention. Although the dietary supplement boom ofrecent years has leveled off somewhat, the FDA esti-mates that US citizens spend more than $ 8.5 billion ayear on dietary supplements and world wide the mar-ket is estimated at more than $ 60 billion (NutritionBusiness Journal, 2004). However, although a majorityof consumers express confidence in the safety of theseproducts, 74% believe the government should be moreinvolved in ensuring that these products are safe andefficacious (FDA, 2003). Recent regulatory initiativessuch as the imminent adoption of cGMPs for dietarysupplements in the US, 31 December 2005 implemen-tation of cGMPs in Canada and the recent EU dietarysupplement initiative represent legislative and industryresponse to public clamor for more comprehensive over-sight of dietary supplements.

2. The foundation is laid

The cGMPs for dietary supplements were first pro-posed under the auspices of the Dietary SupplementHealth and Education Act (DSHEA) in 1994, whichwas enacted to ensure that consumers had access to safedietary supplements (US Congress, 1994). Specifically,the legislation recognized that “improving the health sta-tus of U.S. citizens is national priority and that the use ofdietary supplements may help prevent chronic diseasesand maintain good health” (FDA, 2003).

Although DSHEA amended the Federal Food, Drug,and Cosmetic Act to allow the establishment of good

Fig. 1. Perceived safety of vitamins, minerals and herbal products.

In 2003, the FDA published its proposed rule on cGMPsfor dietary supplements and although the agency is cur-rently reviewing and evaluating more than 1600 pagesof comments, publication of a cGMP final rule is one ofthe agency’s highest priorities. Some key issues beingdebated include FDA’s authority to issue such expan-sive regulations that fall between conventional food anddrug cGMPs, the amount of testing required for indi-vidual ingredients versus final products, as well as con-cerns about estimated financial impact. The FDA and

Fig. 2. FDA CRN cost/benefit analysis associated with dietary supple-ment cGMPs ($ millions).

manufacturing practices for dietary supplements, thefoundation of the proposed cGMPs has had many build-ing blocks. Primary among these is an outline for cGMPssubmitted by representatives of the dietary supplementindustry in 1995. These self-imposed industry recom-mendations have had a steady influence on increasedconsumer confidence. A survey commissioned by theCouncil for Responsible Nutrition (CRN) shows that78% of consumers were either somewhat confident orvery confident in the safety, quality and effectiveness ofdietary supplements (Fig. 1). However, these numbershave increased only marginally from the 74% reportedin 2001 (CRN, 2004). As a result, CRN says industryneeds “to continue to urge government and private fund-ing for scientific research on the safety and effectivenessof supplements, as well as do a better job of communi-cating the kinds of things responsible companies do toensure high quality products” (Fig. 2).

In the Federal Register of 6 February 1997 an advancenotice of proposed rulemaking was published solicitingcomments on the need for, and content of, cGMP regu-lations for dietary ingredients and dietary supplements.

R. Crowley, L.H. FitzGerald / Toxicology 221 (2006) 9–16 11

observers expect the rules to go into effect this year.In November 2004, FDA Acting Commissioner LesterCrawford stated, “We now have a clear roadmap to sharewith the dietary supplement industry, while at the sametime giving consumers a higher level of assurance aboutthe safety of dietary supplement products and the reli-ability of their labeling.” While this is certainly goodnews, industry will need to be ready to adapt to everevolving regulatory guidelines.

3. Primary provisions

The cGMPs for pharmaceutical and food productshave been an integral facet of the successful status andcontinued growth of these industries. The regulationsfor dietary supplements and ingredients are patternedafter those established for conventional food productsand would establish the minimum requirements nec-essary to ensure that the manufacturing, packaging, orholding of ingredients and supplements, are done in amanner that prevents adulteration and misbranding ofproducts. These include a wide variety of activities suchas strict requirements for maintenance of the physicalplant, equipment and utensils, and mandatory record-keeping provisions. In addition, the production and pro-cess controls sections contain specific information on thelevels of testing and quality control which would requiremanufacturers to evaluate the identity, purity, quality,strength, and composition of ingredients and final prod-ua

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also meet specifications the manufacturer establishes forpurity, quality, strength, and composition. These provi-sions are intended to ensure that a product contains whatis listed on the label. If it does not, the dietary supplementwould not only be misbranded but considered adulter-ated as well. In addition to requiring compliance withthe provisions in Part 111, the regulations specify otherapplicable statutes that may apply for some products. Forexample, a manufacturer whose product includes fish oilwould also have to comply with Hazard Analysis andCritical Control Point (HAACP) rules. Table 2 exhibitsthe provisions of proposed cGMPs.

4. Personnel, physical plants, and equipment

Well-trained and diligent personnel are critical toensure the safety of any consumer product. The cGMPsinclude stipulations for prevention of microbial contami-nation as well as qualification and training of personnel.The rules specify the of use hygienic practices to theextent necessary to protect against contamination. Inregard to the qualifications of staff, the cGMPs requirethat each person engaged in manufacturing, packaging,or holding have the training and experience necessary toensure they are competent to produce an unadulteratedproduct. The extent and frequency of the training is leftto the discretion of the manufacturer. Consultants usedfor advice must be qualified by training and experience.

The design and maintenance of the physical plant in

cts. Table 1 demonstrates the product quality concernsddressed by cGMPs.

The regulations would require manufacturers tostablish specifications for the dietary ingredients andietary supplements they produce. As a result, a dietaryupplement with a particular ingredient listed on itsabel must contain that ingredient. The ingredient must

able 1roduct quality concerns addressed by cGMPs

oul odorff tasteuperpotentubpotentrong ingredientrug contaminantsther contaminants (e.g., pesticides)isintegration timeolor variationablet size or size variationnder-filled containeroreign material in a containermproper packaging

islabeling

which ingredients and products are manufactured andstored are critical to the safety and efficacy of sup-plements. The provisions for the design, constructionand maintenance of the facilities include requirementsfor water quality, plumbing, ventilation systems andpest control. The regulations also include comprehen-sive requirements for ground maintenance, sanitation,and the use or holding of toxic materials. Assignmentof one or more employees to supervise sanitation wouldalso be required.

Unintentional contamination of food has always beena concern to consumers and manufacturers alike. Inrecent years, manufacturers have become more diligentabout the maintenance and cleaning of equipment andutensils used in processing. As defined in the cGMP reg-ulations, equipment and utensils would include, but notbe limited to, equipment used to hold, convey, or measureingredients or final products. This includes equipmentusing compressed air or gas or used to carry out processesin closed pipes and vessels. Recognizing the growingreliance on automated systems, hardware and softwareare also cited for specific requirements.

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Table 2Provisions of proposed cGMPs

Subpart A. General provisionsSection 111.1: Who is subject to these Part III regulations?Section 111.2: What are these regulations intended to accomplish?Section 111.3: What definitions apply to this part?Section 111.5: Do other statutory provisions and regulations apply?Section 111.6: Exclusions

Subpart B. PersonnelSection 111.10: What microbial contamination and hygiene requirements apply?Section 111.12: What personnel qualification requirements apply?Section 111.13: What supervisor requirements apply?

Subpart C. Physical plantSection 111.15: What sanitation requirements apply to your physical plant?Section 111.20: What design and construction requirements apply to your physical plant?

Subpart D. Equipment and utensilsSection 111.25: What requirements apply to the equipment and utensils you use?Section 111.30: What requirements apply to automatic, mechanical, or electronic equipment?

Subpart E. Production and process controlsSection 111.35: What production and process controls must you use?Section 111.37: What requirements apply to quality control?Section 111.40: What requirements apply to components, dietary ingredients, dietary supplements, packaging, and labels you receive?

Subpart E. Production and process controls (cont.)Section 111.45: What requirements apply to establishing a master manufacturing record?Section 111.50: What requirements apply to establishing a batch production record?Section 111.60: What requirements apply to laboratory operations?Section 111.65: What requirements apply to manufacturing operations?Section 111.70: What requirements apply to packaging and label operations?Section 111.74: What requirements apply to rejected components, dietary ingredients, dietary supplements, packaging, and labels?

Subpart F. Holding and distributingSection 111.80: What requirements apply to holding components, dietary ingredients, dietary supplements, packaging, and labels?Section 111.82: What requirements apply to holding in-process material?Section 111.83: What requirements apply to holding reserve samples of components, dietary ingredients, and dietary supplements?Section 111.85: What requirements apply to returned dietary ingredients or dietary supplements?Section 111.90: What requirements apply to distributing dietary ingredients or dietary supplements?

Subpart G, Section 111.95: Consumer complaints—what requirements apply to consumer complaints?

Subpart H, Section 111.125: Records and recordkeeping—what requirements apply to recordkeeping?

5. Production and process controls

From a scientific and testing standpoint, productionand process controls are the cornerstone of regulatorycompliance and consumer confidence. Table 3 showsthe information required for batch production record.Although decisions about producing a dietary ingredi-ent or supplement are left up to the manufacturer, theregulations recognize that standard measures designedto ensure that ingredients and supplements are manufac-tured in a safe manner are essential. Because even themost innocuous change in a formulation or preparationmethod or exposure to an unanticipated environmentalcondition could create a health hazard, monitoring of thephysical and chemical characteristics is critical. Thus, a

production and in-process control system as well as theestablishment of a quality control unit are necessary toprovide consistency in production.

6. Quality control and assurance

The regulations mandate that a quality control unit beestablished to ensure that dietary ingredients and sup-plements meet specifications for identity, purity, quality,strength, and composition. It is recommended that allorganizational units involved in critical formulation andmanufacturing steps, such as production, engineering,research, and regulatory affairs, be included in qualitycontrol functions. This unit has a broad range of com-pliance functions such as the review of all processes,

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Table 3Information required for batch production record

Batch, lot, or control numberDocumentation showing the date on which each step of the master

manufacturing record was performed, the initials of the personsperforming each step including the person responsible forweighing or measuring each component used in the batch andthe person responsible for adding the components

Identity of equipment and processing lines usedThe date and time of the maintenance, cleaning, and sanitizing of

the equipment and processing lines usedThe shipment lot unique identifier of each component, dietary

ingredient, dietary supplement, packaging, and label usedThe identity and weight or measure of each componentThe initials at the time of performance or at the completion of the

batch of the person responsible for verifying the weight ormeasure of each component used in the batch

The initials at the time of performance or at the completion of thebatch of the person responsible for verifying the addition ofcomponents to the batch

A statement of the actual yield and a statement of the percentage oftheoretical yield at appropriate phases of processing

Actual test results for any testing performed during productionDocumentation that the dietary ingredient and dietary supplement

meets specificationsCopies of all container labels used and the results of examinations

conducted during the label operation to ensure that thecontainers have the correct label

Any documented material review and disposition decisionSignature of the quality control unit to document batch production

record review and approval for reprocessing or repackaging

documentation and production records. The qualitygroup also has responsibility for the collection of rep-resentative samples for testing. These responsibilitiesare critical in the implementation of cGMP standards.The quality control unit must document the specificsof the review process. This documentation will includethe time and date when the review, approval or rejectionrequirement was performed, and the signature of theperson performing the requirement.

7. Laboratory operations and testingrequirements

Although analytical testing has long been a founda-tion of safe products, the popularity of television showsdepicting science as the silver bullet for all problems haselevated the consumer’s view of the role of chemistryin our everyday lives. Analytical testing is performed toensure that components, ingredients, and supplementsmeet specifications throughout the manufacturing anddistribution process as well as to determine that label-ing reflects the true identity and amounts of ingredients.The establishment of standards for laboratory operations

requires that the appropriate reference materials, meth-ods, instrumentation and personnel are used. It is alsoimperative that each of these factors is adequately docu-mented. The regulations apply to all laboratory facilitiesused, not just those operated within a company. In otherwords, if a private laboratory or raw material supplierperforms the actual tests, you must make sure that thetesting laboratory’s facilities and processes are adequateand conform to cGMP regulations.

A perceived skepticism by the public about the qual-ity of dietary supplements has long been the bane of theindustry, and an assurance that a product is indeed whatit purports will go a long way in improving the imageof these products. The FDA specifies that at least onetest or examination be done to verify that specificationsfor “Identity” are met. In regard to other specifications,several trade associations have recommended that, undercertain conditions, reliance on a raw material supplier’scertificate of analysis could be accepted in lieu of testingfor “Other Specifications” of components, ingredients,or supplements. These conditions would include estab-lishing the reliability of the supplier and confirming thesupplier’s test results at appropriate intervals. The cer-tificate of analysis provided should list a description ofthe appropriate test or examination methods used, testlimits and test results. An ongoing audit or certificationsystem to verify the reliability of suppliers is part of awell-documented quality control system.

Scientists have been hampered in the analysis of cer-tain products due to the lack of standard reference mate-

rials and, the truth is, that standard reference materialsdo not exist for many botanicals. Although the cGMPsallow the use of plant reference material authenticatedby a qualified plant taxonomist as a standard reference inperforming some organoleptic and microscopic exami-nations, a reference standard that is a highly purified andcharacterized compound must be used for quantitativechemical tests. Ideally, compendial reference standardsare used whenever possible. If no compendial standardexists, appropriately characterized materials from repre-sentative lots may be used. Standards used in develop-ing analytical methods include both reference standardsthat identify a single compound or entity and refer-ence materials that represent a matrix of compounds.Although documentation of the reference materials isalways important, extra diligence is required when non-compendial materials are used.

The cGMPs require scientifically validated analyti-cal methods. Table 4 demonstrates the provisions forlaboratory operations mandated by the cGMPs. Thereis currently a gap between what a company might docu-ment as a method that is scientifically valid and Official

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Table 4Provisions for laboratory operations mandated by the cGMPS

Section 111.60(b)(1): Establish and follow laboratory controlprocesses approved by the quality control unit

Section 111.60(b)(1)(iii): Laboratory control processes to includesampling plans for obtaining representative samples ofComponents, dietary ingredients, and dietary supplements

receivedInprocess materials during the batch manufacturing when testing

or examination is required in the master manufacturing recordEach batch of dietary ingredient or dietary supplement

manufactured to determine that the dietary ingredient ordietary supplement meets specifications

Packaging and labels received to determine that the materialsmeet specifications

Each batch of packaged and labeled dietary ingredients ordietary supplements to ensure that the label specified in themaster manufacturing record has been applied

Section 111.60(b)(iv)–(b)(vi): Require the laboratory controlprocesses to includeUse of criteria for selecting standard reference materialsUse of appropriate test method validationsUse of test methods in accordance with established criteria

Section 111.60(b)(2) and (b)(3): Documentation and recordkeepingfor laboratory operations

Section 111.60(c): Verification that the laboratory testingmethodologies are appropriate for their intended use

Section 111.60(d): Identify and use the appropriate validatedtesting method to use for each established specification for whichtesting is required

Methods of AOAC INTERNATIONAL which are con-sidered the scientific gold standard and specified as themethods of choice in the Code of Federal Regulations forlabeling purposes. The cGMPs would put the burden ofdeciding whether a method is valid squarely on the shoul-ders of individual FDA field inspectors. The proposedcGMP rule does not identify any specific analyticalmethods. As a result, evaluation of the most appropriatetest for a component, ingredient, or supplement is a deci-sion left to the manufacturer. Test methodology must bespecific for the component, ingredient, or dietary supple-ment and meet established scientific specifications. ThecGMPs recognize that requiring validated testing meth-ods is not sufficient without documentation that thosemethods were actually used at the time the assay wasconducted. Complete records must also be maintainedfor any testing of standards and reagents used. Further-more the regulations include provisions for calibration oflaboratory instruments, apparatus, gauges, and recordingdevices.

Recognizing the need for development of additionalanalytical methods and reference materials, Congress

has appropriated funds for the NIH Office of DietarySupplements (ODS) to invest in these activities. ODSinitially focused on safety issues by issuing a September2001 contract with AOAC to validate various methodsfor ephedra and for aristolochic acid through the AOACOfficial Methods process. ODS also contracted withAOAC in September 2002 to develop 20 new methodsfor commonly utilized dietary supplement ingredients,with a budget of $ 1 million over a 5-year period.

8. Date of expiration and shelf life

Consumers are very aware of food industry prac-tices that incorporate expiration, best before, and otherdates on the product label to indicate freshness. Theregulations specify requirements for the holding of com-ponents, ingredients and final product at all stages of themanufacturing and distribution process and require thatingredients and supplements be held under conditionsthat will protect against contamination and deterioration.Although the FDA’s proposed rule does not require test-ing to establish expiration or shelf life dating on dietarysupplements, the regulations require that a sample ofeach lot of ingredient and supplement received and eachbatch of finished product shipped must be retained for3 years from the date of manufacture. These sampleswould be used in appropriate investigations including,but not limited to, consumer complaints. One trade asso-ciation recommended the addition of specific expira-

tion or shelf life dating for all products while retainingsamples for 1 year past the shelf life date. Testing fordegradation of each product and container could providesupporting data for written assessment of stability (e.g.,breakdown of specific ingredients), change in physicalcharacteristics (e.g., solubility) and safety (e.g., micro-bial contamination) up to the specified point in time.

9. Consumer complaints and recordkeeping

It has long been recognized that consumer concernsabout manufacturer claims and product safety were adriving force in the development of the cGMPs. Theregulations would mandate the implementation of a for-mal, documented consumer complaint process. The rulesconsider a consumer complaint as a possible failure ofan ingredient or supplement to meet the requirements ofthe cGMPs. The regulations would require that a writ-ten report be kept of every consumer complaint related togood manufacturing practices. The report should includeall information necessary for the quality control unit todetermine whether an investigation is necessary.

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Documentation is the key to a successful cGMP pro-gram and many of the provisions of the regulations hingeon accurate and comprehensive records. The regulationsestablish general recordkeeping requirements and set theminimum duration of time for which records must bekept. The rule would require that records be retained for3 years beyond the date of manufacture of the last batchof the ingredients or dietary supplements associatedwith those records. The allowable format of the recordsincludes original or true copies as well as electronicrecords. If reduction techniques (e.g., microfilming) areused, equipment must be available for inspections. Ifelectronic records are used, compliance with 21 CFRPart 11 is required.

10. The economic impact

The FDA recognizes there will be a significant finan-cial impact and has estimated that the mean annualcosts of the proposed cGMPs at $ 86 million with addi-tional costs incurred in the first year the regulations arefinalized. Industry trade associations have estimated theannual cost to be up to 10–15 times the FDA estimate.The worry of course, is that many of these costs willbe passed on to consumers in the form of higher prices.Estimating the costs involved in conducting the testingrequired for food and supplement products includes abreakdown of financial issues such as the building andmaintenance of laboratory facilities as well as invest-ments in scientific expertise and method development.Tfgot

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Many industry experts have stated that although thereare some supplements that pose a significant risk to pub-lic health (e.g., Ephedra), most do not and thus controlsthat are similar to drugs are not justified. Are we seeingthe beginning of a new herbal medicine drug categorythat mirrors the European model? As consumer trendtoward alternative therapies continues to grow, most ofthese questions will be answered by the response anddesires of the marketplace.

Although the cGMPS do not address the safetyand efficacy of ingredients (except where the cGMPsinsist that the right ingredient or material is in thebottle and labeled as such), the FDA and FederalTrade Commission maintain broad mandates for themonitoring of products including imported goods, andenforcing rules concerning adulteration, contamination,misleading claims, and safety issues. These tools includeseizure, warning letters, and publication on the FDAwebsite.

11. The conclusion: good practices buildconsumer confidence

Regardless of mandated practices, the majority ofdietary supplement manufacturers have done an excel-lent job of protecting the safety and quality of theirproducts. Now, the promulgation of these cGMPs willhelp ensure consumers that equal standards are followedthroughout the industry. For some companies with estab-

he FDA estimates of one-time costs for equipment andacilities are also considered conservative by industryroups. The FDA projected just over $ 54 million inne-time costs, while industry places the cost at morehan $ 600 million. (CRN, 2003).

The final ruling by FDA could threaten the finan-ial viability of some very fine small manufactur-rs if FDA determines that the dietary supplementGMPs should go far beyond the provisions of the foodGMPs and more closely resemble the human drugGMPs. Many believe that Congress did not intenduch restrictive legislation and consequences when itnacted DSHEA in 1994. Most dietary supplement man-facturers welcome the new cGMPs with enthusiasm,aying that the regulations will separate the pretendersrom the manufacturers who are spending the timend money to produce compliant and safe products.f this forces these unqualified, low-quality manufac-urers out of business, the cGMP regulations will beuccessful in their mission to improve overall quality andonsumer confidence in the dietary supplement indus-ry.

lished processes based on existing food or pharmaceu-tical cGMP regulations, the transition will be relativelypainless while, for many, it will represent a significantincrease in the level of documentation and testing. How-ever, consumers deserve and demand that products meetstandards for safety and quality and the implementationof cGMPs for these products are an important first step.It should also be noted that both the FDA and industryconsultants are eager to work with suppliers to resolveminor problems related to compliance with the newcGMPs.

References

Anon., 2004. Global nutrition industry at $ 182 billion: supplementstop $ 60 billion. Nutr. Bus. J. IX (10–11).

Congress of the United States, 1994. The Dietary Supplement Healthand Education Act of 1994, Public Law 103-417, 108 Statute 4325.October 25, 1994.

Council for Responsible Nutrition, 2003. Comments on Docket No.96N-0417, Good Manufacturing Practices for Dietary Supple-ments. Topic: Economic Impact of the Proposed Rule. September,2003.

16 R. Crowley, L.H. FitzGerald / Toxicology 221 (2006) 9–16

Council for Responsible Nutrition, 2004. American confident in dietarysupplements says new IPSOS-Public affairs survey. Press Release,October 25, 2004.

Food and Drug Administration, 2003. Current good manufacturingpractice in manufacturing, packing, or holding dietary ingredientsand dietary supplements: proposed rule. Federal Register. March13, 2003, pp. 12157–12263.

Further reading

American Herbal Products Association, Council for ResponsibleNutrition, National Nutritional Foods Association, 2004. JointIndustry Submission Regarding the Food and Drug Administra-tion’s Proposed Rule. January 30, 2004.