Thursday, March 13, 2003

Part II

Department of Health and Human Services Food and Drug Administration

21 CFR Parts 111 and 112 Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements; Proposed Rule

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DEPARTMENT OF HEALTH AND Table of Contents 6. What Requirements Apply to Laboratory HUMAN SERVICES I. Background Operations? (Proposed § 111.60) A. Dietary Supplement Health and 7. What Requirements Apply to Food and Drug Administration Education Act (DSHEA) Manufacturing Operations? (Proposed B. The Advance Notice of Proposed § 111.65) 8. What Requirements Apply to Packaging 21 CFR Parts 111 and 112 Rulemaking C. Industry and Consumer Outreach and Label Operations? (Proposed [Docket No. 96N–0417] 1. Dietary Supplement Strategic Plan § 111.70) Meetings 9. What Requirements Apply to Rejected RIN 0910–AB88 2. Small Business Outreach Meetings Components, Dietary Ingredients, Dietary 3. Site Visits to Dietary Supplement Supplements, Packaging, and Labels? Current Good Manufacturing Practice Manufacturing Firms (Proposed § 111.74) in Manufacturing, Packing, or Holding D. Food Advisory Committee Report F. Holding and Distributing (Proposed Dietary Ingredients and Dietary E. FDA’s Decision To Propose a Rule Subpart F) Supplements 1. Why Are CGMPs Needed? 1. What Requirements Apply to Holding a. CGMPs help protect the public health Components, Dietary Ingredients, Dietary AGENCY: Food and Drug Administration, b. CGMPs benefit consumers Supplements, Packaging, and Labels? HHS. 2. How Will CGMP Regulations Take Into (Proposed § 111.80). 2. What Requirements Apply to Holding ACTION: Proposed rule. Account Technical Feasibility? 3. How Can FDA Help Industry Achieve In-Process Material? (Proposed § 111.82) SUMMARY: The Food and Drug Compliance With CGMPs? 3. What Requirements Apply to Holding Administration (FDA) is proposing F. Proposal Highlights and Requests for Reserve Samples of Components, Dietary Comments Ingredients, and Dietary Supplements? current good manufacturing practice II. General Issues (Proposed § 111.83) (CGMP) regulations for dietary A. Legal Authority 4. What Requirements Apply to Returned ingredients and dietary supplements. B. Issues From the ANPRM Dietary Ingredients or Dietary The proposed rule would establish the III. Description of the Proposed Rule Supplements? (Proposed § 111.85) minimum CGMPs necessary to ensure A. General Provisions (Proposed Subpart 5. What Requirements Apply to that, if you engage in activities related A) Distributing Dietary Ingredients or to manufacturing, packaging, or holding 1. Who Is Subject to These Part III Dietary Supplements? (Proposed dietary ingredients or dietary Regulations? (Proposed § 111.1) § 111.90) 2. What Are These Regulations Intended to supplements, you do so in a manner G. Consumer Complaints—What Accomplish? (Proposed § 111.2) Requirements Apply to Consumer that will not adulterate and misbrand 3. What Definitions Apply to this Part? Complaints? (Proposed Subpart G, such dietary ingredients or dietary (Proposed § 111.3) § 111.95) supplements. The provisions would 4. Do Other Statutory Provisions and H. Records and Recordkeeping—What require manufacturers to evaluate the Regulations Apply? (Proposed § 111.5) Requirements Apply to Recordkeeping? identity, purity, quality, strength, and 5. Exclusions (Proposed § 111.6) (Proposed Subpart H, § 111.125) composition of their dietary ingredients B. Personnel (Proposed Subpart B) IV. Statement Concerning the Use of Plain 1. What Microbial Contamination and and dietary supplements. The proposed Language Hygiene Requirements Apply? (Proposed V. Paperwork Reduction Act of 1995 rule is one of many actions related to § 111.10) dietary supplements that we (FDA) are VI. Environmental Impact Considerations 2. What Personnel Qualification VII. Analysis of Impacts taking to promote and protect the public Requirements Apply? (Proposed A. Introduction health. § 111.12) B. Preliminary Regulatory Impact Analysis 3. What Supervisor Requirements Apply? DATES: Submit written or electronic 1. The Need for the Proposed CGMP (Proposed § 111.13) Regulations comments by June 11, 2003. Submit C. Physical Plant (Proposed Subpart C) 2. Regulatory Options written or electronic comments on the 1. What Sanitation Requirements Apply to a. No new regulatory action collection of information by April 14, Your Physical Plant? (Proposed § 111.15) b. Fewer requirements for vitamins and 2003. 2. What Design and Construction Requirements Apply to Your Physical minerals ADDRESSES: Submit written comments Plant? (Proposed § 111.20) c. More restrictive CGMP regulations than to the Dockets Management Branch D. Equipment and Utensils (Proposed the proposed regulations (HFA–305), Food and Drug Subpart D) d. HACCP without the other elements of Administration, 5630 Fishers Lane, rm. 1. What Requirements Apply to the CGMP regulations 1061, Rockville, MD 20852. Submit Equipment and Utensils You Use? e. Require final product testing only (Proposed § 111.25) f. Regulate only high-risk products electronic comments to http:// 3. Coverage of the Proposed Rule www.fda.gov/dockets/ecomments. 2. What Requirements Apply to Automatic, Mechanical, or Electronic Equipment? 4. Baseline Practices Fax written comments on the (Proposed § 111.30) 5. Baseline Risk information collection to the Office of E. Production and Process Controls 6. Benefits and Costs Information and Regulatory Affairs, (Proposed Subpart E) a. Reduced illnesses Office of Management and Budget 1. What Production and Process Controls b. Fewer products recalled (OMB), Attn: Stuart Shapiro, Desk Must You Use? (Proposed § 111.35) c. Reduced hypothetical search costs as a Officer for FDA, Fax (202) 395–6974, or 2. What Requirements Apply to Quality measure of the benefit from increased electronically mail comments to Control? (Proposed § 111.37) assurance of quality d. Other benefits [email protected]. 3. What Requirements Apply to Components, Dietary Ingredients, Dietary e. Total measured benefits FOR FURTHER INFORMATION CONTACT: Supplements, Packaging, and Labels You 7. Costs Karen Strauss, Center for Food Safety Receive? (Proposed § 111.40) a. Description of the costs and Applied Nutrition (HFS–821), Food 4. What Requirements Apply to b. Costs of general activity and Drug Administration, 5100 Paint Establishing a Master Manufacturing c. Major costs by type of activities Record? (Proposed § 111.45) d. Estimating costs Branch Pkwy., College Park, MD 20740, 5. What Requirements Apply to 8. Summary of Benefits and Costs 301–436–2375. Establishing a Batch Production Record? C. Initial Regulatory Flexibility Analysis SUPPLEMENTARY INFORMATION: (Proposed § 111.50) 1. Introduction

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2. Economic Effects on Small Entities DSHEA directed the President to notice of proposed rulemaking a. Number of small entities affected appoint a Commission on Dietary (ANPRM) asking for comments on b. Costs to small entities Supplement Labels (the Commission) to whether to institute rulemaking to 3. Regulatory Options consider several issues under DSHEA develop CGMP regulations for dietary a. Exemptions for small entities needing clarification. The Commission ingredients and dietary supplements b. Longer compliance periods 4. Description of Recordkeeping and was to conduct a study on, and provide and what would constitute CGMP Reporting recommendations for, the regulation of regulations for these products. 5. Summary label claims and statements for dietary The ANPRM contained the entire text VIII. Federalism supplements, including the use of of the industry outline. We also asked IX. Request for Comments literature in connection with the sale of nine questions (which we discuss later X. References dietary supplements and procedures for in section II.B of this document) in the ANPRM. The questions focused on I. Background the evaluation of such claims. In making its recommendations, the Commission issues that the industry outline did not A. Dietary Supplement Health and was to evaluate how best to provide address such as those issues noted Education Act (DSHEA) truthful, scientifically valid, and above. We received approximately 100 DSHEA (Pub. L. 103–417) was signed nonmisleading information to letters in response to the ANPRM. Each into law on October 25, 1994. DSHEA, consumers so that such consumers of those letters contained one or more among other things, amended the could make informed and appropriate comments. The comments came from consumers, consumer advocacy groups, Federal Food, Drug, and Cosmetic Act health care choices for themselves and health care professionals, health care (the act) by adding section 402(g) (21 their families. The Commission’s report professional organizations, industry, U.S.C. 342(g)). Section 402(g)(2) of the (Ref. 80) states that the Commission and industry trade associations. The act provides, in part, that the Secretary supports the efforts of industry and FDA majority of comments responded both to of Health and Human Services (the to develop appropriate CGMPs for the nine questions we asked in the Secretary) may by regulation prescribe dietary supplements. Guidance on the ANPRM and on certain provisions in good manufacturing practices for dietary type of information that a responsible manufacturer should have to the industry outline. We also address supplements. Such regulations shall be substantiate statements of nutritional the comments on the nine questions in modeled after CGMP regulations for support and safety is also included in section II.B of this document. We food and may not impose standards for the Commission’s report. The discuss significant comments about which there is no current and generally Commission’s report states that the certain provisions in the industry available analytical methodology. No substantiation files should include outline in our discussion of related standard of CGMP may be imposed assurance that CGMPs were followed in proposed requirements. unless such standard is included in a the manufacture of the product. Included with its comments to the regulation issued after notice and ANPRM, the United States opportunity for comment in accordance B. The Advance Notice of Proposed Pharmacopeia (USP) submitted a copy with 5 CFR chapter V. Rulemaking of its general chapter, ‘‘Manufacturing Congress enacted DSHEA to ensure On November 20, 1995, Practices for Nutritional Supplements,’’ consumers’ access to safe dietary representatives of the dietary (Ref. 2) and in March/April 2002, USP supplements. In the findings supplement industry submitted to FDA proposed revisions to this general accompanying DSHEA, Congress stated an outline for CGMP regulations for chapter to introduce provisions that improving the health status of U.S. dietary supplements and dietary pertaining to botanical preparations citizens is a national priority and that supplement ingredients. We evaluated (Ref. 82). In February 2000, we received the use of dietary supplements may help the outline and determined that it a copy of the National Nutritional Foods prevent chronic diseases and maintain provided a useful starting point for Association’s (NNFA) ‘‘NNFA Good good health (Ref. 1). If dietary developing CGMP regulations. Manufacturing Practice in supplements are adulterated because Nonetheless, we believed that the Manufacturing, Packing, or Holding they contain contaminants (such as industry outline did not address certain Dietary Supplements’’ (Ref. 3). We filth), because they do not contain the issues that should be considered when found that the industry outlines dietary ingredient they are represented developing a proposed rule on CGMPs published in the ANPRM, the USP to contain (for example, a product for dietary ingredients and dietary manufacturing practices, and the NNFA labeled as vitamin C that actually supplements. For example, the industry standards were useful in developing this contains niacin), or because the amount outline did not address the need for proposed rule. We included certain of the dietary ingredient thought to specific controls for automatic, provisions found in these outlines in provide a health benefit (for example, computer-controlled or assisted this CGMP proposed rule. These three folic acid to reduce the risk of neural systems. outlines indicate that dietary ingredient tube defects or calcium in an amount to In addition to identifying a number of and dietary supplement manufacturers reduce the risk of osteoporosis) is not issues that were not included in the already recognize that there are basic, actually present in the supplement, then industry outline but on which we common steps needed to manufacture a the consumer may suffer harm or may wanted public comment, we also dietary ingredient or dietary supplement not obtain the purported health benefit recognized that other interested parties, that is not adulterated although, as from their consumption. CGMP such as consumers, other industry established in the regulatory impact regulations for dietary ingredients and segments who had not participated in analysis, a large percentage of dietary supplements will help to ensure developing the outline, and the health manufacturers do not follow a good that the potential health benefits that care community should have an manufacturing model. For example, Congress identified as the basis for opportunity to provide comments on these practices include requirements DSHEA are obtained and that CGMPs for dietary supplements before for: consumers receive the dietary we developed a proposal. Therefore, in • Designing and constructing ingredients that are stated on the the Federal Register of February 6, 1997 physical plants that facilitate product label. (62 FR 5700), we issued an advance maintenance, cleaning, and proper

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manufacturing operations or to prevent the activities we should undertake as • CGMPs should require that mixup between different raw materials part of an overall strategy and the companies report adverse reactions; and and products; prioritization of those activities. In the • CGMPs should include guidance on • Establishing a quality control unit; notices for these meetings, we identified testing for ingredient identity and • Establishing and following written the development of CGMPs for dietary adulteration with toxic substances. procedures for: supplements as one activity that should 2. Small Business Outreach Meetings 1. Maintaining and cleaning be considered in an overall strategy. equipment and utensils; During and after the strategic We held public meetings on July 12, 2. Receiving, testing, or examining meetings, we received comments from September 28, and October 21, 1999, to materials received and testing of consumers, consumer advocacy groups, collect information from industry and finished product; health care professionals, health care others that would help us to understand 3. Using master and batch control professional organizations, industry, the economic impact on small records; and industry trade associations. The businesses of CGMP regulations for 4. Handling consumer complaints; comments addressed a wide range of dietary supplements. Transcripts of and activities related to regulating dietary these public meetings (docket number 5. Maintaining records for laboratory supplements. (These comments can be 96N–0417, ‘‘Development of Strategy for tests, production control, distribution, seen at our Dockets Management Branch Dietary Supplements’’) are available at and consumer complaints. (see ADDRESSES) in docket number 99N– our Dockets Management Branch or Based on the ANPRM, the comments 1174.) The comments generally electronically at http://www.fda.gov/ that we received in response to the identified the development of CGMP ohrms/dockets/dockets/96n0417/ ANPRM, our outreach activities (which regulations as a high priority activity tr00001.pdf. Public comments from we discuss below), and our own that should be included in any FDA small businesses included both support knowledge and expertise about CGMPs strategic plan for regulating dietary of and concern for CGMP regulations. for foods, drugs, cosmetics, devices, and supplements. Some comments that Small businesses expressed concerns biologics, we are proposing to establish addressed the development of CGMPs about the cost and the time involved in these CGMP regulations for dietary are summarized as follows: complying with any rule that contains ingredients and dietary supplements. • It would be useful to industry to the following requirements: The proposed regulations would impose have FDA establish CGMPs especially • Conducting tests to determine requirements for: (1) Personnel, (2) for small and intermediate-size firms identity, purity, quality, strength, and physical plants, (3) equipment and that are not clear on what they should composition of dietary ingredients and utensils, (4) production and process be doing; dietary supplements; controls, (5) holding and distributing, • CGMPs would establish a level • Maintaining written procedures and (6) consumer complaints related to good playing field for industry, which would records documenting that procedures manufacturing practices, and (7) records help prevent irresponsible firms from are followed; and • and recordkeeping. making and selling adulterated Providing data that support expiration dating. C. Industry and Consumer Outreach products; • CGMPs should be able to Public comments from small business During 1999, we conducted a number accommodate a wide variety of firms, expressed support for dietary of outreach activities related to dietary that is, small and large firms that supplement CGMP regulation. Some supplements. We held several public manufacture a wide array of different small businesses (1 with 15 employees) meetings to obtain input from the public types of products and ingredients; commented that they have CGMPs in on developing our overall strategy for • CGMPs should ensure that place with written procedures tailored achieving effective regulation of dietary consumers get dietary supplements with to the size of their operations. One small supplements, which could include the strength and the purity that business with sales under $1 million establishing CGMP regulations. We also consumers expect; commented that their plant materials held public meetings focused • CGMPs should ensure that every received in fresh form are identified specifically on CGMPs and the dietary supplement on the market has onsite by a botanist, and when the economic impact that any CGMP rule the safety, identity, purity, quality, and onsite botanist is not able to confirm for dietary ingredients and dietary strength it purports in the label to identity, the plant material is sent to an supplements may have on small possess; outside laboratory that conducts businesses. Additionally, FDA staff • CGMPs should include ingredient chemical analysis to confirm identity. toured several dietary supplement identity testing and other testing; 3. Site Visits to Dietary Supplement manufacturing firms to better • CGMPs should ensure that dietary Manufacturing Firms understand the manufacturing processes supplements are produced using a and practices that potentially would be master formula procedure and produced During the summer and fall of 1999, subject to a CGMP regulation for dietary in a sanitary facility; we visited eight dietary supplement ingredients and dietary supplements. • CGMPs should require that manufacturing firms. These visits Each of these activities contributed to manufacturers have documented included firms that: (1) Manufacture a our knowledge about the industry. evidence that their manufacturing vitamin using a fermentation process; process is under control on a consistent (2) grind, sift, blend, and otherwise treat 1. Dietary Supplement Strategic Plan basis; raw agricultural commodities (e.g., Meetings • CGMPs should require botanicals); (3) manufacture dietary We held public meetings on June 8 manufacturers to test dietary ingredients for use in manufacturing and July 20, 1999, to collect stakeholder ingredients, particularly imported dietary supplement tablets, capsules, comments on the development of our botanicals, for heavy metals, pesticides, softgels, and powders; (4) manufacture overall strategy for achieving effective and industrial contaminants; dietary supplements for packaging and regulation of dietary supplements. We • CGMPs should require expiration labeling by others; and (5) manufacture, designed the meetings to provide an dating and testing for dissolution and package, and label dietary supplements opportunity for public comment on both bioequivalence; under their own and others’ labels. The

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firms varied in size and were located in requirements in more detail later in this In deciding whether to propose CGMP several parts of the country. document. regulations for dietary supplements, we We found an array of manufacturing, asked ourselves: E. FDA’s Decision To Propose a Rule packaging, and holding practices in the • Why Are CGMP regulations firms. The practices included the needed? This proposed regulation, which sets • following: forth proposed CGMPs for dietary How will CGMP regulations take • Using CGMPs similar to those into account technical feasibility? and ingredients and dietary supplements, is • included in the ANPRM; part of our overall strategy for regulating How can FDA help industry • Using automatic systems to dietary supplements in a manner that achieve compliance with CGMPs? quarantine, segregate, approve, and promotes and protects the public health. 1. Why Are CGMPs Needed? release inventory; Before drafting the proposal, FDA CGMP regulations for dietary • Following written procedures; considered public comment in response ingredients and dietary supplements are • Having quality control units with to the ANPRM and to public meetings, necessary to promote and protect the the responsibility and authority observations at site visits to dietary public health. In addition, CGMP outlined in the ANPRM; supplement manufacturers, and • regulations would benefit consumers Performing one or more tests on advisory group reports. In drafting this economically and would benefit dietary ingredients and dietary proposal, FDA used, in part, the industry. supplements to determine the identity, industry coalition outline that was a. CGMPs help protect the public purity, quality, strength, and published as an ANPRM (62 FR 5700) health. The dietary supplement industry composition; in which the industry adopted broad • is one of the fastest growing product Verifying the reliability of provisions beyond those found in part areas that FDA regulates. In 1999, suppliers’ certifications; and 110 (21 CFR part 110). FDA’s purpose Prevention magazine conducted a • Documenting and maintaining at this proposed rule stage is to present survey entitled ‘‘Consumer Use of records for certain procedures, such as a broad enough scope so that it may Dietary Supplements’’ (Ref. 5). The master and batch production, quality receive comment on the depth and survey used data from telephone control and laboratory operations, breadth of what should be considered interviews with a nationally- distribution, and processing consumer by the agency in developing a final rule. representative sample of 2,000 adults complaints. Our intent is to provide the proper living in households with telephones in balance of regulation so that dietary D. Food Advisory Committee Report the continental United States. The ingredients and dietary supplements are telephone interviews were done in April In February 1998, the Food Advisory manufactured in a manner to prevent and May, 1999. Using population Committee (FAC) established a Dietary adulteration using recognized scientific estimates based on the Census Bureau’s Supplement Working Group to consider principles and both industry and March 1998 Current Population Survey what constitutes adequate testing for consumer expectations that are Estimates, the survey stated that identity of different dietary ingredients reasonable and appropriate. Therefore, approximately 186,014,712 adults live and what records are necessary to FDA seeks comment on whether each of in the households with telephones in demonstrate that CGMPs are maintained the proposed provisions are necessary to the United States and that an estimated throughout the manufacturing and ensure the safety and quality of dietary 158.1 million of these Americans in distribution process. The working group ingredients and dietary supplements households with telephones use dietary issued a report that discussed the and whether they are adequate to supplement products. These consumers selection of the most appropriate and protect the public health. In addition, spend approximately $8.5 billion a year reliable identity test and the general we seek comment on whether there are on dietary supplements. The survey also principles for consideration in setting certain provisions that are not proposed found that: performance standards for such tests but that may be necessary. Comments • Only 41 percent of the surveyed (Ref. 4). The report also identified the should include justification for why consumers who use vitamins and types of records that would be necessary provisions may or may not be necessary, minerals think they are very safe and to demonstrate that CGMPs are including supporting data where only 50 percent think they are maintained throughout the appropriate. If comments assert that somewhat safe; manufacturing and distribution process. certain provisions are not necessary, • Only 24 percent of the surveyed On June 25, 1999, the working group comments should include an consumers who use herbal products presented its report, in draft form, explanation on how, in the absence of think they are very safe; and only 53 during an FAC public meeting. We the requirement, one can ensure that percent think they are somewhat safe; received public comments during and there would be adequate protection of and after the June 25, 1999, public meeting. the public health when there is risk of • Twelve percent of the surveyed Although this proposal does not adulteration. Comments also should consumers who have used dietary address dietary ingredient identity address whether the gains to consumers supplements say they have experienced testing in the same detail as the working in product safety and quality are side effects or adverse reactions from group’s report, we considered the report warranted. Moreover, assuming that this their use of dietary supplements. in developing requirements for identity proposal does advance the public The survey also found strong public testing and CGMP records requirements health, comments should address support for increased Government in this proposal. The working group’s whether there is any reason to apply regulation of dietary supplements; 74 report may be useful in developing different requirements, including greater percent of the surveyed consumers industry guidance to supplement a or lesser requirements on small firms as reported that they think that the CGMP regulation for dietary ingredients compared to larger firms and the Government should be more involved in and dietary supplements. We discuss rationale for doing so. Finally, ensuring that these products are safe dietary ingredient and dietary comments should address the agency’s and do what they claim to do. supplement identity testing and legal authority to issue these However, unlike other major product recordkeeping for CGMP proposed regulations. areas, there are no FDA regulations that

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are specific to dietary ingredients and have to establish specifications for of these dietary supplements contained dietary supplements that establish a botanicals that may contain toxic dietary ingredient levels that could have minimum standard of practice for compounds and conduct testing to caused serious illness or injury. manufacturing, packaging, or holding. ensure that there are not toxic Illnesses or injuries such as nausea, The absence of minimum standards has compounds present that may adulterate vomiting, liver damage, and heart attack contributed to the adulteration and the dietary ingredient or dietary were reported from superpotent niacin misbranding of dietary ingredients and supplement. at an average level of 452 milligrams dietary supplements by contaminants or • We have found manufacturers using (mg) niacin, well above the upper limit because manufacturers do not set and nonfood-grade chemicals to for adults of 45 mg daily (Ref. 26). meet specifications for their products, manufacture dietary supplements (Ref. Recalls for subpotent dietary including specifications for identity, 15). The proposed rule would require supplements have included a recall of purity, quality, strength, and that manufacturers establish folic acid because the dietary composition. Thus, CGMP regulations specifications for components used in supplement contained 34 percent of the are necessary to protect the public manufacturing and also would require declared level (Ref. 27). Such a product health because a CGMP rule would manufacturers to establish and follow would be misbranded under section 403 establish a minimum standard of laboratory control procedures that of the act (21 U.S.C. 343). Folate plays practice for manufacturing, packaging, include criteria for establishing a well-documented and important role and holding dietary ingredients and appropriate specifications. The proposal in reducing the risk of neural tube dietary supplements. would further require manufacturers to defects. Neural tube birth defects, The following examples illustrate the conduct testing to confirm that their primarily spina bifida and anencephaly, wide range of dietary ingredient and specifications are met. These cause serious lifetime debilitating dietary supplement adulteration caused requirements, if finalized, would ensure injuries and disabilities, and even death. by manufacturing, packaging, or holding that manufacturers establish and use Thus, use of subpotent folic acid by practices. The examples, although not appropriate criteria, such as using food- women who are or may become exhaustive, demonstrate why CGMPs grade rather than industrial-grade pregnant may result in increased risk of are necessary to protect public health: chemicals, and would ensure that having a child with a neural tube defect. • In 1997, we received an adverse manufacturers conduct testing to The proposed rule would require event report (AER) regarding a young confirm that food-grade chemicals were manufacturers to establish woman who had taken a dietary received from the supplier. specifications for the dietary supplement and experienced a life- • Also during inspections, we have supplement the manufacturer makes threatening abnormal heart function found insanitary conditions in physical and then meet those specifications. (Ref. 6). We investigated the AER and plants where dietary ingredients or Therefore, if the proposed rule is determined that the dietary supplement dietary supplements were finalized, if the label for a folic acid the woman consumed contained manufactured, packaged, or held (Ref. supplement declares that the dietary Digitalis lanata, a plant that can cause 16). Pest infestation, building and supplement contains a certain level of life-threatening heart reactions (Refs. 6 equipment defects, and leaking pipes folic acid, the folic acid supplement through 10). We found D. lanata in that drip onto dietary supplements are must actually contain that level, or we samples of raw material labeled examples of insanitary conditions that would consider the folic acid ‘‘plantain’’ that was a dietary ingredient we have found that may lead to product supplement to be adulterated under in one of the dietary supplement adulteration and could cause consumer section 402(g) of the act. products used by this woman (Ref. 6). illnesses and injuries. The proposed • Other recalls have been necessary A nationwide listing of manufacturers rule would require a manufacturer, because of undeclared ingredients, indicated that 183 firms may have used packager, or holder to maintain its including color additives (Refs. 28 and the contaminated dietary ingredient in physical plant used for these activities 29), lactose (Ref. 30), and sulfites (Ref. dietary supplements. The proposed in a sanitary condition. 31). Undeclared ingredients, such as CGMP regulations, had they been in • In the past, we have been involved color additives, lactose, and sulfites, effect, would have required identity and in the recall of dietary supplements may cause potentially dangerous purity tests of dietary ingredients and contaminated with lead (Ref. 17), reactions in susceptible persons (Ref. dietary supplements and would likely salmonella (Ref. 18), Klebsiella 32). The proposed rule would require have prevented the use of the D. lanata pneumonia (Ref. 19), botulism (Ref. 20), manufacturers to verify that the correct in these dietary supplements. and glass (Ref. 21). These contaminants labels have been applied to dietary • In 1998, the American Herbal can cause serious illness or injury and, ingredients and dietary supplements Products Association (AHPA) surveyed in the case of lead, may result in chronic produced. The master manufacturing its members about commonly irreversible cognitive defects in children record would have to identify each adulterated botanicals and methods and progressive renal failure in adults. ingredient required to be declared on useful in detecting adulteration in The proposed rule would require the ingredient list under section 403 of botanicals (Ref. 11). AHPA members dietary ingredients and dietary the act. identified 43 botanicals, including D. supplements to be manufactured, • A study found that dietary lanata contaminated plantain, that are packaged, and held in a manner that ingredient content varied considerably commonly adulterated with prevents adulteration, including from the declared content (Ref. 33). The contaminants, the common adulterant adulteration by the contaminants such study examined ephedra alkaloids in 20 for each botanical, and a method for as those described. herbal dietary supplements containing identifying the adulterant. For example, • We also have been involved in ephedra (Ma Huang) to determine their aflatoxin and mycotoxin (toxic recalls for super- and subpotent dietary ephedra alkaloid content. This study compounds produced by certain molds) supplements. Recalls of superpotent found that norpseudoephedrine was are known to contaminate certain herbal dietary supplements have included the often present in the ephedra dietary and botanical dietary supplements following dietary ingredients: Vitamin A supplements. The study also observed (Refs. 11 through 14). Under this (Ref. 22), vitamin D (Ref. 23), vitamin B6 significant lot-to-lot variations in proposed rule, a manufacturer would (Ref. 24), and selenium (Ref. 25). Each alkaloid content for four products,

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including one product that had lot-to-lot Establishing CGMP regulations for the science, but would give you variations of ephedrine, dietary supplements is only part of our maximum flexibility in meeting the pseudoephedrine, and methylephedride broad science-based regulatory program requirement. For example, there are that exceeded 180 percent, 250 percent, for dietary supplements that is tests available for identity, purity, and 1,000 percent, respectively. Half of necessary to give consumers a high quality, strength, and composition of the products tested differed in their degree of confidence in the safety, certain dietary ingredients or dietary label claims for ephedra alkaloid composition, and labeling of dietary supplements. Because many tests for content and their actual alkaloid supplements. Aside from our CGMP identity, purity, quality, strength, and content. In some cases, the discrepancy efforts, we have taken other steps to composition of dietary ingredient or exceeded 20 percent. One product did protect the public health, such as: dietary supplements have not been not have any ephedra alkaloids. Lot-to- • Reviewing claim notifications officially validated, the proposal would lot variation in dietary ingredients is a under section 403(r)(6) of the act to permit tests using methods other than public health problem particularly identify unlawful claims; those that are officially validated. By because conditions of use recommended • Reviewing new dietary ingredient using the term ‘‘officially validated,’’ we or suggested in the labeling of dietary notifications to ensure that new dietary mean that the method is validated using supplements are presumably based on ingredients are reasonably expected to an interlaboratory collaborative study by the dietary supplement containing a be safe under section 413 of the act (21 which a proposed method is validated certain amount of the dietary ingredient. U.S.C. 350b); by independent testing in separate • If the dietary supplement contains more Evaluating the nutrition labeling of laboratories under identical conditions or less than the amount that the dietary supplements; • (Ref. 35). An AOAC International manufacturer represents, then the Monitoring, through AERs (formerly the Association of Official consumer does not receive the potential voluntarily submitted to FDA, the Analytical Chemists) Official Method is health benefit from the dietary occurrence of adverse events to identify an example of an officially validated supplement or is exposed to an amount potentially unsafe products; and • method. We discuss test methods that could present risk of injury or Taking compliance actions against validation in more detail later in this illness. The proposed rule would products that are adulterated or document. misbranded. require manufacturers to establish In areas where scientific study is still controls, including master The CGMP regulation, if finalized, would, along with our other dietary evolving, we did not propose specific manufacturing and batch production requirements. For example, we did not records to ensure that they use the ingredient and dietary supplement initiatives, contribute further to the propose requirements for dissolution, correct amount of the dietary ingredient disintegration, bioavailability, or to produce the dietary supplement, and protection of public health. expiration dating. In those areas, it may that they apply the correct label to the b. CGMPs benefit consumers. In be premature to propose a requirement dietary supplement. addition to the public health benefits for • A private company analyzed a consumers, CGMP regulations for at this time. In the preamble to this rule, sample of dietary supplements and dietary ingredients and dietary we identify those areas where additional found that some dietary supplements supplements will benefit consumers in scientific study is necessary before we did not contain the dietary ingredients other ways. Consumers should not have can propose a dietary supplement claimed on the label (Ref. 34). The study to wonder whether the dietary CGMP requirement. For example, we found that 25 percent of gingko biloba supplements they buy are adulterated or did not identify defect action levels products, 20 percent of saw palmetto, 33 whether they contain the correct dietary (DALs) for dietary ingredients because percent of glucosamine, chrondroitin ingredients or contain the dietary there are not enough data available to and combined glucosamine/ ingredients in the amount stated on the identify an appropriate DAL for most chondroitin, and 50 percent of SAMe product’s label. Consumers who dietary ingredients. Likewise, further did not contain the dietary ingredients purchase a product that does not study is needed for some dietary claimed in their product labels. The contain the amount or strength listed on ingredients before dissolution, proposed rule would require the label experience an economic loss disintegration, bioavailability, manufacturers to establish and meet because they are paying for something expiration dating, or other quality specifications for the identity, purity, that they did not receive. CGMPs would standard requirements can be proposed. quality, strength, and composition of require manufacturers to establish and 3. How Can FDA Help Industry Achieve dietary supplements. meet specifications for identity, purity, Compliance With CGMPs? Given the wide range of public health quality, strength and composition of concerns presented by the dietary supplements to help ensure that During small business outreach public manufacturing, packaging, and holding consumers buy dietary supplements that meetings and in comments to the practices for dietary ingredients and are not adulterated, contain the dietary ANPRM, members of the dietary dietary supplements, a comprehensive ingredients declared on the product’s supplement industry told us that they system of controls is necessary to label, and contain the amount or would like our help in determining how prevent adulteration and misbranding. strength listed on the label. Therefore, to implement CGMP regulations for CGMPs are intended to establish such a CGMPs would benefit consumers. dietary ingredients and supplements. comprehensive system. Manufacturers We have heard that issuing guidance who operate in accordance with CGMPs 2. How Will CGMP Regulations Take documents and education and training would be less likely to distribute Into Account Technical Feasibility? would be helpful. We invite comment adulterated and misbranded dietary In developing this proposed rule, we on the use of guidance documents, ingredients or dietary supplements than were careful not to propose education, training, or other approaches those who do not meet the requirements that are not technically and potential sources of education and requirements. Quality assurance will feasible to meet. In some areas where training that you believe would assist maximize the probability that there has been scientific study but industry efforts to implement the unadulterated dietary supplements will where the science is still evolving, the proposed CGMP regulations, if finalized reach the marketplace. proposal recognizes the evolving state of as proposed.

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F. Proposal Highlights and Requests for products are truthful and not the manufacturing process where Comments misleading. The agency would review control is necessary to ensure that the This proposed rule is intended to the lawfulness of such statements under dietary supplement contains the ensure that manufacturing practices will sections 403(a)(1) and 201(n) of the act. identity, purity, quality, strength, and not result in an adulterated dietary We propose requirements for: (1) composition claimed on the label. We supplement and that supplements are Personnel, (2) the physical plant propose flexible testing requirements: properly labeled. This proposed rule, if environment, (3) equipment and You would be required to test final finalized as proposed, will give utensils, (4) production and process products for adherence to specifications, consumers greater confidence that the controls, (5) holding and distributing, unless a scientifically valid analytical dietary supplements they choose to use (6) consumer complaints related to method does not exist; in the latter case, will have the identity, strength, purity, CGMPs, and (7) records and you would be required to test incoming quality, or composition claimed on the recordkeeping. Key provisions of the shipment lots of components, dietary label. A manufacturer of a dietary proposed rule are highlighted below. ingredients, or dietary supplements for ingredient or a dietary supplement We also seek comment on whether any such specification, and to test in- cannot make claims that state or imply certain additional provisions should be process for any such specification in that the dietary ingredient or dietary included as requirements in a final rule. accordance with the master Proposed ‘‘personnel’’ requirements supplement is safe and/or effective manufacturing record where you would require that you have qualified simply because it has been determine control is necessary to ensure employees and supervisors, to take manufactured in compliance with the identity, purity, quality, strength, measures to exclude any person from current good manufacturing practice and composition of the product. your operations who might be a source Proposed ‘‘holding and distributing’’ (CGMP) requirements. However, we of microbial contamination, and to use requirements would protect believe that a voluntary labeling hygienic practices to the extent components, dietary ingredients, dietary statement about the fact that a dietary necessary to protect against supplements, packaging, and labels ingredient or dietary supplement has contamination. against contamination and deterioration. been made in compliance with CGMP Proposed ‘‘physical plant’’ You would be required to hold requirements might be made lawfully requirements are intended to help components, dietary ingredients, dietary under the act, provided that such a prevent contamination from your supplements, packaging, and labels statement is made in an appropriate physical plant environment. You would under appropriate conditions of context and with adequate disclaimers be required to design and construct your temperature, humidity, and light so that so that consumers fully understand it physical plant in a manner to protect their quality is not affected; and under and are not misled by it. The proposed dietary ingredients and dietary conditions that do not lead to the rule governing CGMP requirements for supplements from becoming adulterated mixup, contamination, or deterioration. dietary supplements address during manufacturing, packaging, and Proposed ‘‘consumer complaints’’ manufacturing controls to ensure that holding. You would be required to keep requirements would require that you dietary ingredients and dietary your physical plant in a clean and keep a written record of each consumer supplements are produced in a manner sanitary condition and in sufficient complaint related to good that will not adulterate or misbrand repair to prevent contamination of manufacturing practices; review such such products. Compliance with any components, dietary ingredients, dietary complaints to determine whether the final rule, based on the proposal, will supplements, or contact surfaces. consumer complaint involves a possible not ensure that the dietary ingredient or Proposed ‘‘equipment and utensils’’ failure of a dietary ingredient or dietary dietary supplement itself is safe or provisions would require that you use supplement to meet any of its effective. Thus, the agency believes that equipment and utensils that are of specifications, or any other an unqualified statement saying simply appropriate design, construction, and requirements of this part, including ‘‘produced in compliance with dietary workmanship for their intended use and those that may result in a possible risk supplement current good manufacturing that you provide for adequate cleaning of illness or injury (i.e., an adverse practice requirements,’’ without more, and maintenance. You would be event); and investigate a consumer could well suggest that a product may required to maintain and calibrate your complaint when there is a reasonable be safe and effective or somehow instruments and controls for accuracy possibility of a relationship between the superior to other dietary ingredient and and precision and to ensure that consumption of a dietary supplement dietary supplement products that are automatic, mechanical, and electronic and an adverse event. For the purposes subject to the same CGMP requirements. equipment works as intended. You of this regulation, a consumer complaint Such a statement would likely be would also be required to maintain, about product quality may or may not considered misleading by FDA under clean, and sanitize, as necessary, all include concerns about a possible sections 403(a)(1) and 201(n) of the act. equipment utensils and contact surfaces hazard to health. However, a consumer We believe however, that it might be that are used to manufacture, package, complaint does not include an adverse possible to cure an unqualified or hold dietary ingredients or dietary event, illness, or injury related to the statement by including language supplements. safety of a particular dietary ingredient clarifying to consumers that all dietary Under the proposed ‘‘production and independent of whether the product is ingredients and dietary supplements process controls’’ requirements, you produced under good manufacturing must be manufactured in compliance would be required to establish and use practices. with CGMP requirements and that such a quality control unit in your Proposed ‘‘records and compliance does not mean that the manufacturing, packaging, and label recordkeeping’’ requirements would tell dietary ingredient or dietary supplement operations. We propose requirements you how long you must keep certain is safe or effective. As usual, the for establishing and using master records to show how you complied with manufacturer would be responsible for manufacturing records and batch the CGMP requirements. We would ensuring that any such voluntary control records to ensure batch-to-batch require that you keep written records for labeling statements on its dietary consistency. Specifications would be 3 years beyond the date of manufacture ingredient and dietary supplement required for any point, step, or stage in of the last batch of dietary ingredients

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or dietary supplements associated with bottling of bottled drinking water; 21 903, 348, 371(a), 374, and 381) and those records and have all required Part CFR 120, Hazard Analysis and sections 402 and 403 of the act and records, or copies of such records, Critical Control Point (HAACP) section 361 of the Public Health Service readily available during the retention Procedures for the Safe and Sanitary Act (the PHS Act) (42 U.S.C. 264). period for authorized inspection and Processing and Importing of Juice; 21 Section 402(g) of the act gives us copying by FDA when requested. CFR Part 123, Fish and fishery products; explicit authority to issue a rule CGMP records document the 21 CFR Part 106 Infant formula quality regulating conditions for manufacturing, manufacturer’s operation throughout control procedures; and 21 CFR Part packaging, and holding dietary time and are essential to an enforceable 113, Thermally processed low-acid supplements. Section 402(g)(1) of the regulation. Because FDA does not foods packaged in hermetically sealed act states that a dietary supplement is observe the manufacturer’s operation containers). Further, records are adulterated if ‘‘it has been prepared, fulltime, records can ensure that the included in the CGMPs submitted to packed, or held under conditions that FDA has the information needed to FDA by industry, the National do not meet current good manufacturing identify noncompliance and to bring a Nutritional Foods Association practice regulations.’’ Section 402(g)(2) non-compliant manufacturer into Standards, the NSF International draft of the act authorizes us to, by regulation, compliance. Records can show that standards (Ref. 83), and the USP draft ‘‘prescribe good manufacturing practices appropriate monitoring is performed, Manufacturing Practices for Dietary for dietary supplements.’’ In addition, pinpoint with confidence when a Supplements. section 402(g)(2) of the act states that deviation began and ended, and prove We seek comment on whether certain any such regulations ‘‘shall be modeled that required quality control measures additional provisions should be after current good manufacturing and practices were performed as often included as requirements in a final rule. practice regulations for food and may as necessary to ensure control. Review For example, we invite comment on not impose standards for which there is of manufacturing records with sufficient whether a final rule should include a no current and generally available frequency can ensure that any problems requirement for certain personnel analytical methodology.’’ are uncovered promptly and can records; for written procedures in a In section 402(g)(2) of the act, which facilitate prompt modification, have an number of areas; for equipment describes the general parameters of impact on the production of subsequent verification; and for expiration dating CGMPs for dietary supplements, batches of the product, and prevent and related testing. Written procedures Congress stated that the regulations introduction of potentially hazardous are included in the dietary supplement were to be ‘‘modeled after current good dietary supplements into the market CGMP outline submitted to FDA by manufacturing practice regulations for place. Review of consumer complaint industry, National Nutritional Foods food.’’ To determine what Congress records can facilitate the identification Association standards, the NSF meant, we look to the plain meaning of of trends in reports of illness or injury, International draft standards, and the the phrase. Webster’s II New Riverside identify related batch records to identify USP draft Manufacturing Practices. In University Dictionary defines ‘‘model’’ previously undetected manufacturing order to limit the burden to as ‘‘[a] preliminary pattern serving as deviation, and have an impact on the manufacturers, FDA is not proposing to the plan from which an item not yet prompt recall of any potentially require written procedures. However, constructed will be produced’’ (Ref. 81). hazardous dietary supplement. FDA is proposing that manufacturers Thus, when Congress used the term ‘‘modeled after’’ Congress intended that We seek comment on whether the maintain appropriate records to ensure proposed recordkeeping requirements we use the food CGMPs as a the identity, purity, quality, strength, are not necessary to prevent ‘‘preliminary pattern’’ for the dietary and composition of a given product and adulteration; to ensure the identity, supplement CGMPs. If Congress had records that are necessary for efficient purity, quality, strength, and intended for the agency to adopt food enforcement and to permit trace back. composition of the dietary ingredient or CGMPs as the CGMPs for dietary Although we have not proposed dietary supplement; to an enforceable supplements, Congress could have requirements for written procedures as regulation; and for the other reasons explicitly stated that dietary did these other groups, we seek cited. If comments assert that supplements were subject to food comment on whether such practices recordkeeping provisions are not CGMPs. should be included in a final rule. Later necessary, comments should include an The provisions in the dietary explanation of why recordkeeping in this document, we request comments supplement CGMP proposal are requirements are not necessary on specific written procedures and modeled after food CGMPs. The general including how, in the absence of the describe FDA’s current thinking CGMP provisions for food in part 110 requirements, one can prevent concerning what could be included in relate not only to insanitary production adulteration, ensure the identity, purity, such a written procedure. practices, but other practices, such as We also seek comment on whether quality, strength, and composition of the having appropriate quality control this rule should include specific dietary ingredient or dietary operations, to ensure that a food is supplement, ensure an enforceable requirements for the use of animal- manufactured in a manner that will not regulation, and the other reasons cited. derived dietary ingredients, and adulterate the food. Further, the CGMPs If comments agree that the requirements for persons who handle in part 110 describe the minimally recordkeeping requirements are raw agricultural commodities. Specific acceptable practices for all food necessary for reasons other than those requests for comment of this type are handling operations. They are not we have provided, the comments should contained below in relevant sections of intended to cover specific issues that so state and provide an explanation. this preamble. may relate to a particular product type, Although records are not required in II. General Issues rather, are general provisions concerned 21 CFR Part 110, CGMPs in with practices relating to the receiving, manufacturing, packing, or holding A. Legal Authority inspecting, quality control operations, human food, records are required in the We are proposing these regulations packaging, segregating, processing, other commodity-driven food CGMPs under sections 201, 393, 409, 701(a), storing, and transporting of food. The (i.e., 21 CFR Part 129, Processing and 704, and 801 of the act (21 U.S.C. 321, specific provisions of the food CGMPs

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are linked to hazards that are inherent manufacturer must test or examine the a food additive under section 409 of the to foods (e.g., microbial contamination ingredient using appropriate methods. act, unless they are subject to an and contamination with macroscopic The ‘‘modeled after’’ language in section exception to the definition of ‘‘food filth). 402(g) of the act provides the agency additive’’ under section 201(s) of the The proposed dietary supplement with the flexibility to devise CGMPs act. CGMPs are modeled after the food that make sense for dietary Moreover, dietary ingredients and CGMPs in part 110 in that they cover supplements, and that are based on the dietary supplements may contain the scope of practices related to the same principles as food CGMPs in part pathogenic bacteria or viruses that pose receiving, inspecting, quality control 110, i.e., to prevent adulteration related serious public health and safety operations, packaging, segregating, to insanitary conditions or other concerns (Ref. 36). Botanical dietary processing, storing, and distribution of conditions that may be necessary to ingredients are living plants that may dietary ingredients and dietary prevent adulteration, given the nature of contain different microorganisms. These supplements. Dietary supplements the specific food product and the include Lactobacillus, Leuconostoc, require many of the same types of characteristics of, and hazards inherent Pseudomonas, and Xanthomonas sanitary practices and other practices as in, that food. species and molds. Potential pathogens conventional food production in order The scope of the legal authority for such as Listeria monocytogens, to produce a product that is not the proposed dietary supplement Pseudomonas aeruginosa and adulterated; dietary supplements are CGMPs includes the legal authorities Enterobacteriacae may also be present. Secondary microbial contamination subject to many of the same hazards as upon which the food CGMPs are based. are conventional foods. However, from soil (Bacillus cereus, Clostridium For example, section 402(a)(3) of the act dietary supplements have their own set perfringens and mycotoxin-producing states that a food is deemed adulterated of unique requirements as a result of the molds, etc.), animal feces (Salmonella if ‘‘it consists in whole or in part of any characteristics and hazards due to their and Shigella spp., Escherichia coli) and filthy, putrid, or decomposed substance, ‘‘hybrid’’ nature, e.g., dietary handling (Staphylococcus aureus) can or if it is otherwise unfit for food.’’ supplements can be considered as also occur during harvesting, Section 402(a)(4) of the act states that a falling somewhere along the continuum processing, and transportation (Ref. 36). food is deemed adulterated if ‘‘it has between conventional foods on the one Animal-derived dietary ingredients or been prepared, packed, or held under hand and drugs on the other. Thus, the dietary supplements may also pose a insanitary conditions whereby it may CGMPs for dietary supplements need to risk. For example, bovine colostrum, the address the characteristics and hazards have become contaminated with filth, or lacteal secretion which precedes milk of dietary supplements, the operations whereby it may have been rendered after a cow gives birth, is a substance and processes used to manufacture injurious to health.’’ While section that is used in dietary supplements and dietary supplements, particularly those 402(a)(3) of the act focuses on the food likely presents the same potential health necessary to ensure the identity, purity, itself, section 402(a)(4) of the act focuses risks as does milk. Bovine milk may quality, strength, and composition on the conditions under which the food contain pathogenic organisms capable of claimed on the label. is prepared, packed, or held. Courts causing diseases in man such as Dietary supplements, unlike have adopted a broad reading of section tuberculosis or undulant fever. Glands conventional foods, contain ingredients 402(a)(4) of the act when we have taken and other animal tissues may contain that are consumed in very small actions to advance the public health (see the infective agent that causes quantities, for example, in a tablet or U.S. v. Nova Scotia Food Products transmissible spongiform capsule. Such ingredients may be Corp., 568 F. 2d 240, 248 (2d Cir. 1977)). encephalopathy (TSE) if they originate intended to have an anticipated, specific The agency tentatively concludes that from an animal infected with the physiological response. Such the authorities that it relied on for its disease (Ref. 37). ingredients are more ‘‘drug-like’’ than umbrella CGMPs in part 110 for food are We have authority to issue regulations ‘‘food-like,’’ in part, because very small relevant to the authorities that it needs under section 361 of the PHS Act. The changes in the strength, purity, or for this proposed rule for dietary Secretary delegated authority to the quality of the ingredient can have supplement CGMPs. In addition, section Commissioner of FDA (the significant, and possibly adverse, health 409 of the act is another provision that Commissioner) to exercise the functions consequences to those who ingest it. is relevant to dietary supplement vested in the Secretary under section Thus, the dietary supplement CGMPs, CGMPs. Section 409 of the act addresses 361 of the PHS Act (see 21 CFR by necessity, need to include provisions circumstances under which a food may 5.10(a)(3)). This authority authorizes the related to identity, purity, strength, be deemed adulterated based on the use Commissioner to issue and enforce quality, and composition of the product of a food additive. Section 409 of the act regulations that, in the Commissioner’s so that the dietary supplement ‘‘food’’ is relevant to good manufacturing judgment, are necessary to prevent the product will be manufactured in a practices for foods, including dietary introduction, transmission, or spread of manner that will not result in supplements, because a food would be communicable diseases from one State adulteration. deemed adulterated if it contained a to another. Because this authority is Further, plant products that are used food additive that was not used in a designed to eliminate the introduction to produce dietary supplements may be manner consistent with the statutory of diseases from one State to another, ground or in a powder and not easily and regulatory requirements under the Commissioner may exercise the recognized compared to conventional section 409 of the act (see sections authority over the disease-causing food that is readily identifiable (e.g., one 402(a)(2)(C) and 409 of the act). substance within the State where the can readily distinguish between white Although Congress explicitly excluded food is manufactured, packaged, or flour and white sugar, but not between ‘‘dietary ingredients,’’ as defined in held. The Commissioner, therefore, ground plaintain and ground D. lanata). section 201(ff) of the act, from the assumes the authority to issue Thus, for the manufacturer to be sure definition of food additive, (see section regulations under the PHS Act to assure that the dietary supplement contains the 201(s)(6) of the act), ingredients other that foods are manufactured, packaged, correct ingredient and the amount of the than dietary ingredients in a dietary and held under conditions that will ingredient that is intended, the supplement are subject to regulation as prevent the introduction, transmission,

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or spread of communicable diseases In addition to the broad authority in aware of any potential problems relating between States. Thus, the agency is section 402(g) of the act, we look to the to a particular dietary ingredient and invoking its authority under the PHS statutory scheme of DSHEA as a whole these CGMPs, and so that a Act in this proposed rule to prevent the in proposing regulations related to the manufacturer can take appropriate spread of communicable disease from manufacture, packaging and holding of action when necessary. The proposed dietary ingredients or dietary dietary ingredients and dietary CGMPs would reflect the act’s supplements in intrastate and interstate supplements. Section 403(q)(5)(F) of the regulatory scheme generally and, more commerce. act (section 7(b) of DSHEA) requires that specifically, DSHEA’s provisions that In developing proposed CGMPs for a dietary supplement product provide contemplate consistent, controlled dietary supplements, we relied on the nutrition information. To comply with manufacture of dietary supplements (see basic concept underlying the food section 403(q)(5)(F) of the act, you must sections 402(f) and 403(q)(5)(F) and (s) CGMPs and upheld by the courts. As a be able to identify the dietary ingredient of the act). We tentatively conclude that, result, the basic concept for the food or ingredients in a dietary supplement therefore, section 402(g)(2) of the act CGMPs and the proposed dietary and the quantity of each. Moreover, the gives us the authority to develop dietary supplement CGMPs is the same: To provisions in section 403(s) of the act supplement CGMPs that are not establish regulations that will help relate to identity, purity, quality, identical to our food CGMPs and that ensure that your practices for preparing, strength, and compositional are appropriately tailored to the packaging, and holding dietary specifications of a dietary supplement. manufacturing, packaging, and holding ingredients and dietary supplements do Thus, Congress sought to ensure in of dietary ingredients and dietary not result in an adulterated food DSHEA that dietary supplements would supplements. entering interstate commerce. Sections 701(a) and 704 of the act also provide accurate information to the In addition to relying on the broad give us authority to establish regulations consumer on the identity of the dietary authority in relevant sections of the act related to CGMPs for dietary ingredients ingredient and, if an herb or botanical, that we used to issue the food CGMP and dietary supplements. Under section the source from which it is derived. regulations, we look to the other 701(a) of the act, we have the authority Moreover, Congress sought to ensure relevant statutory language in section to issue regulations for the efficient that the dietary supplement would have 402(g) of the act and the act as a whole enforcement of the act, and such the strength or meet the quality, purity, in deciding the basis for our legal regulations have been held to have the authority in proposing regulations and compositional specifications that force and effect of law (see National related to the manufacture, packaging, the dietary supplement is represented to Nutritional Foods Ass’n v. Weinberger, and holding of dietary ingredients and meet. Because Congress established 512 F.2d 688, 697–98 (2d Cir. 1975)). dietary supplements. We note that section 403(s) of the act—a provision Section 704 of the act gives us the certain terms Congress used in section that requires that a dietary supplement authority to inspect factories, 402(g)(2) of the act, i.e., ‘‘standards’’ and that bears representations about warehouses, and other establishments in ‘‘current and generally available identity, purity, quality, strength, and which foods, including dietary analytical methodology,’’ show that compositional specifications meet those ingredients and dietary supplements, Congress intended to give us the representations—it is reasonable for us are manufactured, processed, packed, or authority to establish regulations in this to establish regulations for held and to inspect their facilities, rule that do not have parallel provisions manufacturing, packaging, and holding equipment, finished and unfinished in other food CGMPs. Specifically, the addressing those same features. These materials, containers, and labeling. second phrase of the second sentence in representations relate to characteristics In addition to having the authority to section 402(g)(2) of the act states that we and hazards to which dietary establish broad regulations for ‘‘may not impose standards for which supplements are subject. Further, in manufacturing, packaging, and holding there is no current and generally section 402(f) of the act, Congress dietary ingredients and dietary available analytical methodology.’’ identified circumstances under which a supplements, we also have the authority ‘‘Standards’’ and ‘‘current and generally dietary supplement or a dietary to require recordkeeping as part of these available analytical methodology’’ are ingredient would be deemed adulterated regulations. Two questions that we terms of art in the scientific field, and because it may present a significant or considered in deciding whether to we are relying on the meaning of these unreasonable risk of illness or injury. propose requirements for recordkeeping terms in the field of science in these Congress expected that a dietary included whether the statutory scheme proposed CGMPs regulations, which supplement would be manufactured in as a whole justified the proposed implement that provision. This statutory a way that ensures that the dietary regulation and whether the proposed language does not limit CGMPs for supplement contains dietary ingredients recordkeeping requirements would be dietary supplements solely to the food that do not present an unreasonable risk limited, would clearly assist in the CGMP regulations at the time DSHEA of illness or injury and for which the efficient enforcement of the act, and was enacted. If Congress had intended conditions of use are based. Because one would not create an unreasonable for the CGMPs for dietary supplements must be able to measure or analyze a recordkeeping burden. In the other to be identical to the CGMPs for food, dietary ingredient in order to determine relevant sections of this document, we the language in section 402(g)(2) of the whether a supplement in fact contains explain in more detail the act relating to ‘‘standards’’ and ‘‘current that dietary ingredient, it is reasonable recordkeeping provisions that we and generally available analytical for a proposed rule on CGMPs to believe are limited to what are necessary methodolog[ies]’’ would be include provisions related to identity, for the efficient enforcement of the act, meaningless. Thus, CGMP regulations purity, quality, strength, and and because the requests are limited, for dietary ingredients and dietary composition of a dietary ingredient or a would therefore not create an supplements may include provisions dietary supplement. Moreover, it is unreasonable recordkeeping burden. relevant to dietary ingredients and reasonable to propose a requirement For this proposed CGMP rule for dietary supplements that were not in that records of complaints be kept and dietary ingredients and dietary current food regulations at the time investigations be done, as necessary, so supplements, recordkeeping is DSHEA was enacted. that the manufacturer and FDA can be necessary to provide the type of

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documentation that would demonstrate The nine questions in the ANPRM, whether a DAL for a dietary ingredient that dietary ingredients and dietary comments, and our responses are as should be established at a different level supplements are manufactured, follows: than what has been established for the packaged, and held under the Question 1. Is there a need to develop same ingredient used in conventional conditions that would be required under specific defect action levels (DALs) for food. the proposed CGMP regulations. dietary ingredients? DALs are established for a food Further, FDA is using its authority The ANPRM stated that the use of a ingredient on a per weight basis. The under sections 801 and 701(a) of the act botanical in a dietary supplement may DALs for whole ginger for ‘‘insect filth in proposing recordkeeping result in a much greater exposure to the and/or mold’’ is an ‘‘average of 3 requirements for dietary ingredients and botanical ingredient for consumers percent or more pieces by weight are dietary supplements that may not be because the dietary supplement will be insect-infected and/or moldy’’ and for marketed or sold in the United States consumed in greater amounts than if the ‘‘mammalian excreta’’ is an ‘‘average of and that are exported under section ingredient was in a food as a spice or 3 mg or more of mammalian excreta per 801(e) of the act. flavoring agent. pound’’ (Ref. 41). Because the DAL is Several comments stated that In addition to having the authority established by weight of the whole establishing DALs for dietary under the act to require recordkeeping, ginger, the DAL for ginger would apply ingredients that are different than DALs we also have authority to require access whether it is used as an ingredient in a for food is not necessary. The comments to the records. Because the practices set conventional food or a dietary disagreed with our statement that forth in the proposed CGMP rule are ingredient in a dietary supplement. dietary ingredients in dietary necessary to providing consumers with Therefore, if we have established a DAL supplements and conventional foods are dietary supplements that are not in the industry compliance document consumed in different quantities. For adulterated, access to records that for a conventional food ingredient, that example, the comments stated that demonstrate that firms follow CGMPs is DAL also would apply to that ingredient generally botanical ingredients are when used as a dietary ingredient in a essential to confirming systematic present in dietary supplements in dietary supplement until such time that compliance with CGMPs. We also have approximately the same amounts we would establish a different DAL for the authority to copy the records when normally consumed in conventional its use as a dietary ingredient (Ref. 41). necessary. We may consider it necessary foods. to copy records when, for example, our Other comments generally opposed However, we do not have many dietary investigator may need assistance in applying the current DALs for foods to ingredients that are included in the DAL reviewing a certain record from relevant dietary ingredients and instead compliance guide. We agree that DALs experts in headquarters. If we were supported the development of DALs for may be needed for some dietary unable to copy the records, we would dietary ingredients, especially for ingredients, especially ingredients like have to rely solely on our inspector’s botanicals and herbals. Many comments botanicals that are subject to the same notes and reports when drawing recommended that we cooperate with type of defects (such as mold and insect conclusions. A failure to have a required industry, outside the rulemaking parts) as other food for which DALs record would mean that a food is process, to develop DALs for dietary have been established. We base DALs on adulterated under section 402(g) of the ingredients. scientific information such as literature act. We disagree with the comments that surveys, scientific market surveys, and Recordkeeping will not only help the state that establishing DALs for dietary laboratory analyses and also on agency to determine whether dietary ingredients that are different than DALs information gained through physical ingredients or dietary supplements were for food is not necessary because an plant inspections. If and when we manufactured, packaged, and held ingredient in food and in a dietary determine that we have sufficient consistent with CGMP regulations, but supplement would be consumed in the information to develop DALs for dietary also will provide a public health benefit same amounts. The comment did not ingredients, we will consider whether to to consumers. When manufacturers provide evidence or examples to do so. keep records, for example, of lot or support the comment. Some food Question 2. We requested comments batch numbers, the records facilitate a ingredients for which DALs have been on appropriate testing requirements to manufacturer’s recall of suspect established also are dietary ingredients provide positive identification of dietary products in case a recall becomes used in dietary supplements. For ingredients, particularly plant materials, necessary. This benefits consumers example, a DAL has been established for used in dietary supplements. because the manufacturer can recall its whole ginger used in a conventional The ANPRM explained that the products that may be adulterated or food. Ginger is also a dietary ingredient misidentification of dietary ingredients, misbranded more quickly. used in dietary supplements. We have particularly plant materials, used in found dietary supplements that dietary supplements may present a B. Issues From the ANPRM recommend a daily intake of ginger of significant public health and economic As stated previously, in addition to 4,815 mg, 1,260 mg, and 2,200 mg (Ref. concern. The ANPRM also noted that inviting comment on the industry- 38). One teaspoon of raw ginger root is the analytical methodology available for drafted CGMP outline, we asked nine equal to 2,000 mg (2 grams (g)) and one identifying many dietary ingredients is questions in the ANPRM on CGMP teaspoon of ground ginger is equal to limited. We invited comments on the issues for dietary supplements that the 1,800 mg of ginger (1.8 g) (Ref. 39). A technical and scientific feasibility of industry outline did not address. In this recipe for gingersnaps yielding 18 identifying different types of dietary section, we summarize each question cookies specifies 1 teaspoon ginger (Ref. ingredients. We also solicited and the principal comments we 40). Thus, ginger would be consumed in information on what constitutes received, and we respond to the greater amounts as a dietary supplement ‘‘adequate testing’’ for identity of comments. We address other significant than as an ingredient in a conventional different types of dietary ingredients, comments about the ANPRM, other than food. However, we have tentatively and, in the absence of testing, what the nine questions we asked, elsewhere concluded that we do not have types of practices would be effective in this document. sufficient information to determine alternatives to testing to ensure the

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identity of different types of dietary comments noted that test methods that identity testing may be useful, and we ingredients. are presently available and used for will consider future development of Comments generally supported identifying botanicals are not officially ingredient identity testing guidance requiring tests of some kind to validated. If an officially validated documents. positively identify dietary ingredients method is not available for a dietary Manufacturers should be responsible and to verify dietary ingredient identity. ingredient, several comments suggested for identifying the ingredients that they The comments put forth different working towards AOAC International use in their products and, in addition, reasons, which ranged from ensuring validation and, in the interim, for verifying that the dietary ingredients public safety to preventing economic instituting peer review of less formal or dietary supplements they make adulteration. Some comments suggested test methods. Other comments noted contain the identity, purity, quality, that suppliers should be responsible for that the dietary supplement industry strength, and composition that the identifying the dietary ingredients they has begun an effort to develop validated manufacturer intends the product to supply to manufacturers and that test methods for several botanical have. As discussed previously in this manufacturers should be responsible for ingredients. One comment suggested document, we have found serious only verifying the identity of the that it is important to develop methods adverse events to be related to dietary finished product. Other comments that are subject to peer review and to ingredient misidentification. The stated that the manufacturer should be institute a certification program for manufacturer must conduct identity responsible for identification and testing facilities because the analysis of tests to ensure that they used the correct should not rely on a supplier’s natural products requires specialized ingredient to prevent potential serious certification. training in natural product chemistry. adverse events. We discuss identity Some comments raised issues relating The comment did not indicate who (e.g., testing for dietary ingredients and to the actual identity tests that should FDA or another organization) should dietary supplements later in this be recommended or required and develop a certification program. document. discussed analytical method selection Some comments only addressed We agree with the comments that and method options, use of and identity testing of unprocessed certification of testing facilities could be availability of official validated botanicals. These comments said that an important step in ensuring analytical analytical methods, and certification of for unprocessed botanicals in whole or quality. However, certification of testing testing facilities that conduct identity in part (e.g., flowers, roots, leaves, etc.), facilities is outside the scope of this tests on natural products. Some organoleptic techniques are sufficient rule. comments suggested that identity test provided that accurate records are Question 3. FDA requested comments method options should include maintained and that the manufacturing on standards that should be met in organoleptic and microscopic methods process provides a paper trail of positive certifying that a dietary ingredient or and chemical analytical methods. The identification. One comment suggested dietary supplement is not contaminated comments noted that selecting the that a ‘‘voucher specimen’’ (a sample of with filth; that it is free of harmful appropriate method is dependent on the the plant material) from the supplier contaminants, pesticide residues, or type and form of the ingredient. Other along with a certificate of botanical other impurities; that it is comments said that manufacturers identity would be an adequate record. microbiologically safe; and that it meets should be responsible for selecting the The certificate of botanical identity specified quality and identity standards. appropriate method to confirm would follow the material through the The ANPRM noted that, under ingredient identity. Most comments manufacturing process, thus creating a § 110.80, a food manufacturer may recommended that we provide guidance paper trail. The voucher specimen accept a supplier’s certification that its to industry in defining what comprises would be held for a specific period of products do not contain adequate testing for different types of time or, if necessary, serve as a microorganisms, filth, or other foreign ingredients, but did not support permanent record. material that would adulterate the regulations prescribing the test method Dietary ingredient identification is an product instead of testing or evaluating or methods for specific ingredients. important part of CGMPs. We agree with the supplier’s products itself. As a Comments generally supported the the comments that identity testing result, we asked for comments on use of a standard compendial method, requirements are needed but that no whether a certification will provide such as those published by the USP or single approach or test method may be assurance that dietary ingredients are AOAC International. Where no appropriate for every dietary ingredient. not contaminated or whether specific published method exists, the comments For example, microscopic or testing requirements are necessary. suggested that manufacturers should be organoleptic tests might be appropriate Comments generally supported responsible for developing adequate and for herbs or plant parts (because you can relying on a supplier’s certification that effective identification testing see, taste, or smell them), but not a dietary ingredient is what it purports procedures, requirements, or practices appropriate for amino acids (which to be and is not contaminated. The to ensure the identity of the dietary cannot be identified by the naked eye or comments stated that reliance on the ingredients they use. One comment identified by using your senses). A supplier’s certification should be an from a vitamin manufacturer noted that microscopic test might be appropriate alternative to testing raw materials to most of its products have recognized for herbs that still have their leaves or detect microorganisms, filth, or foreign and established identity tests as part of other distinguishing marks or material so long as the reliability of the their compendial status. Other characteristics, but not for ground-up supplier’s certification is confirmed. comments from botanical dietary herbs. Thus, we agree with the Most comments stated that supplement manufacturers noted that comments stating that the key principle manufacturers are responsible for their current methods for identifying in dietary ingredient identification determining, on a case-by-case basis, plant material are adequate, but that testing is to establish an appropriate whether a supplier’s certification they will, over time, be enhanced by the procedure that will identify, with provides adequate assurance that a availability of more widely recognized certainty, the dietary ingredients used in dietary ingredient is what it purports to methods and techniques as a result of making a dietary supplement. We agree be and is not adulterated. Some current work in this field. The that a guidance document on ingredient comments based their support for

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relying on a supplier’s certification on follow written procedures and noted final rule. We discuss written § 110.80(a)(2) through (a)(4); these that the industry outline in the ANPRM procedures for various stages of provisions allow food manufacturers to would require written procedures for manufacturing, packaging, labeling, rely on a supplier’s guarantee or many processes and functions. Some holding, and for handling consumer certification that raw materials or other comments noted that written procedures complaints later in this document. ingredients do not contain levels of and day-to-day records documenting We disagree, however, that records microorganisms or toxins that may that the procedures were followed will are not necessary to show that certain produce illness or are otherwise ensure that products are safely and operations and processes are being contaminated. The comments suggested properly manufactured on a day-to-day performed. Records document that various means for determining the basis and that this can be confirmed by quality control operations and processes reliability of a supplier’s certification, periodic independent internal audits. such as calibrating instruments and including independent analysis, in- One comment stated that the controls; manufacturing a dietary house testing, and review of protocols. manufacturer should be responsible for ingredient or dietary supplement batch; Other comments stated that, because ensuring, through employee training, and handling consumer complaints the CGMP regulations in part 110 permit self-audit programs, and batch records, were performed. We further discuss the reliance on a supplier’s certification and that quality control and other basis for the proposed recordkeeping because section 402(g)(2) of the act procedures prescribed for the requirement for certain operations and specifies that the CGMP regulations for manufacture of a dietary supplement are processes later in this document. We dietary supplements should be modeled properly and diligently executed. Other believe that section 402(g) of the act after the CGMP regulations for food, a comments stated that it is good business allows us to require written procedures supplier’s certification for dietary practice to ensure product quality and documentation that the procedures supplements must be acceptable. through periodic review of records and were followed. As explained previously, We have considered the comments on quality control audits and that failure to such records may be necessary for whether a supplier’s certification could establish procedures will result in ensuring that dietary ingredients and provide adequate assurance that a product recalls, potential injury, and dietary supplements are manufactured, dietary ingredient is what it purports to litigation for damages for defective packaged, and held consistent with be and is not adulterated. We disagree goods. these regulations. Moreover, we believe that manufacturers may rely on such Some comments objected to any that the fact that the food CGMPs in part certifications to determine that an requirement for written procedures or 110 do not have recordkeeping ingredient is not contaminated, for documentation that the procedures were requirements does not preclude us from example, with filth or microorganisms. followed. The comments stated that proposing recordkeeping requirements Using a supplier certification, guarantee, section 402(g)(2) of the act states that in this proposed rule, although we seek or certification in lieu of performing dietary supplement CGMPs must be further comment on the issue. testing on each shipment lot of modeled after the food CGMP Question 5. We invited comment on components, dietary ingredients, or regulations and the food CGMP whether dietary supplement CGMP dietary supplements is not appropriate regulations do not require written regulations should require that firms because a supplier’s certification or procedures or documentation that have competent medical authorities guarantee would not necessarily ensure procedures were followed. evaluate reports of injuries or illnesses that the identity, purity, quality, We agree with those comments that and to determine if followup action is strength, or composition of a support the development and use of necessary to protect the public health. component, dietary ingredient or dietary written procedures by manufacturers The ANPRM explained that many supplement is met. We discuss testing and are considering whether we should dietary supplements contain requirements and why we believe that require written procedures in a final pharmacologically active substances, the use of supplier’s guarantee or rule. We are proposing requirements for which distinguish dietary supplements certification is not sufficient in lieu of documenting certain operations and from many foods, and some dietary a manufacturer’s own testing in more processes while not requiring written supplements may contain potential detail later in this document. procedures to remove underlying costs allergens. Because the characteristics Question 4. We asked for comments for establishing and updating such may result in adverse events in certain on whether a CGMP rule should require written procedures while preserving the consumers, we asked whether we manufacturers to establish procedures to records necessary to permit trace back. should consider requiring firms to take document, on a continuing or daily When manufacturers develop and certain actions with respect to reviewing basis, that they followed preestablished follow written procedures such AERs. We also sought comments on procedures for making dietary procedures help to ensure that whether a CGMP rule should require supplements. manufacturers produce a consistent firms to establish procedures for The ANPRM noted that the food dietary ingredient or dietary supplement determining whether a reported injury CGMP regulations under part 110 do not that is of a predictable quality and that constitutes a serious problem, and what require manufacturers to document that is not adulterated. Following written actions are to be taken when serious they are following established procedures and documenting problems are identified. procedures prescribed for compliance with those procedures will Comments generally opposed manufacturing a food. However, the ensure regular performance of a firm’s requiring manufacturers to establish a ANPRM also noted that section 402(g) of established programs and procedures procedure for evaluation and followup the act does not preclude us from and will provide additional assurance of of reports of illness and injuries. adopting CGMP requirements for dietary effective communication of appropriate Comments also opposed requiring that a ingredients and dietary supplements information from the firm management competent medical authority evaluate that have no counterpart in part 110 if to the line personnel. We invite all reports of illness or injuries to we have an appropriate basis for doing comment on whether written determine if followup action is so. procedures should be required in a final necessary to protect the public health. Most comments generally supported rule, and whether there are other Some comments, opposing requiring requiring manufacturers to develop and procedures, that we should include in a written procedures and evaluation,

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suggested alternatives to requirements, problems are rare. These comments also ingredient caused the adverse event. such as using the Centers for Disease stated that a costly and burdensome The fact that the wrong ingredient Control and Prevention, poison control safety surveillance system is not appeared in your product would centers, FDA’s MedWatch program, and warranted for these products, that the indicate that some type of problem consumer complaint files to monitor term ‘‘serious adverse event’’ is occurred in your manufacturing process and record injuries and illnesses ambiguous, and that most of that product. Once you identify the attributed to marketed products. manufacturers lack trained medical ingredient as the cause of the problem, In contrast, several comments personnel to serve this function. you would be able to take steps to supported a requirement for written Because we have found dietary remove any such product from the procedures or medical evaluation of supplement problems that could have market and prevent the problem from serious adverse events. Some comments been prevented by CGMPs and that recurring, helping to ensure product stated that an evaluation procedure is resulted in product recalls, we find that quality and purity, and restore necessary and that manufacturers are manufacturers must be able to identify consumer confidence that your products and should be responsible for these types of problems with their contain the correct ingredients. In short, establishing procedures to respond products. It is a manufacturer’s investigations of consumer complaints appropriately to reports of serious responsibility to do so. We disagree benefit both manufacturers and illness and injury that may have with those comments stating that we do consumers and these benefits will exist resulted from using a dietary not have legal authority to require a regardless of whether there are many or supplement. Other comments stated that manufacturer to evaluate consumer few injuries or illnesses believed to be medical evaluations are not necessary complaints as we propose to define that associated with your product. because manufacturers should be using term in this proposed rule. Question 6. We invited comment on appropriate internal quality control We also disagree that written whether a CGMP regulation for dietary procedures within their quality control procedures would present unwarranted supplements should require units or elsewhere to identify the cause potential criminal liability. Persons manufacturers to establish procedures to of adverse events and respond subject to regulation under the act and identify, evaluate, and respond to appropriately. its implementing regulations may face potential safety concerns with dietary We agree with those comments stating civil or criminal action if they fail to ingredients. We asked whether such an that manufacturers are and should be comply with the act or our regulations evaluation is necessary, and, if so, what responsible for evaluating consumer (see, e.g., sections 301, 302, and 303 (21 elements need to be included in such an complaints. Manufacturers have an U.S.C. 331, 332, and 333) of the act). evaluation and their relative importance obligation to ensure that the dietary The fact that such an outcome is (e.g., the presence and potency of supplements that they put on the market possible under the statutory scheme pharmacologically active substances, are not adulterated or misbranded. does not mean that a provision that the presence of different Consumer complaints about a dietary would require written procedures and microorganisms, the presence of supplement might indicate a CGMP- evaluation of consumer complaints is different contaminants and impurities). related problem associated with a ‘‘unwarranted.’’ If we were to accept We also asked whether we should dietary supplement. For example, a such a claim, then we would find it require that these evaluations be consumer complaint might identify a difficult to issue any regulation to documented in a firm’s records, and, if previously unknown manufacturing implement the act, and that result so, what type of records would be deviation that caused a batch of dietary would conflict with our obligation to adequate to document that such an supplements to be adulterated. Thus, a protect the public health. Therefore, we evaluation had occurred. procedure for reviewing and reject the comments’ argument In general, the comments opposed investigating consumer complaints is regarding potential criminal liability requiring manufacturers to establish recommended. Records of consumer and its effect on rulemaking. procedures to identify, evaluate, and complaints related to CGMPs, and the We also disagree with the claim that respond to potential safety concerns review and investigation of such there is no basis for requiring an with dietary ingredients. Most records, are necessary and we discuss evaluation of adverse events because comments claimed that such procedures such a record requirement later in this there are many unsubstantiated reports are unnecessary because dietary document. In that discussion, we of injuries or illness and because dietary ingredients have a history of safe use in address what we mean by a consumer supplement safety problems are rare. In food and that DSHEA is based on this complaint and we address the the past, voluntary reports of injury or history of prior use in food. Other comments on the type of evaluation that illness have identified adulterated comments argued that, because DSHEA would be necessary for consumer dietary supplements. Consumer is based on a history of prior use of complaints and whether the comments’ complaint reports associated with the existing dietary supplements and suggested alternatives to written use of marketed dietary supplements, established a notification procedure for procedures and medical evaluations are such as D. lanata contaminated new dietary ingredients, a requirement sufficient to identify potential concerns. plantain, identified the need for further concerning potential safety concerns for Some comments objected to written investigation and led to recalls or dietary ingredients would be beyond the procedures and medical evaluation warnings to protect the public health scope of this rulemaking. arguing that such requirements go (Ref. 6). Evaluation of consumer Several comments noted that for those beyond the CGMP regulations for food complaint reports can reveal patterns of dietary ingredients that do not have a and, therefore, would be contrary to adverse events that assist us and history of safe use in food and are section 402(g)(2) of the act. Other manufacturers in identifying the need considered ‘‘new dietary ingredients,’’ comments claimed that written for further investigation to determine as defined in section 413(c) of the act, procedures would present unwarranted what public health actions are needed. DSHEA established procedures for potential criminal liability, that there For example, assume that, after you evaluating safety concerns. Section are many unsubstantiated injuries and investigate an AER, you find that the 413(a)(2) of the act requires a illness inherent in the food industry, product contained an ingredient that manufacturer to submit a ‘‘new dietary and that dietary supplement safety should not have been used and that the ingredient’’ notification to FDA 75 days

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before introducing or delivering a CGMPs. As the comments recognize, ingredients it uses before it markets the dietary supplement containing a new manufacturers have an essential and product. dietary ingredient into interstate critical responsibility to substantiate the The proposed CGMP rule focuses on commerce. The notification must safety of the dietary ingredients they use ensuring that the manufacturer knows provide the basis upon which the in manufacturing a product. what it is putting in its product and is petitioner has concluded that the Section 402(g) of the act is not the manufacturing, packaging, and holding dietary supplement containing the new only provision relevant to whether a the product in a manner that will not dietary ingredient is reasonably dietary ingredient or dietary supplement adulterate or misbrand the product. For expected to be safe. Therefore, the may be deemed to be adulterated. example, assume that you use a comments argued that procedures to Section 402(f)(1) of the act, in part, particular herb as your dietary identify, evaluate, and respond to declares a dietary supplement to be ingredient. However, there are different potential safety concerns are not adulterated if it: species of that herb. Some species are necessary in a CGMP rule. • Presents a significant or poisonous; others are not. Additionally, Other comments stated that FDA unreasonable risk of illness or injury there are variations within the same should not require procedures to under conditions of use described in the species of herb depending on where the identify, evaluate, and consider labeling or, if no conditions of use are herbs were grown. Some variants may potential safety concerns with dietary suggested or recommended in the contain higher levels of a particular ingredients because manufacturers labeling, under ordinary conditions of dietary ingredient or marker compound already have an essential and critical use; than other variants. So, how do you responsibility to substantiate the safety • Is a new dietary ingredient for know whether you have the right herb of the dietary ingredients they use in which there is inadequate information (nonpoisonous species of herb intended manufacturing a product. The to provide reasonable assurance that the for use) and whether it meets your comments suggested that FDA does not dietary ingredient does not present a specifications? CGMPs would require need to require written procedures significant or unreasonable risk of that you check the identity of the herbs because manufacturers must consult the illness or injury; or you receive; by doing so, you would be generally known and generally available able to tell whether you have the correct • Is or contains a dietary ingredient scientific literature to determine that a herbs, whether your herbs are that renders it adulterated under section dietary ingredient is safe. Some poisonous, or whether they meet your 402(a)(1) of the act under the conditions comments suggested that, instead of specifications. In this example, the of use recommended or suggested in the FDA requiring safety evaluations, a potential safety concerns involve the labeling. (Section 402(a)(1) of the act third-party could evaluate safety dietary ingredient itself rather than any declares a food to be adulterated if it concerns. Several comments suggested issue concerning contamination which contains substances that are poisonous that manufacturers who use dietary would adulterate or may lead to or deleterious substance that may render ingredients that have little history of use adulteration of the dietary ingredient, it injurious to health.) in food in the United States should and thus, the dietary supplement which retain documentation concerning the Additionally, section 301(a) of the act contains the dietary ingredient. dietary ingredient’s safety. One prohibits the introduction of adulterated As for the comments’ arguments comment suggested that we issue a food into interstate commerce. concerning a dietary ingredient’s history guidance document to identify the types So, for a dietary ingredient or dietary of use, we do not need to address of acceptable ‘‘history of use’’ standards supplement manufacturer to comply history of use as part of this CGMP for dietary ingredients having little with sections 301(a) and 402(f)(1) of the proposal. CGMPs focus on how a history of use in food in the United act, it must take steps regarding product is made under current States and to describe the potential safety concerns before it manufacturing processes. A dietary documentation that would be needed markets the product. Otherwise, if the ingredient’s history of use does not regarding a dietary ingredient’s safety. manufacturer had no obligation to provide any assurance that a particular Although the comments focused on evaluate possible safety concerns before product has the identity, purity, quality, the safety of using particular dietary marketing a product, sections 301(a) and strength, and composition that it ingredients, the safety concerns 402(f)(1) of the act would not make purports to have. Further, history of use described in question 6 actually consist sense and the manufacturer would be does not necessarily provide any of two concepts: (1) Is the product acting contrary to the basic assurance that a particular product formulated using safe dietary congressional intent behind DSHEA, would not pose a significant or ingredients; and (2) is the product which was to ensure that safe dietary unreasonable risk of illness or injury manufactured, packaged, and held in a supplements are available to consumers. under conditions of use recommended manner that would not adulterate or For example, assume that a or suggested in the labeling or under misbrand the product? The proposed manufacturer wanted to market a new ordinary conditions of use. rule focuses on safety concerns related dietary ingredient but lacked evidence As for those comments discussing to the latter concept. Specifically, the to show that it is safe. Under section whether manufacturers or other parties proposed rule focuses on the steps and 402(f)(1)(B) of the act, the manufacturer should evaluate potential safety processes used in the manufacturing, must have adequate information to concerns, the proposed rule would packaging, and holding of the product to provide reasonable assurance of the require a manufacturer to evaluate a ensure, for example, that the product dietary ingredient’s safety before it consumer complaint to determine has the identity, purity, quality, markets the dietary ingredient; whether the complaint relates to good strength, and composition claimed and otherwise, the dietary ingredient is manufacturing practices. Such an does not become adulterated or adulterated under section 402(f)(1)(B) of evaluation would include possible misbranded. The agency notes that no the act, and section 301(a) of the act hazards to health resulting from the comments appeared to argue that safety would prohibit its sale in interstate manufacturing, packaging, or holding of issues relating to potential commerce. Thus, the manufacturer has a product. Nevertheless, you should contamination or adulteration related to a statutory obligation to examine safety note that, insofar as compliance with manufacturing processes are outside concerns relating to the dietary the act and any CGMP regulations are

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concerned, persons who market dietary Several comments supported dietary supplement that is adulterated. ingredients and dietary supplements requirements for specific controls, but Computer-controlled or computer- always remain responsible for their opposed using validation-of-operation assisted operations are not perfect; products. If the manufacturer markets mandates like those in the CGMP computers are subject to malfunctions the product, it would have to meet all regulations for drugs. One comment and ‘‘bugs’’ (errors) in the software they proposed CGMP requirements, if the suggested that we regulate computer- use. Problems with data entered into the agency finalizes the rule as proposed. If controlled and computer-assisted computer may produce unreliable another person buys a product (such as operations for dietary supplements in results. For these reasons, specific bulk dietary ingredients) from a the same way that we regulate such controls for computer-controlled or manufacturer and distributes the operations in the pharmaceutical computer-assisted operations are product under its own name, that industry, but only where an operation is necessary to prevent the manufacture of person must meet all applicable CGMP directly related to the product’s an adulterated dietary ingredient or requirements. concentration or purity. One comment dietary supplement. Question 7. We invited comment on suggested that we consider adopting the A few comments stated that no whether specific controls are necessary computer-controlled and computer- specific requirements for computer- for computer-controlled or assisted assisted procedures specified in the controlled or computer-assisted operations and how best to ensure that proposed infant formula CGMP. operations are needed because computer the software programs and equipment We propose general requirements to hardware and software are simply used to direct and monitor the ensure that equipment is suitable for its specialized plant equipment so that no manufacturing process are properly intended use. However, we seek special regulations are needed. designed, tested, validated, and comment, in the proposed rule, about We agree that computers are monitored. whether we should include specialized pieces of plant equipment and, therefore, should be subject to Comments generally supported requirements, written procedures, and additional requirements beyond those specific controls for computer- records for equipment verification and re-verification. We request comment on which would apply to plant equipment. controlled or computer-assisted what verification manufacturers should Computers are specialized pieces of operations. One comment suggested be using in their computer-controlled or equipment because they are subject to requiring manufacturers to confirm, by computer-assisted operations to ensure malfunctions and ‘‘bugs’’ (errors) in the adequate and documented testing, that that a dietary ingredient or a dietary software, they are reliant upon data their computer software programs supplement that is produced is not entered into a computer, and they may perform their intended functions when adulterated during manufacturing. In be used to perform important roles such computers are used as part of an addition, we request comment on as component or dietary ingredient automated production system having a whether we should issue guidance identification, measuring components significant and direct impact on product documents on verification procedures and dietary ingredients, and safety. Another comment suggested for use with computer-controlled or quarantining materials. Consequently, requiring that software programs and computer-assisted operations. Guidance proposed § 111.30 would establish equipment used to direct and monitor documents generally represent FDA’s requirements for automatic, mechanical, manufacturing processes are properly advice or current thinking on a or electronic equipment. The proposed designed, tested, evaluated, and particular matter and are not binding on requirements would cover, among other monitored. The comment added that, if any person. In contrast, regulations things, automatic equipment design, we consider imposing specific create enforceable requirements that and routine calibration, inspection, and requirements on how firms document apply to all persons engaged in the same checks to ensure proper performance. the adequacy of their computer- action or who make the same product. As stated previously, we are seeking controlled or assisted operations, we As discussed in greater detail later in comment on whether we should include should address those recommendations this document, certain processes are requirements for verification and re- through a guidance document instead of necessary to ensure that computer- verification of automatic, mechanical, or issuing regulations. controlled or computer-assisted electronic equipment and processes and We agree that computer-controlled or equipment functions properly. This is whether we should include computer-assisted operations need to be because of the important role of such requirements for computerized systems properly designed, tested, evaluated, equipment in manufacturing. For that are separate from requirements for and monitored to ensure that the example, if computer-controlled or other mechanical or automatic computers do what they are supposed to computer-assisted equipment is used to equipment. We discuss proposed do. Manufacturers should confirm, by control components, inprocess § 111.30 in greater detail later in this adequate and documented testing, that materials, and rejected materials document. their computer software programs unsuitable for use, the operation must Question 8. We asked for comments perform their intended functions function as expected to ensure that on whether certain, or all, of the because computer use as part of an components suitable for use in requirements for manufacturing and automated production system has a manufacturing dietary ingredients and handling dietary ingredients and dietary significant and direct impact on product dietary supplements are not mixed up supplements may be more effectively safety. Computers are an important with components held under quarantine addressed by a regulation based on the controlling piece of equipment in the such as those components that have principles of Hazard Analysis and manufacture of dietary supplements been rejected as unsuitable for use. If Critical Control Point (HACCP), rather because they often direct and control computer-controlled or computer- than the system outlined in the industry key steps or processes in the assisted operations are used for the submission. manufacture of dietary supplements. If addition and mixing of components, In the ANPRM, we noted that, computers do not operate correctly, the they must function properly to ensure because of the wide variety of dietary dietary supplements manufactured that the correct components are added ingredients and dietary supplements using those computers may be and appropriately mixed to avoid and because of the heterogenous adulterated. producing a dietary ingredient or composition of the dietary supplement

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industry, CGMPs based on HACCP proposed part 111 would be treated as We agree that some manufacturing principles may provide a more flexible records under this proposal. operations are subject to greater hazards and less burdensome regulatory Question 9. We invited comment on than others, and have drafted the framework for manufacturers and whether broad CGMP regulations will proposed rule accordingly. For example, distributors than the approach set out in be adequate, or whether it will be there are microbial hazards associated the industry submission. necessary to address the operations of with raw botanicals. To address these Most comments opposed basing a particular segments of the dietary hazards, the proposal would require that CGMP regulation for dietary ingredients supplement industry. you perform tests on the botanicals. On and dietary supplements on HACCP Most comments supported broad the other hand, there are fewer hazards principles. Most comments supported CGMP regulations covering all segments associated with holding and distributing applying traditional CGMP of the dietary supplement industry finished dietary supplements, so the requirements on manufacturing, instead of specific regulations tailored proposal would impose less packaging, and holding to dietary to distinct segments of the industry. One comprehensive requirements for ingredients and dietary supplements. In comment stated that the differences holding and distributing operations. general, the comments that opposed between distinct segments of the dietary We are persuaded by the comments requiring HACCP for dietary ingredients supplement industry, such as that support a broad CGMP regulation as and dietary supplements asserted that: manufacturers of raw materials or preferable to multiple regulations (1) A HACCP program would not be distributors of finished products, are no focused on particular segments of the appropriate because HACCP focuses on more pronounced than similar segments industry. We agree with the comments microbial contamination of products in the food industry. Another comment that multiple regulations might be that provide a favorable environment for stated that having numerous CGMPs confusing and burdensome, especially growth of microbes that may be present, could subject raw materials and dietary to firms that manufacture products that and these hazards are not a major ingredients to multiple CGMPs, thus fall into multiple categories. For concern for dietary supplements; (2) making manufacturing operations more instance, it would be easier for regulated firms and for us if firms were required CGMPs are the best means of assuring complex. This comment also questioned the safety, quality, and composition of to adhere to one set of CGMP whether issuing multiple regulations is dietary ingredients and dietary requirements rather than follow, for necessary or economically justified in supplements; (3) HACCP is not required example, one set of CGMP requirements an era of limited corporate and for the food industry as a whole; and (4) for vitamins and a different set of CGMP government regulatory resources. Other HACCP would provide minimal requirements for minerals. comments emphasized the importance incremental value at significant We also recognize, though, that there of ensuring that all dietary supplement additional costs. may be some reasons to treat different Other comments opposed mandatory manufacturers (i.e., both small and large types of dietary ingredients or dietary HACCP regulations for dietary manufacturers, and foreign supplements differently in specific ingredients and dietary supplements, manufacturers planning to import instances. For example, it may be but said manufacturers could dietary supplements into the United appropriate to require one type of test implement voluntarily HACCP instead. States) follow the same CGMP for confirming the identity of amino One comment, which supported requirements. acids and another type of test for voluntary implementation of HACCP, In contrast, some comments confirming the identity of herbals. wanted manufacturers to be exempt supported drafting regulations for However, for the reasons discussed from having to disclose HACCP records particular segments of the dietary previously, we are proposing to to any Federal agency. supplement industry. One comment establish one set of broad CGMP HACCP principles can be applied to stated that certain stages of the regulations for all types of products. a broad range of manufacturing manufacturing process, such as the Because we recognize that one set of practices and HACCP principles are not distribution of raw dietary ingredients, specific requirements may not be solely focused on microbial should be more strictly and appropriate for all types of dietary contamination, but instead, are intended comprehensively regulated than other ingredients and dietary supplements, to identify and appropriately control stages because potential hazards are we have proposed regulations that allow steps in manufacturing where any type more prevalent during these manufacturers to develop practices to of adulteration can occur. Nevertheless, manufacturing stages. The comment meet CGMP requirements. Depending after considering the comments, we stated that conversely, the holding, on our experience with this proposed have decided to propose a CGMP distribution, and sale of a finished rule, we will consider whether we need approach for dietary ingredients and dietary supplement may require less to reevaluate our decision to establish dietary supplements. We believe that comprehensive regulations because they one set of requirements for all dietary CGMPs would establish a system of are subject to fewer potential hazards. ingredients and dietary supplements. controls that, given the variations in Other comments supported different We agree with the comments that the size, technological sophistication, and levels of safety testing for different types proposed rule should not make any regulatory experience among dietary of dietary supplement products. For distinction between dietary ingredients ingredient and dietary supplement example, some comments said that or dietary supplements made in the firms, would create a strong regulatory products such as melatonin and United States and those made in a foundation throughout the industry. dehydroepiandrosterone resemble foreign country. The proposed rule You may voluntarily choose to drugs, so we should require safety would require that foreign firms that implement a HACCP plan that meets the testing in animals and humans and want to export dietary ingredients and requirements of the National Advisory impose druglike CGMP requirements for dietary supplements to the United Committee on Microbiological Criteria manufacturing. Another comment stated States manufacture, package, and hold for Foods, however, proposed part 111 that less stringent CGMPs would be dietary ingredients and dietary would still apply to you (Ref. 42). Any appropriate for herbal dietary supplements consistent with proposed HACCP plans that also are intended to supplements because they have long part 111. Moreover, under this proposed meet the records requirements under histories of food use and safety. rule, if a U.S. firm contracts with a

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foreign firm to package dietary ‘‘General Provisions’’ [Reserved]; 1. Who Is Subject to These Part III supplements for sale in the United Subpart B ‘‘New Dietary Ingredients’’ Regulations? (Proposed § 111.1) States, the imported product would [Reserved]; and Subpart C ‘‘Restricted Proposed § 111.1 entitled ‘‘Who is have to comply with the requirements Dietary Ingredients’’ [Reserved]. subject to these regulations?’’ describes in proposed part 111. In addition, the Proposed subpart C would include the scope of the rule. Proposed § 111.1 U.S. firm would be required to meet all restrictions for substances used in states that you are subject to the applicable CGMP regulations under this dietary supplements, such as the requirements in part 111 if you proposed CGMP rule related to those proposed rule for dietary supplements manufacture, package, or hold a dietary activities in which it engages under the containing ephedrine alkaloids, if ingredient or dietary supplement. As proposed rule. We invite comment on finalized. stated previously in this document, in These proposed changes are made for how best to ensure that dietary our response to question 9 of the ingredients and dietary supplements ease of use and clarity. CGMP ANPRM, this proposed CGMP rule exported to the United States have been regulations will be found more easily if would apply to a wide variety of manufactured, packaged, and held located in one part, part 111, and clarity activities associated with the consistent with part 111. will be enhanced by using subparts to This proposal does not include organize categorical CGMP practices. manufacture, packaging, and holding of requirements for safety testing in Similarly, restrictions for substances dietary ingredients and dietary animals and humans for certain types of used in dietary supplements will be supplement products. These activities dietary ingredients and dietary found more easily if located in one part, include labeling, testing, quality control, supplements. As discussed in several part 112, and clarity will be enhanced holding, and distribution. For example, parts of this preamble, you are if the restrictions for substances used in if you contract with a manufacturer to responsible for ensuring that the dietary dietary supplements are located in one perform an operation subject to ingredients or dietary supplements that subpart, subpart C. proposed part 111, you will need to you make are safe prior to marketing The proposed part 111 consists of comply with those regulations directly such products. Although we are eight subparts. Several of the proposed applicable to the operation that you focusing on the manufacturing steps in provisions in the CGMP regulations for perform. For example, if you are a firm actual production and distribution of dietary ingredients and dietary that has contracted with a dietary dietary ingredients and dietary supplements are similar to the CGMP supplement manufacturer to package a supplements, there may be the need for regulations for food products at part dietary supplement, you are responsible specific regulations related to the use of 110. However, we edited the text in for complying with all the regulations, animal tissue. We invite comment on many cases to make the proposed rule including recordkeeping, that would whether there is a need for such specific easier to read and to understand otherwise be required of a manufacturer regulations. consistent with plain language who does its own onsite packaging. principles under the presidential Further, if you are a manufacturer and III. Description of the Proposed Rule memorandum of June 1, 1998 (Ref. 43). you contract with a firm to perform a This proposal will supercede what the Some provisions are derived from the particular manufacturing step, you agency said about the placement in Title industry outline that we included in the would remain responsible for ensuring 21 of the Code of Federal Regulations ANPRM; others are derived from that such step is done in a manner that for any regulations resulting from the comments we received on the ANPRM complies with the requirements in proposed rule for dietary supplements or from our outreach efforts described proposed part 111. As in the previous containing ephedrine alkaloids (62 FR previously. We also developed example, a manufacturer who contracts 30678, June 4, 1997). That proposal provisions based on our knowledge and with a firm to package a product is still included proposed revisions of part 111 expertise in the areas of dietary responsible for the actions of its and the table of contents for part 111 supplements, manufacturing, and contractor for the packaging activities and we are now proposing those for 21 contamination. and must ensure that its contractor CFR part 112 (as explained below). We tentatively decided to exclude complies with the applicable CGMP This proposal for dietary supplement certain CGMP requirements in part 110 regulations. CGMPs amends part 111 (21 CFR part for food products because they do not Proposed part 111 also would apply 111), revising the heading from ‘‘Current appear to be appropriate for dietary to foreign firms that manufacture, Good Manufacturing Practice for Dietary ingredients and dietary supplements. package, or hold dietary ingredients and Supplements’’ to ‘‘Current Good There are differences in the nature of dietary supplements that are imported Manufacturing Practice in the product (i.e., conventional food or offered for import into the United Manufacturing, Packing, or Holding versus dietary ingredients or dietary States, unless imported for further Dietary Ingredients and Dietary supplements) and in the manufacturing processing and export under section Supplements.’’ Proposed part 111, with practices used to produce the product 801(d)(3) of the act, to persons who the heading ‘‘Current Good that require specific practices distribute such imported dietary Manufacturing Practice in appropriate for dietary ingredients and ingredients and dietary supplements, Manufacturing, Packing, or Holding dietary supplements. We invite and to persons who export dietary Dietary Ingredients and Dietary comment on whether any provision ingredients and dietary supplements Supplements,’’ includes only the CGMP from part 110 that we have not included from the United States, unless exported for dietary supplements and the table of should be included in this proposed in compliance with section 801(e). contents contains categorical CGMP CGMP for dietary ingredients and One comment to the ANPRM, relating practices in subparts A through H. dietary supplements. to the scope of the CGMPs, requested an Further, we propose the heading and exemption from the CGMP for table of contents for part 112. Proposed A. General Provisions (Proposed ‘‘herbalist’’ practitioners who part 112 has the heading ‘‘Restrictions Subpart A) individually manufacture dietary for Substances Used in Dietary Proposed subpart A contains five supplements for their clients. Supplements.’’ The table of contents for provisions that would provide basic We decline to exempt herbalist proposed part 112 includes: Subpart A information to the reader. practitioners from the proposed rule. If

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an herbalist practitioner introduces or supplements that it makes. Thus, under specified time period according to a delivers for introduction into interstate the proposed CGMPs, a dietary single manufacturing record during the commerce, a dietary ingredient or supplement with a particular dietary same cycle of manufacture.’’ dietary supplement, that practitioner ingredient listed on its label must The phrase ‘‘identity, purity, quality, must use the same good manufacturing contain that particular dietary strength, and composition,’’ means that practices as other manufacturers to ingredient. Moreover, that dietary the production on a batch-by-batch basis ensure that their clients receive dietary ingredient must meet certain is consistent with the master supplements that are not adulterated. specifications that the manufacturer manufacturing record and is what it is The risks of adulteration are not establishes as to the purity, quality, represented on the label to be (identity); eliminated just because the practitioner strength, and composition. CGMPs are is without impurities and is the desired is an herbalist. Therefore, we decline to intended to ensure that a dietary product (purity); is the identity, purity, exempt ‘‘herbalist’’ practitioners who supplement contains what the label says and strength for its intended purpose manufacture dietary ingredients and it contains. If it does not, the dietary (quality); is the concentration, that is, dietary supplements. Herbalist supplement would not only be the amount per unit of use intended practitioners who introduce or deliver misbranded under section 403 of the (strength); and is the intended mix of for introduction into interstate act, but also would be adulterated under product and product-related substances commerce, a dietary ingredient or section 402(g) of the act. (composition). dietary supplement, are manufacturers Proposed § 111.3 defines ‘‘batch 3. What Definitions Apply to This Part? who must meet CGMPs. number, lot number, or control number’’ (Proposed § 111.3) as ‘‘any distinctive group of letters, 2. What Are These Regulations Intended Proposed § 111.3 defines various numbers, or symbols, or any To Accomplish? (Proposed § 111.2) terms used in proposed part 111. In combination of them, from which the Proposed § 111.2, entitled ‘‘What are general, we have used definitions that complete history of the manufacturing, these regulations intended to are similar to definitions in part 110 for packaging, or holding of a batch or lot accomplish?’’ discusses the purpose of food and other CGMP regulations. of dietary ingredients or dietary the CGMP regulations. The proposal However, we have modified some supplements can be determined.’’ You states that the regulations establish the definitions for ‘‘plain language’’ should note that the proposed definition minimum CGMPs that you must use to purposes under the presidential ‘‘plain would have the batch, lot, or control the extent that you manufacture, language’’ memorandum (Ref. 43) and to number be ‘‘distinctive,’’ which means, package, or hold a dietary ingredient or make other definitions more appropriate for the purposes of this proposal, that it dietary supplement. By using the phrase for dietary ingredients and dietary is unique in some fashion, and is not a ‘‘to the extent,’’ we mean that you must supplements. reused number. Numbers must be comply with the provisions that are In some cases, we based a definition distinctive because, if a problem applicable to you or to the operations on provisions in the industry outline involving a marketed dietary ingredient that you perform and that, depending on published in the ANPRM. However, we or dietary supplement later results, a the type of operations you perform, did not adopt all of the definitions in distinctive batch number will make it some provisions may not apply to you. the industry outline. For example, the possible for you to investigate the For example, some provisions discuss industry outline defined terms such as, source of the problem and the requirements for automatic, mechanical, ‘‘adequate,’’ ‘‘composition,’’ ‘‘raw manufacturing history for the batch. and electronic equipment; if you do not material,’’ ‘‘representable sample,’’ and This would help you to take appropriate use such equipment, you would not ‘‘rework.’’ We omitted those definitions actions concerning that batch more have to comply with those provisions. from this proposal because the terms are quickly. Our primary purpose in proposing generally understood, or because Proposed § 111.3 defines these regulations is to protect definitions for those terms are ‘‘component’’ as ‘‘any substance consumers from adulterated and unnecessary for purposes of intended for use in the manufacture of misbranded dietary supplements due to understanding the proposed rule. a dietary ingredient or dietary improper manufacturing, packaging, or Proposed § 111.3 states that the supplement including those that may holding practices. By observing CGMP definitions and interpretations of terms not appear in the finished dietary regulations that require that dietary in section 201 of the act apply to such ingredient or dietary supplement.’’ ingredients and dietary supplements are terms when used in these regulations. Proposed § 111.3 states that manufactured, packaged, or held in a Section 201 of the act defines various ‘‘component’’ includes ingredients and controlled environment, manufacturers terms that appear throughout the act, dietary ingredients as described in can ensure that dietary ingredients and including ‘‘dietary supplement’’ (see section 201(ff) of the act. Under dietary supplements are not adulterated section 201(ff) of the act). Other terms proposed § 111.3, components would or misbranded during manufacturing, in section 201 of the act, such as ‘‘label’’ include ingredients, dietary ingredients, packaging, and holding operations. (section 201(k) of the act) and ‘‘pesticide manufacturing aids (such as solvents Manufacturing, packaging, and holding chemical’’ (section 201(q)(1) of the act), that are removed during manufacturing), dietary ingredients and dietary have a long history of use. The and reagents that are used to synthesize supplements under CGMPs will provide definitions and interpretations of such a product. consumers with greater confidence that terms apply when we use those terms in Under the proposed definition of dietary supplements contain the dietary this rule. ‘‘component,’’ a component may or may ingredients that they are supposed to Proposed § 111.3 defines specific not appear in the finished product. For contain and that these dietary terms used in the proposal. example, solvents that are used to ingredients were evaluated for their Proposed § 111.3 defines ‘‘batch’’ as produce herbal extracts do not identity, purity, quality, strength, or ‘‘a specific quantity of a dietary necessarily appear in a finished dietary composition. The CGMP regulations, if ingredient or dietary supplement that is supplement, but the proposed rule still finalized as proposed, would require a intended to meet specifications for would consider the solvents to be manufacturer to establish specifications identity, purity, quality, strength, and ‘‘components.’’ As another example, for the dietary ingredients and dietary composition, and is produced during a ingredients, such as cellulose (which is

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used to make tablets) or gelatin (which aristolochic acid would not be ingredients are components but not all is used to make capsules), might be used considered a ‘‘consumer complaint.’’ components are ingredients. to produce dietary supplements; these We consider that a dietary supplement Proposed § 111.3 defines ‘‘in-process ingredients remain in the finished containing a dietary ingredient such as material’’ as ‘‘any material that is product, but would be ‘‘components’’ aristolochic acid, a substance that is fabricated, compounded, blended, under the proposed rule. nephrotoxic and carcinogenic, is ground, extracted, sifted, sterilized, Proposed § 111.3 defines ‘‘consumer adulterated under section 402(a)(1), derived by chemical reaction, or complaint’’ as: (f)(1)(A), and (f)(1)(D) of the act. processed in any other way for use in * * * communication that contains any Proposed § 111.3 defines ‘‘contact the manufacture of a dietary ingredient allegation, written or oral, expressing surface’’ as: or dietary supplement.’’ In-process material differs from a component dissatisfaction with the quality of a dietary * * * any surface that contacts a component, ingredient or a dietary supplement related to dietary ingredient, or dietary supplement, because in-process material is created good manufacturing practices. Examples of and those surfaces from which drainage onto and used during manufacturing. For product quality related to good the component, dietary ingredient, or dietary example, assume you manufacture a manufacturing practices are: Foul odor, off supplement, or onto surfaces that contact the dietary supplement in hard tablet form. taste, superpotent, subpotent, wrong component, dietary ingredient, or dietary During the manufacturing process, you ingredient, drug contaminant, other supplement ordinarily occurs during the mix various ingredients, and you add contaminant (e.g., bacteria, pesticide, normal course of operations. mycotoxin, glass, lead), disintegration time, binding agents and water to mix the color variation, tablet size or size variation, Proposed § 111.3 gives some examples ingredients thoroughly before making under-filled container, foreign material in a of contact surfaces, such as containers, individual tablets. The mixture would dietary supplement container, improper utensils, tables, contact surfaces of be an ‘‘in-process material’’ because it is packaging, or mislabeling. For the purposes equipment, and packaging. Under the a blend or processed material that you of this regulation, a consumer complaint proposed definition the term drainage will use to make your dietary about product quality may or may not includes both liquid and dry materials. supplement. include concerns about a possible hazard to The proposed definition of ‘‘contact Proposed § 111.3 defines ‘‘lot’’ to health, which would include a consumer mean: complaint. However, a consumer complaint surface’’ is similar to the definition of does not include an adverse event, illness, or ‘‘food-contact surface’’ in § 110.3(g), * * * a batch, or a specific identified portion injury related to the safety of a particular except we have used the terms of a batch intended to have uniform identity, dietary ingredient independent of whether ‘‘component, dietary ingredient, or purity, quality, strength, and composition; or, the product is produced under good dietary supplement’’ instead of food, in the case of dietary ingredient or dietary manufacturing practices. and we have added several examples of supplement produced by continuous process, a specific identified amount produced in a Communication about prices, package contact surfaces. The proposed specified unit of time or quantity in a manner size or shape, or other matters that definition would include the inside of that is intended to have uniform identity, could not possibly reveal the existence containers. purity, quality, strength, and composition. of a hazard to health or do not concern Proposed § 111.3 defines ‘‘ingredient’’ The proposed definition for ‘‘lot’’ is the appearance, taste, odor, or quality of as ‘‘any substance that is used in the similar to the definition for ‘‘lot’’ in the a dietary ingredient or a dietary manufacture of a dietary ingredient or a proposed CGMP regulations for infant supplement are not considered dietary supplement that is intended to formula (61 FR 36154 at 36209, July 9, ‘‘consumer complaints’’ under the be present in the finished dietary 1996), but would refer to ‘‘identity, proposed rule. Consumer complaints ingredient or dietary supplement.’’ The purity, quality, strength, and related to an illness or injury related to proposed definition would explain that composition’’ instead of ‘‘character and a pharmacologically active substance of an ingredient ‘‘includes, but is not quality’’ to reflect the different a dietary ingredient such as aristolochic necessarily limited to, a dietary characteristics of dietary ingredients acid would not be related to good ingredient as described in section and dietary supplements. manufacturing practices. The use of 201(ff) of the act.’’ Thus, under Proposed § 111.3 defines products containing aristolochic acid proposed § 111.3, an ‘‘ingredient’’ may ‘‘microorganisms’’ as ‘‘yeasts, molds, has resulted in several life-threatening be a substance that is present in the bacteria, viruses, and other similar adverse incidents. Aristolochic acids are finished dietary ingredient or dietary microscopic organisms having public potent carcinogens and nephrotoxins supplement that is intended to have health or sanitary concern.’’ The that are present, primarily, in plants of some activity (such as a vitamin, proposed definition would include, but the family Aristolochiaceae. A product mineral, or amino acid), but could also would not be limited to, species that: that contains a large amount of it may be a substance that is not intended to • Have public health significance; result in the rapid onset of acute toxicity have any activity (such as the gelatin • Could cause a component, dietary symptoms in a consumer using the used to make the capsule holding the ingredient, or dietary supplement to product. A product containing a small dietary ingredients). This proposed decompose; amount could be used for years with no definition and the proposed definition • Indicate that the component, apparent adverse effects, until serious, for ‘‘component’’ in proposed § 111.3 dietary ingredient, or dietary irreversible effects, such as renal failure, differ in that ‘‘component’’ includes the supplement is contaminated with filth; has occurred. Such adverse effects are various materials used to manufacture a or related to a pharmacologically active dietary supplement that may not appear • Otherwise may cause the substance of a particular dietary in the final product. Because an component, dietary ingredient, or ingredient, aristolochic acid. Thus, for ingredient is defined as a substance that dietary supplement to be adulterated. the purpose of this regulation, a is intended to be present in the finished The definition of ‘‘microorganisms’’ communication from a consumer that dietary ingredient or dietary supplement includes microorganisms of public contains any allegation, written or oral, and a component is defined as a health concern and microorganisms that related to the safety of the use of a substance that may or may not be are of sanitary concern. Proposed product because it contained a included in the finished dietary § 111.3 is similar to the definition of particular dietary ingredient, e.g., ingredient or dietary supplement, all microorganism in § 110.3 but we added

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‘‘sanitary concern’’ to the definition of in this proposed rule because mites are risk using a contaminated component or microorganism. We added ‘‘sanitary’’ to capable of causing allergic reactions in dietary ingredient in manufacturing and clarify that we intend to include persons who consume mite- you may distribute an adulterated microorganisms of public health and contaminated foods (Ref. 44). dietary ingredient or dietary sanitary concern. Although the term Proposed § 111.3 defines ‘‘physical supplement. ‘‘sanitary’’ is not included in part 110, plant’’ as ‘‘all or parts of a building or Proposed § 111.3 defines this change does not alter the generally facility used for or in connection with ‘‘reprocessing’’ as: recognized and scientific and legal manufacturing, packaging, or holding a * * * using, in the manufacture of a dietary meaning of the definition of dietary ingredient or a dietary ingredient or a dietary supplement, clean, ‘‘microorganism’’ in part 110, because supplement.’’ The proposed definition unadulterated components, dietary part 110 is similarly concerned with is similar to the definition of ‘‘plant’’ at ingredients, or dietary supplements that have sanitation. Under proposed § 111.3, E. § 110.3(k), except that we added the been previously removed from coli O157:H7 would be a word ‘‘physical’’ before ‘‘plant’’ to manufacturing for reasons other than ‘‘microorganism’’ because it is a species distinguish between plants that are insanitary conditions and that have been that has public health significance. herbs, vegetables, and growing made suitable for use in the manufacture of Other forms of E. coli, however, might organisms, and buildings or facilities a dietary ingredient or dietary supplement. not be of public health significance that are used in manufacturing, The phrase ‘‘for reasons other than because not all forms of E. coli are packaging, and holding a dietary insanitary conditions’’ means that the pathogenic and present a public health ingredient or a dietary supplement. We component, dietary ingredient, or risk. However, the presence of other also expanded the definition to cover dietary supplement was removed from forms of E. coli would be of sanitary the types of activities that would be manufacturing because the incorrect concern. subject to a CGMP rule for dietary amount of a component was added or One comment to the ANPRM objected ingredients and dietary supplements. other reason not due to insanitary to including viruses in a definition of Proposed § 111.3 defines ‘‘quality conditions. However, the component, ‘‘microorganisms’’ because it might control’’ as ‘‘a planned and systematic dietary ingredient, or dietary imply that a manufacturer is able to operation or procedure for preventing a supplement that was removed from demonstrate the absence of viral dietary ingredient or dietary supplement manufacturing because it became contamination in its dietary from being adulterated.’’ A planned and contaminated because of insanitary supplement. systematic operation or procedure conditions, that is, it became We recognize that there are few provides a framework of current and contaminated with a microorganism of effective virus detection methods and effective methods and procedures for public health concern or a that the industry may be incapable of each dietary ingredient or dietary microorganism of sanitary concern, showing the presence or absence of supplement you manufacture that will must not be reprocessed. specific viruses in its products. prevent dietary ingredients and dietary Proposed § 111.3 defines ‘‘sanitize’’ However, we have included viruses in supplements from being adulterated. We as: the definition for ‘‘microorganisms’’ discuss quality control in more detail because animal tissues are used in the later in this document. * * * to adequately treat equipment Proposed § 111.3 defines ‘‘quality containers, utensils, or any other dietary manufacture of dietary supplements, product contact surface by applying and the use of virus-containing tissue control unit’’ as ‘‘any person or group cumulative heat or chemicals on cleaned would adulterate the product. In order that you designate to be responsible for food contact surfaces that when evaluated for to ensure that animal tissue that may be quality control operations.’’ The quality efficacy, yield a reduction of 5 logs, which used in or as a dietary ingredient does control unit should consist of as many is equal to 99.999 percent reduction, of not contain viruses of public health people as necessary to perform the representative disease microorganisms of significance, certain precautions may be quality control operations. Other public health significance and substantially needed to be taken in procuring and provisions in this proposed rule address reduce the numbers of other undesirable handling such tissue. We discuss in the quality control unit’s authority and microorganisms, but without adversely section III.A.4 of this document what responsibilities, and we discuss those affecting the product or its safety for the consumer. precautions we are seeking comment on provisions later in this document. that manufacturers take to prevent the Proposed § 111.3 defines One comment to the ANPRM pointed use of tissue that may contain viruses of ‘‘representative sample’’ as ‘‘a sample out that the industry-drafted outline’s public health significance for dietary that consists of a number of units that definition of sanitize differed from ingredient or dietary supplement are drawn based on rational criteria, FDA’s Food Code definition of manufacture or to prevent the such as random sampling, and intended sanitization (Ref. 45). introduction of such viruses into a to ensure that the sample accurately The FDA ‘‘Food Code’’ is a reference dietary ingredient or a dietary portrays the material being sampled.’’ that guides retail outlets, such as supplement. By stating that the ‘‘sample accurately restaurants and grocery stores and Proposed § 111.3 defines ‘‘must’’ to portrays the material being sampled,’’ institutions such as nursing homes in indicate that you have to comply with we mean that it correctly represents and how to prevent foodborne illnesses from a particular requirement. ‘‘Must’’ is the is typical of the material being sampled. food that is consumed without further plain language term that replaces It is important that the sample drawn processing by the consumer. Because ‘‘shall.’’ accurately portrays the material being dietary supplements also are consumed Proposed § 111.3 defines ‘‘pest’’ as sampled because your analysis of the without further processing by the ‘‘any objectionable insects or other representative sample will be used to consumer, the FDA ‘‘Food Code’’ animals including, but not limited to, determine whether the material received definition also is appropriate for use in birds, rodents, flies, mites, and larvae.’’ is suitable for use in manufacturing or sanitizing contact surfaces used in the Proposed § 111.3 is similar to § 110.3(j), to determine that the dietary ingredient manufacture of dietary ingredients and although the proposed definition would or dietary supplement is not adulterated dietary supplements. The FDA ‘‘Food add ‘‘mites’’ to the list of pests. We and may be released for distribution. If Code’’ definition of sanitization is to added mites to the definition of ‘‘pest’’ the sample is not representative, you apply cumulative heat or chemicals on

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cleaned food contact surfaces that when ingredient, or dietary supplement and is as required by part 123 as well as these evaluated for efficacy, yield a reduction the quotient of the water vapor pressure CGMP provisions, if this rule is of 5 logs, which is equal to 99.999 of the substance divided by the vapor finalized, that apply to the dietary percent reduction of representative pressure of pure water at the same supplement. These other statutory disease microorganisms of public health temperature.’’ The proposed definition provisions and regulations may apply significance. Because dietary is consistent with the definition at because of the type of manufacturing supplements are consumed without § 110.3(r) and 21 CFR 113.5(w) and process used or the type of ingredient in further processing, and for consistency 114.5(h). Water activity can play an the dietary supplement. with other agency definitions and important role in promoting microbial Certain dietary ingredients, e.g., an standards, we are persuaded to propose growth, and that, in turn, can play a part animal-derived ingredient, may require the FDA ‘‘Food Code’’ definition of in the contamination of your certain manufacturing, packaging, and ‘‘sanitize.’’ The agency believes that components, dietary ingredients, and holding practices because, without such there may be a number of agents that dietary supplements. practices, they may pose serious public can reduce the number of Proposed § 111.3 defines ‘‘we’’ as health and safety concerns related to the microorganisms present on contact meaning the U.S. Food and Drug transmission of communicable disease. surfaces. A tolerable level of risk may be Administration. For purposes of this discussion, the achieved by interventions that have Proposed § 111.3 defines ‘‘you’’ as ‘‘a term ‘‘animal-derived dietary been validated to achieve a cumulative person who manufactures, packages, or ingredient’’ refers to materials, 5-log reduction in the target pathogens. holds dietary ingredients or dietary substances, tissues, body fluids, or body However, we do not specify the manner supplements.’’ ‘‘You’’ is the secretions from animals, birds, reptiles, in which the risk is reduced. The recommended ‘‘plain language’’ term insects, and other living creatures and proposed requirement mandates that designed to make regulations easier to substances that may be derived from you validate that the control measures understand. In this proposed rule, them. We do not consider human are both appropriate to their operation ‘‘you’’ refers to any person, within the tissues and other parts of humans, other and scientifically sound. In many cases, meaning of section 201(e) of the act, than human milk, to be eligible to be a processors may rely on a written who engages in any activity covered by dietary ingredient under section 201(ff) certification from the equipment this proposed rule. You should note that of the act because such products have manufacturer or may obtain a written ‘‘you’’ includes, but is not limited to, not been used as a ‘‘dietary substance scientific evaluation of a process, the owner of the manufacturing firm as for use by man to supplement the diet especially in cases where two or more well as supervisors responsible for by increasing the total dietary intake’’ control measures are used to accomplish ensuring that these CGMPs are followed. (21 U.S.C. 321(ff)(1)(E)). the 5-log reduction in the target In other words, ‘‘you’’ can be the person Certain animal-derived dietary pathogen, to ensure that the process is who owns the dietary ingredient or ingredients, as well as the handling adequate to destroy microorganisms of dietary supplement company as well as practices associated with such public health significance or to prevent persons who work for the company. ingredients, may pose serious public health and safety risks, and therefore, their growth. The agency requests 4. Do Other Statutory Provisions and may require regulations. Animal- comments on its approach to pathogen Regulations Apply? (Proposed § 111.5) reduction. In particular, the agency derived materials, substances, and requests comments on whether all Proposed § 111.5 would require that tissues have the potential to cause contact surfaces should be subject to you comply with the regulations in serious illnesses or injuries when proposed § 111.3 ‘‘sanitize.’’ proposed part 111, and with other ingested. For example, bovine colostrum Proposed § 111.3 defines ‘‘theoretical applicable statutory provisions, and is a substance that is used in dietary yield’’ as ‘‘the quantity that would be regulations under the act, related to supplements (Ref. 46). Bovine colostrum produced at any appropriate step of manufacturing, packaging, or holding which is the lacteal secretion which manufacture or packaging of a particular dietary ingredients or dietary precedes milk after a cow gives birth, dietary ingredient or dietary supplements. Other statutory provisions likely presents the same potential health supplement, based upon the quantity of or regulations that may apply to the risks as does milk. Bovine milk may components or packaging to be used, in manufacture, packaging, or holding of contain pathogenic organisms capable of the absence of any loss or error in actual dietary ingredients or dietary causing diseases in man such as production.’’ We would complement supplements include, but are not tuberculosis, undulant fever, and this definition by defining ‘‘actual limited to: (1) The PHS Act to prevent gastrointestinal disease (Ref. 47). Such yield’’ in proposed § 111.3 as ‘‘the the introduction, transmission, or milk must be pasteurized in accordance quantity that is actually produced at any spread of communicable diseases; (2) with 21 CFR 1240.61. We have proposed appropriate step of manufacture or part 110 (‘‘Current Good Manufacturing a specific requirement at § 111.65(c)(5) packaging of a particular dietary Practice in Manufacturing, Packing, or that would require that you sterilize, ingredient or dietary supplement.’’ Holding Human Food’’); (3) part 113 (21 pasteurize, freeze, refrigerate, control Comparing theoretical yields to actual CFR part 113) (‘‘Thermally Processed hydrogen-ion concentration (pH), yields may help identify deviations or Low-Acid Foods Packaged in control humidity, control water activity, problems in the manufacturing or Hermetically Sealed Containers’’); (4) or use any other effective means to packaging process. To illustrate this part 123 (21 CFR part 123) (‘‘Fish and remove, destroy, or prevent the growth point, you should understand that the Fishery Products’’); (5) parts 70 through of microorganisms and to prevent theoretical yield is the quantity or 82 (21 CFR parts 70 through 82) (for decomposition. This requirement, amount that you expect to see at a color additives); and (6) parts 170 which would apply to bovine colostrum particular step, while the actual yield is through 189 (21 CFR parts 170 through for use in a dietary supplement, is the quantity or amount that you actually 189) (for food additives). For example, necessary to remove certain potential obtain at a particular step. a manufacturer who produces a dietary health risks. Milk also may contain Proposed § 111.3 defines ‘‘water supplement that includes fish and contaminants, such as drug residues if activity’’ as ‘‘a measure of the free fishery products, such as fish oil, would the cow has been treated with such moisture in a component, dietary have to comply with HACCP regulations substances prior to beginning lactation,

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that can cause serious adverse health is no broadly applicable or validated comment on whether there are animal- effects in humans consuming the diagnostic test available to derived materials from BSE countries colostrum (Ref. 48). For example, if the manufacturers to identify BSE agent that do not present a safety concern and, colostrum contains drug residues, a infected ruminant animals or BSE agent if so, whether FDA should consider dietary supplement containing infected materials, the agency is exempting such materials from a colostrum could cause an adverse effect considering whether to require, in our possible requirement that would in a person who is allergic to the drug final rule, specific requirements under prevent the use of animal-derived residue. In addition, some dietary proposed § 111.35 that are designed to materials from BSE countries in dietary supplements contain raw brain tissue or prevent the use of materials derived supplements and why. The agency will glands (Ref. 49) that have a high risk of from certain animals from regions (‘‘BSE consider whether to include, in the final containing the infective agent that Countries’’) identified in 9 CFR 94.18. rule, provisions specifically related to causes bovine spongiform Such requirements would likely include the manufacture, packaging, and encephalopathy (BSE) if they originate manufacturer procedures and records holding of animal-derived dietary from an animal infected with the and supplier certifications to ensure that ingredients or dietary supplements. One disease (Ref. 37). In fact, dietary a component, dietary ingredient, or of the more obvious and serious hazards ingredients derived from different wild dietary supplement is free of the agent is the transmission of TSE (Ref. 37). We and domesticated animals may present of BSE. To prevent use of BSE agent- have communicated with the public and microbiological and contaminant contaminated components, dietary manufacturers of FDA-regulated hazards that are unique to animal- ingredients, or dietary supplements, products about appropriate steps to derived dietary ingredients simply requirements for supplier certifications increase product safety and minimize because the ingredient may not be would likely include certification: the risk of products contaminated with amenable to physical treatments (for • Of the species of animal, the BSE agent. We published a notice in example, sterilization to eliminate • Of the geographic origin of the the Federal Register of August 29, 1994 pathogens) or there may not be animal, (59 FR 44592), entitled ‘‘Bovine-Derived appropriate methods to identify or • That no BSE was present in any of Materials; Agency Letters to correct a potential risk (as in the case of the animals in the herd from which the Manufacturers of FDA-Regulated BSE or other transmissible spongiform animal came and that none of the Products’’ (Ref. 50). The notice, in part, encephalopathies (TSEs)). animals from the herd consumed published the November 1992 and The PHS Act is intended to prevent mammalian-derived protein prohibited December 1993 letters to manufacturers. the introduction, transmission, or from use in ruminant feed, In November 1992, we wrote to spread of communicable diseases (42 • That any foreign manufacturer from manufacturers of dietary supplements to U.S.C. 264). Dietary supplements may which the material derived from alert them to the developing concern be regulated under the PHS Act to the animals was obtained: about TSEs in animals and Creutzfeldt- extent necessary to prevent the 1. Did not co-mingle material derived Jakob Disease in humans and introduction, transmission, or spread of from animals from BSE countries with recommended that they investigate the communicable diseases in intrastate and material derived from animals from geographic source of any bovine and interstate commerce. Dietary non-BSE countries, ovine material used in their products. supplements that contain animal- 2. Established, validated, and We suggested that manufacturers derived ingredients may carry infective followed plans or procedures to develop plans to ensure, with a high agents that may not be able to be identify, track, and segregate material degree of certainty, that bovine and identified or that may be resistant to derived from animals from BSE ovine materials used in their products inactivation, as described previously. countries from material derived from were not from BSE countries or from We are not aware of dietary supplement animals from non-BSE countries, and sheep flocks (foreign or domestic) manufacturers’ current procurement and 3. Used dedicated manufacturing infected with scrapie. In December handling practices of such dietary operations to prevent co-mingling of 1993, we issued a letter recommending ingredients, nor the extent to which materials derived from animals from against the use of bovine-derived such dietary ingredients may be used. BSE countries with materials derived materials from cattle that resided in, or However, because the animal-derived from animals from non-BSE countries. originated from, BSE countries in FDA- dietary ingredients present important Manufacturers that rely on supplier regulated products. In this letter, we public health and safety issues, we are certifications to ensure that materials recommended that manufacturers: (1) seeking comment on whether we should derived from animals are BSE-free Identify bovine-derived materials in include in the final rule specific would likely need to verify the their products and identify all countries requirements for manufacturing, reliability of supplier certifications by where the animals used to produce the packaging, or holding animal-derived conducting supplier audits at materials had lived, (2) maintain dietary ingredients. The U.S. appropriate intervals. We invite traceable records for each lot of bovine Department of Agriculture (USDA) has comment on whether there are other materials and for each lot of FDA- imposed certain restrictions (see 9 CFR requirements that should be considered regulated product using these materials, 94.18) on importation from certain by FDA for supplier certification or (3) document the country of origin of regions of meat and edible products other manufacturing requirements to the live animal source of any bovine- from certain animals. The USDA has prevent the use of BSE agent- derived materials used in the determined that these regions present an contaminated components, dietary manufacture of the regulated products, undue risk of introducing BSE into the ingredients, or dietary supplements. and (4) maintain copies of the records United States because BSE exists in the These specific requirements may be identified above for FDA-regulated regions, because the regions have import issued under the authority of the act or products manufactured using bovine- requirements less restrictive than those may need to be issued under PHS Act derived materials at foreign sites or by that would be acceptable for import into authority and may need to include foreign manufacturers. To assure the the United States, and/or because of relevant remedies available under the safety and suitability for human use of inadequate surveillance. Because there PHS Act. In addition, we invite animal-derived biologics, our Center for

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Biologics Evaluation and Research contamination in dietary ingredients who might be a source of microbial (CBER) has developed guidances for and dietary supplements. Nevertheless, contamination of any material including industry that describe steps that the proposal does not contain components, dietary ingredients, dietary manufacturers should take. For requirements for persons handling such supplements, or contact surfaces used in example, CBER guidances have commodities before distribution to a the manufacture, packaging, or holding recommendations that address viral dietary ingredient or dietary supplement of a dietary ingredient or a dietary safety, infections, disease risks, and manufacturer because the scientific supplement. We based proposed BSE-risk reduction of biologic products basis for reducing or eliminating § 111.10(a) on similar requirements in that are animal-derived (see 63 FR pathogens in various settings is § 110.10. 51074, September 24, 1998, and 63 FR evolving. We invite comments on Proposed § 111.10(a)(1) would require 50244, September 21, 1998) (Refs. 51 whether we should include provisions that you exclude any person who, by and 52). Because we believe that the use in the CGMP proposal that would medical examination or supervisory of an animal-derived material, include persons who handle raw observation, is shown to have, or substance, or tissue in a dietary agricultural commodities. appears to have an illness, open lesion supplement may raise many of the same Even though the proposed rule would (such as a boil, sore, or an infected serious public health and safety issues not cover persons who harvest or wound), or any other abnormal source as animal-derived materials, substances, otherwise handle raw agricultural of microbial contamination from any or tissues, in a biologic, we are commodities before distribution of these operations, which may be expected to considering whether the procedures that commodities to a dietary ingredient or result in microbial contamination of CBER recommends for a product with dietary supplement manufacturer, we components, dietary ingredients, dietary animal-derived materials, substances, or recommend some practices to help you supplements, or contact surfaces, from tissues would be appropriate for dietary minimize microbial food safety hazards working in any operations until the ingredients and dietary supplements in such commodities that you may use condition is corrected. For example, if that contain animal-derived materials, in a dietary ingredient or dietary an employee tells you that his or her substances, or tissues. We, therefore, supplement. We recommend that you physician has diagnosed that the invite comment on whether there adapt, to your practices, the good employee has a fever, and the employee should be specific CGMP requirements agricultural practices (GAPs) and good normally handles your dietary for the use of animal-derived materials, manufacturing practices for fruits and supplements, you must take steps to substances, or tissues in dietary vegetables that we issued as a guidance ensure that the employee does not come ingredients and dietary supplements. document: ‘‘Guide to Minimize into contact with your dietary We invite comment on these issues and Microbial Food Safety Hazards for Fresh supplements because the fever may specifically on whether there is a Fruits and Vegetables’’ (Ref. 53). This suggest that the employee has an scientific basis for FDA to treat animal- guidance document includes infection and there is a reasonable derived dietary ingredients in a manner recommended GAPs for water, worker possibility of contamination. Likewise, that is different from, or that would offer health and hygiene, sanitary facilities, if your supervisors see that an employee less protection than, what is field sanitation, packing, and has an open wound or sore, and the recommended for animal-derived transportation. Those who harvest, employee normally handles dietary biologics when the same public health store, or distribute raw agricultural ingredients, you must take steps to and safety risks may be present. We also commodities for incorporation into ensure that he or she is excluded from invite comment on our legal authority dietary ingredients or dietary handling dietary ingredients because the with respect to these issues. supplements should adapt these open wound or sore could be a source practices to their specific operations. of microbial contamination and because 5. Exclusions (Proposed § 111.6) there is a reasonable possibility of Proposed § 111.6 would state that B. Personnel (Proposed Subpart B) contamination. these CGMP regulations do not apply to Proposed subpart B contains three Proposed § 111.10(a)(2) would require a person engaged solely in activities provisions dealing with personnel that you instruct your employees to related to the harvesting, storage, or matters. In general, the proposed notify their supervisor(s) if they have, or distribution of raw agricultural provisions are similar to the current if there is a reasonable possibility that commodities that will be incorporated CGMP requirements for food personnel they have, a health condition that could into a dietary ingredient or dietary in § 110.10. contaminate any components, dietary supplement by other persons. This ingredients, dietary supplements, or any 1. What Microbial Contamination and proposed exclusion is similar to the contact surface. exclusion in § 110.19 for raw Hygiene Requirements Apply? Proposed § 111.10(b) would apply if agricultural commodities. Accordingly, (Proposed § 111.10) you work in operations where persons who engage in such activities Individuals who handle components adulteration of components, dietary related to raw agricultural commodities or dietary supplements may affect the ingredients, dietary supplements, or (which are defined in section 201(r) of purity or quality of those components or contact surfaces may occur. The the act), although not subject to these dietary supplements if they fail to take proposal would require that you use proposed CGMP regulations under precautions to guard against microbial hygienic practices to the extent section 402(g) of the act, would contamination or other types of necessary to protect against continue to be subject to other contamination. For example, an contamination of those components, adulteration provisions in section 402 of employee who has an illness could dietary ingredients, dietary the act. unintentionally transfer bacteria or supplements, or contact surfaces. We recognize that including in the viruses causing such illness to a dietary These hygienic practices would proposed rule persons who engage in supplement by simply handling the include, but would not be limited to: the activities related to the harvesting, dietary supplement. • Wearing outer garments in a storage, or distribution of such Proposed § 111.10(a), therefore, would manner that protects against commodities, as described previously, require that you take measures to contamination of components, dietary could reduce the risk of microbial exclude from any operations any person ingredients, dietary supplements, or any

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contact surface. Outer garments may establish and follow written procedures must apply to all operations where a include gowns or aprons; to ensure that you comply with the person may contaminate a component, • Maintaining adequate personal requirements of that section. As stated dietary ingredient, dietary supplement, cleanliness; previously, we invite comment on or contact surface. For example, an • Washing hands thoroughly (and whether such written procedures should employee could contaminate a dietary sanitizing if necessary to protect against be required in a final rule, and whether supplement (of agricultural origin or contamination with microorganisms) in there are other procedures, that we synthetic origin) or contact surface an adequate hand-washing facility: should include in a final rule. If during packaging operations. However, 1. Before starting work; and comments assert that written procedures if we adopted the comment’s suggested 2. At any time when hands may are necessary, comments should include limitation, contamination of a synthetic become soiled or contaminated. Hands an explanation of why the requirement dietary supplement could occur, and may become soiled or contaminated is necessary to prevent adulteration there would be no regulatory after meals or after using the bathroom; including how such a requirement requirement to guard against such • Removing all unsecured jewelry would ensure the identity, purity, contamination. and other objects that might fall into quality, strength, and composition of the As for employees with open wounds, components, dietary ingredients, dietary dietary ingredient or dietary proposed § 111.10(a) would require that supplements, equipment, or packaging, supplement. Conversely, if comments you exclude a person with an open and removing hand jewelry that cannot assert that written procedures are not lesion or any other abnormal source of be adequately sanitized during periods necessary, comments should include an microbial contamination from any when you manipulate components, explanation of why the requirement is operation which may adulterate the dietary ingredients, or dietary not necessary including how, in the component, dietary ingredient, dietary supplements by hand. If the hand absence of the requirement, one can supplement, or contact surface. Whether jewelry cannot be removed, the proposal prevent adulteration and ensure the the proposed rule would require that would require that it be covered by identity, purity, quality, strength, and you exclude a person with an open material that is intact, clean, and in composition of the dietary ingredient or lesion or another abnormal source of sanitary condition that effectively dietary supplement. Further, we seek microbial contamination from working protects against contamination of your comment on whether any of the in a closed system area, such as when components, dietary ingredients, or proposed requirements in this section the product is contained completely in dietary supplements, or contact are not necessary to prevent closed pipes or vessels, would depend surfaces. adulteration and to ensure the identity, on whether, as a result of exposure, • Maintaining gloves used in purity, quality, strength, and there would be a reasonable possibility handling components, dietary composition of the dietary ingredient or of the component, dietary ingredient, ingredients, or dietary supplements in dietary supplement. If comments assert dietary supplement, or contact surface an intact, clean, and sanitary condition; that certain provisions are not becoming contaminated. Thus, when a • Wearing, where appropriate, in an necessary, comments should include an dietary ingredient or dietary supplement effective manner, hair nets, caps, beard explanation of why the requirement is is manufactured in a completely closed covers, or other hair restraints; not necessary including how, in the system, this proposed requirement on • Not storing clothing or other absence of the requirement, one can open lesions might not apply if there is no reasonable possibility of personal belongings in areas where prevent adulteration and ensure the contamination. However, you must take components, dietary ingredients, dietary identity, purity, quality, strength, and the measures that would be required by supplements, or any contact surfaces are composition of the dietary ingredient or § 111.10(a) if there is a reasonable exposed or where contact surfaces are dietary supplement. If comments agree possibility that any person might cause washed; that the proposed requirements are contamination of components, dietary • Not eating food, chewing gum, necessary for reasons other than those ingredient, dietary supplements, or drinking beverages, and using tobacco we have provided, the comments should so state and provide an explanation. contact surfaces. products in areas where components, A comment to the ANPRM stated that Comments to the personnel dietary ingredients, dietary any requirements on disease control provisions, and other provisions, stated supplements, or any contact surfaces are should be limited to manufacturing, that the industry-drafted outline used exposed or where contact surfaces are processing, and handling of raw phrases such as ‘‘includes, but are not washed; and • agricultural material and are not limited to,’’ when giving examples of Taking any other necessary appropriate for manufacturing dietary how to comply with various precautions to protect against supplements derived from chemicals. requirements. The comments suggested contamination of components, dietary The comment stated that chemical that this phrase be changed to ‘‘may ingredients, dietary supplements, or processes are carried out in closed pipes include’’ to clarify that items that follow contact surfaces by microorganisms, and vessels, so the risk for human the phrase are simply examples of how filth, or other extraneous materials, contamination is very low. The to comply with a particular requirement including, but not limited to, comment, therefore, said that FDA and are not binding or do not represent perspiration, hair, cosmetics, tobacco, should allow workers who have wounds an exhaustive list of examples. chemicals, and medicines applied to the to continue working in manufacturing We decline to draft the proposal as skin. operations. suggested by the comments because we Each of these procedures is necessary We disagree that the regulations on do not agree that when we state because good personal hygiene should disease control should be limited to ‘‘includes, but are not limited to,’’ we help prevent contamination from manufacturing, processing, and are providing examples of how to microbial sources (such as bacteria) as handling raw agricultural material. comply with the regulations. When we well as from nonmicrobial sources (such Because contamination may occur at state that a regulation requires a as dirt and hair). any time during manufacturing, manufacturer, packager, or holder to We seek comment on whether we packaging, or holding operations, establish certain practices which should require, in a final rule, that you requirements concerning disease control ‘‘includes, but is not limited to’’ a list

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of procedures or activities, we are ingredients during batch production to have experience or training on the stating that compliance with the should have sufficient training or job, but also require that the employee regulation requires that you adopt, at expertise to perform those functions. If have the appropriate educational the minimum, the procedures or that employee does not know how to background, for example, to understand activities listed in the regulation. measure correctly, the employee may the significance of using a particular test Therefore, when we state ‘‘includes, but add too much of an active ingredient, method or understanding the is not limited to,’’ we mean that the list which may cause the product to be significance of a processing deviation of procedures or activities following the adulterated. Thus, proposed § 111.12 and how to respond to such deviation. ‘‘includes’’ statement is a list of would establish requirements for your The word ‘‘and’’ includes situations requirements. employees. where on-the-job training may be We invite comment on whether we adequate and also situations where 2. What Personnel Qualification should require, in a final rule, a educational training may be required. Requirements Apply? (Proposed requirement that you document and Therefore, proposed § 111.12(a)(2) refers § 111.12) keep records regarding each employee’s to ‘‘training and experience.’’ Proposed § 111.12 would establish training. We believe that the records, if basic qualification requirements for required, should show the content and 3. What Supervisor Requirements employees. Proposed § 111.12(a)(1) date of the training. Such records may Apply? (Proposed § 111.13) would require that you have qualified be useful in determining whether an Proposed § 111.13 would establish employees to manufacture, package, or employee has received the training general supervision requirements and is hold dietary ingredients or dietary necessary to perform his or her duties. similar to a provision that appeared in supplements. We are not proposing a We invite comment on not only whether the industry-drafted outline. Proposed general standard for determining how such records should be required in a § 111.13(a) would require that you many employees are necessary, but final rule, but also what types of clearly assign to qualified supervisory there should be enough to manufacture, information such records should personnel the responsibility for package, or hold dietary ingredients or contain. ensuring that all CGMP requirements in dietary supplements consistent with You may use consultants to advise part 111 are met. You should assign an these proposed CGMPs. A one-person you on any aspect of the manufacture, adequate number of qualified personnel operation is not precluded provided that packaging, or holding of dietary to supervise the manufacturing, one person is sufficient to achieve, ingredients or dietary supplements. Any packaging, or holding of dietary maintain, and document CGMPs. consultant you use should be qualified ingredients and dietary supplements. However, general manufacturing by training and experience to provide We are not proposing a general standard practice suggests the need for a the advice they give to you. We invite for determining how many supervisors minimum of two persons, the first to comment on whether we should require, are necessary and a one-person perform the work and a second person in a final rule, that you document each operation is not precluded provided that to check the work performed to ensure consultant’s name, address, and one person is sufficient to supervise that a manufacturing deviation or an qualifications and include a description CGMPs. As stated previously, we invite unanticipated occurrence is not of the services that the consultant comment on whether there is a overlooked. However, we leave the provided. Such records may assist you minimum number of qualified determination of the actual number of in knowing who to contact and where personnel to supervise the employees necessary to your discretion. to contact him or her if questions arise manufacturing, packaging, or holding of As stated previously, we invite concerning the advice given. dietary ingredients or dietary comment on whether there is a A comment to the ANPRM suggested supplements. Proposed § 111.13(b) minimum number of employees needed that the employee qualification would require you and your supervisors to manufacture dietary ingredients or requirements in the industry outline to be qualified by training and dietary supplements. should, in part, state that ‘‘proper experience to supervise. Proposed § 111.12(a)(2) would require education, training, or experience’’ is Making supervisors responsible for that each person engaged in required instead of ‘‘proper education, compliance with the regulations would manufacturing, packaging, or holding training, and experience’’ is required be an important step in manufacturing, must have the training and experience (emphasis added). packaging, and holding dietary to perform the person’s duties. Training We disagree with the use of ‘‘or’’ ingredients and dietary supplements is necessary to ensure that employees instead of ‘‘and.’’ We omitted the term under conditions that will not cause know how to correctly and fully ‘‘proper education’’ because ‘‘training’’ adulteration and misbranding. We perform the operations in question and may be considered a form of believe that clearly designating to ensure that the employees are ‘‘education.’’ However, the proposed compliance responsibilities to competent to produce an unadulterated rule uses the conjunction ‘‘and’’ individuals increases the likelihood of product. The extent and frequency of because, while some might consider compliance with the regulations. the training is left to the manufacturer’s ‘‘experience’’ to be a form of ‘‘training,’’ One comment to the ANPRM discretion. The extent and frequency of most consider ‘‘experience’’ to be questioned why supervisory personnel training needed for your employees will knowledge that a person gains over time must be ‘‘qualified’’ when the food depend on the scope of the employee’s as he or she becomes increasingly CGMP regulations require supervisory activities and experience. For example, familiar with a particular action or piece personnel to be ‘‘competent’’ (see training may be necessary when you of equipment. § 110.10(d)). hire new employees, when employees Training, however, may not just We consider the terms to be engage in new activities, when your include on-the-job training, but may equivalent in this case. The Webster’s II physical plant implements new include some type of educational New Riverside University Dictionary manufacturing practices, or when you experience derived from attending defines competent as ‘‘able to perform add new equipment or new processes to classes or lectures or some other formal as required: competent’’ and further manufacturing. For example, an instruction on a particular subject. Some defines ‘‘qualified’’ as ‘‘having met the employee responsible for measuring positions not only require the employee requirements for a specific position or

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task’’ (Ref. 54). Therefore, we consider constitute a source of contamination in microorganisms of public health the words ‘‘qualified’’ and ‘‘competent’’ areas where food is exposed; significance and are safe and adequate in proposed § 111.13 and § 110.10(d), • Adequately draining areas that may under their conditions of use. Such respectively, should be considered contribute to the contamination to food verification may include buying these synonymous. by seepage, filth, other extraneous substances under a supplier’s guarantee Another comment to the ANPRM materials, or by providing a breeding or certification or you may examine questioned making supervisors place for pests; and them for contamination. • responsible for ensuring compliance by Adequately operating systems for Several comments on the industry all personnel with all CGMP waste treatment and disposal in an outline published in the ANPRM requirements. The comment stated that adequate manner so that they do not objected to the idea that compliance absolute compliance with each and constitute a source of contamination in ‘‘may be verified by any effective means every CGMP requirement cannot be areas where food is exposed. including purchase of these substances ensured, but that requiring a supervisor For example, rodents, insects, and other under a supplier’s guarantee or to be responsible may make the pests may be attracted to garbage, and if certification, or examination of these supervisor personally liable in the event you do not take adequate steps to substances for contamination.’’ The of noncompliance. remove or dispose of garbage, you may comments stated that such language is Proposed § 111.13(a) would require be risking contamination from those unnecessary and may be interpreted as that manufacturers assign responsibility rodents, insects, or other pests. Rodents, too restrictive and that manufacturers to qualified supervisory personnel. insects, and other pests are sources of should be able to determine the Doing so will help ensure that the feces, hair, and other potential appropriate means of assuring CGMPs are followed. In general, if the contaminants (Refs. 55 and 56). We compliance. proposed rule is finalized, invite comment on whether we should We agree with the comments that you manufacturers, packagers, and holders require, in a final rule, that you take may determine the appropriate means of would be responsible for complying these steps and/or other steps to protect assuring compliance with this with these CGMP requirements and for against contamination. regulation. The proposed rule would not ensuring that they assign responsibility 1. What Sanitation Requirements Apply require that you follow any particular to qualified supervisors. We consider to Your Physical Plant? (Proposed method for assuring compliance; many factors when we take enforcement § 111.15) instead, the proposal would give you the flexibility to decide how to ensure action, and so the facts surrounding a Proposed § 111.15(a), like § 110.35(a), that your cleaning compounds and CGMP violation will influence the type would require that you keep your sanitizing agents are free from of enforcement action we take. The physical plant in a clean and sanitary contamination and are safe and manufacturer is responsible under condition and in sufficient repair to adequate under the conditions of use. § 111.13(a) for ensuring that qualified prevent contamination of components, Proposed § 111.15(b)(2) would require supervisory personnel are assigned to dietary ingredients, dietary that you not use or hold toxic materials oversee the implementation of these supplements, or contact surfaces. For in a physical plant in which contact CGMPs. example, holes in your physical plant’s surfaces, components, dietary C. Physical Plant (Proposed Subpart C) walls or windows could allow pests or contaminants to enter, so proposed ingredients or dietary supplements are Proposed subpart C consists of § 111.15(a) would require that you manufactured or exposed, unless those provisions intended to help prevent toxic materials are necessary: repair those holes. • contamination from your physical plant. Proposed § 111.15(b) pertains to To maintain clean and sanitary These provisions are similar to the food conditions, cleaning compounds, sanitizing agents, • CGMP requirements found in §§ 110.20, and pesticides you use. The proposal is For use in laboratory testing 110.35, and 110.37 which pertain to similar to § 110.35(b) and, in essence, procedures, • buildings and facilities. would require that you use cleaning For maintaining or operating the We have not proposed requirements compounds and sanitizing agents that physical plant or equipment, or • similar to the food CGMP requirements are free from microorganisms of public For use in the physical plant’s found in § 110.20(a) for keeping the health significance and are safe and operations. grounds bordering your physical plant adequate under the conditions of use. If at least one of the listed conditions is in a condition that protects against By saying that the cleaning compounds not met, you must not use or hold the contamination of components, dietary and sanitizing agents should be ‘‘free toxic material because there would be ingredients, or dietary supplements. In from microorganisms,’’ we mean that no reason to risk contamination from order to limit the burden to your use of those cleaning compounds exposure to such material if it is not manufacturers, FDA is not proposing and sanitizing agents should not necessary to your operations. such requirements. However, we invite contaminate your components, dietary Proposed § 111.15(b)(3) would require comment on whether such requirements ingredients, dietary supplements, or that you identify and hold toxic should be included in a final rule. contact surfaces with microorganisms. cleaning compounds, sanitizing agents, Section § 110.20(a), identifies several We are proposing this requirement pesticides, and pesticide chemicals in a methods necessary for adequate ground because microorganisms, if present in manner that protects against maintenance, such as: your cleaning compounds or sanitizing contamination of components, dietary • Properly storing equipment, agents, can contaminate your contact ingredients, dietary supplements, and removing litter and waste, and cutting surfaces or deactivate the sanitizing contact surfaces. You must take steps to weeds or grass within the immediate agent and, as a result, adulterate your store your toxic materials in a way that vicinity of your physical plant so that it components, dietary ingredients, dietary prevents them from contaminating your does not attract pests, harbor pests, or be supplements, or contact surfaces. We dietary ingredients and dietary used by pests for breeding; advise that you should verify that supplements. If such products were • Maintaining roads, yards, and cleaning compounds and sanitizing stored in manufacturing areas or where parking lots so that they do not agents are free from contamination by dietary ingredients or dietary

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supplements may be otherwise exposed of adequate sanitary quality,’’ at suitable regulations. Proposed § 111.15(d) to such products, those toxic materials temperatures and under pressure as provides you with the flexibility to raise may come in contact with the dietary needed in all areas where water is your water quality above the minimum ingredients or dietary supplements and necessary for: criteria to meet your particular thereby contaminate them. In addition, • Manufacturing dietary ingredients manufacturing needs. We acknowledge clearly identifying the containers in or dietary supplements; that foreign firms may not be subject to which such toxic materials are held will • Making ice that comes into contact EPA water requirements or adhere to prevent accidental use. with components, dietary ingredients, EPA requirements. Nevertheless, water One comment to the ANPRM objected dietary supplements, or contact quality is an important part of CGMPs, to the provision in the industry outline surfaces; so we invite comment on our proposed that would require manufacturers to • Cleaning surfaces; and requirement that does not distinguish register and use rodenticides, • Employee bathrooms and hand between foreign or domestic insecticides, and fungicides in washing facilities. requirements, and, therefore, would accordance with the Federal Insecticide, Proposed § 111.15(d)(2) would require require foreign firms to meet the NPDW Fungicide, and Rodenticide Act and to that water that contacts components, regulations. follow all relevant Federal, State, and dietary ingredients, dietary A number of comments to the local government requirements. The supplements, or any contact surfaces, at ANPRM suggested that we should comment said the requirement would be a minimum, comply with the National require the use of potable water (water that is fit to drink) or a higher quality redundant with other regulations. Primary Drinking Water (NPDW) Although this CGMP proposed rule water or establish potable water as the regulations prescribed by the does not propose a requirement that you minimum quality water standard. One Environmental Protection Agency (EPA) follow all relevant Federal, State, and comment stated that the industry and any State and local government local government requirements when outline, by referring to potable water, requirements. (EPA’s NPDW regulations applying, using, or holding toxic prevents the use of water whose quality can be found at 40 CFR part 141.) cleaning compounds, sanitizing agents, exceeded a potable water standard Proposed § 111.15(d) would require and pesticides, the proposed rule does because a higher quality water would that you use water that is of safe and not relieve you from such obligations. not be in compliance. Proposed § 111.15(c) pertains to pests. sanitary quality in all aspects of your We agree that potable water should be Proposed § 111.15(c)(1) would require operation where, if such water was not a minimum water quality standard, and that you exclude animals or pests from used, could result in contamination and proposed § 111.15(d) would reflect that all areas of your physical plant, while adulteration of your dietary ingredients standard. Proposed § 111.15(d)(1) would proposed § 111.15(c)(2) would require and dietary supplements. Further, under require water to be ‘‘safe and of that you take effective measures to proposed § 111.15(d)(2), in any adequate sanitary quality.’’ Water that is exclude pests from your physical plant operation where water contacts ‘‘safe and of adequate sanitary quality’’ and to protect against the contamination components, dietary ingredients, dietary is or should be potable. Proposed of components, dietary ingredients, supplements or any contact surfaces, the § 111.15(d)(2) would require water that dietary supplements, or contact water must comply with the EPA’s contacts components, dietary surfaces. Therefore, if you have pests in NPDW regulations. We believe that the ingredients, dietary supplements, or your physical plant, you must take EPA’s NPDW water regulations are contact surfaces to meet, at a minimum, immediate action to get rid of them. In necessary because contaminated water EPA’s NPDW regulations and State and addition, you must take measures to can contaminate dietary ingredients and local requirements. Water meeting these prevent those and any other type of dietary supplements both when used as requirements is potable. pests from entering your physical plant. an ingredient in the dietary ingredient Please note that proposed § 111.15(d) You should note that, like § 110.35(d), or dietary supplement and when does not prevent you from using water proposed § 111.15(c)(1) would allow contaminated water is allowed to enter that is more pure or of higher quality guard dogs and guide dogs in your the product indirectly, as can occur, for than that required under EPA’s NPDW physical plant if their presence will not example, when water is used to cool a regulations. We reiterate that proposed result in the contamination of product or to clean a contact surface. § 111.15(d) would establish minimum components, dietary ingredients, dietary We recognize that, for some water quality standards. supplements, or contact surfaces. operations, you may want to use water Proposed § 111.15(d) does not make Proposed § 111.15(c)(3) would require that is more pure or of higher quality any distinctions between water from that you not use insecticides, fumigants, than that required under the NPDW public sources and water from private fungicides, or rodenticides unless you regulations. For example, to ensure the sources. Consequently, if you use water take precautions to protect against purity of your dietary supplements, you from private sources, you would need to contamination of your components, might use water that has gone through ensure that the water meets the dietary ingredients, dietary water purification and filtering minimum water quality standards in supplements, or contact surfaces. For equipment to ensure that the water is proposed § 111.15(d). For example, if example, some pesticides may cause clean and sterile. In contrast, to clean you use a well as your water source, you adverse effects in humans, so you must contact surfaces and other surfaces, would need to ensure that the well take precautions to ensure that any sterilized water may be unnecessary design meets government water quality pesticides you use will not contaminate because a contact surface that is standards and you may need to perform your components, dietary ingredients, exposed to the environment will not appropriate water treatment procedures, dietary supplements, or contact remain sterile; airborne microorganisms including filtration, sedimentation, and surfaces. and microorganisms on your employees chlorination. These actions are Proposed § 111.15(d) would apply to will find their way onto the contact necessary because private water sources, water supplies and is patterned after the surface, thereby rendering it nonsterile. such as surface waters or water from food CGMP requirement at § 110.37(a). Proposed § 111.15(d) would not prevent shallow wells, may be subject to Proposed § 111.15(d)(1) would require you from using water that is more pure microbiological, chemical, or that you provide water that is ‘‘safe and than that required under the NPDW radiological contamination. For

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example, fertilizer runoff can enter § 111.15(e) would require your physical § 111.15(d) would not require water to streams and contaminate surface water. plant’s plumbing to be adequate size be available in all parts of a physical Contaminants in the ground may enter and design and to be adequately plant. In areas where water is a well and contaminate well water. installed and maintained to: unnecessary, we would not expect you Therefore, it is important that water • Carry sufficient amounts of water to to make water available or to have any from any source comply with the required locations throughout the particular quantity of volume of water requirements set out in proposed physical plant; available. However, there are areas § 111.15(d). • Properly convey sewage and liquid where water is necessary to ensure that Another comment to the ANPRM disposable waste from your physical any unadulterated dietary ingredient or suggested that a potable water standard plant; dietary supplement is manufactured, is inappropriate for use in • Avoid being a source of packaged or held. In those areas where manufacturing dietary ingredients and contamination to components, dietary water is necessary, your plumbing must dietary supplements from chemicals. ingredients, dietary supplements, water carry sufficient amounts to those The comment would limit the use of supplies, or any contact surface, or locations. potable water to manufacturing, creating an unsanitary condition; Proposed § 111.15(f) would require processing, and handling of vegetables, • Provide adequate floor drainage in that you dispose your physical plant’s ready-cooked dishes, etc. all areas where floors are subject to sewage into an adequate sewage system We disagree with the comment. If flooding-cleaning or where normal or through other adequate means. This water is not suitable for drinking operations release or discharge water or proposed provision is similar to the (nonpotable), the water may contain other liquid waste on the floor; and sewage provisions at § 110.37(c). Proper microorganisms or contaminants that • Not allow backflow from, or cross- sewage disposal is essential to ensure will contaminate your dietary connection between, piping system that that you maintain your manufacturing ingredients or dietary supplements. For discharge waste water or sewage and facility in a sanitary condition, and this example, water from private sources piping systems that carry water used for would include protecting the processing may be untreated, so it may be manufacturing dietary ingredients or environment against pathogenic contaminated by pesticides due to water dietary supplements, or cleaning contact microorganisms shed in fecal material. runoff from fields or may contain surfaces, or for use in bathrooms and For example, bathroom floors can microorganisms, algae, particulates, etc. hand washing facilities. become contaminated with pathogens if Therefore, proposed § 111.15(d) would This provision is intended to ensure your sewage disposal system fails to require that you use water that is of safe that your plumbing system does not remove fecal material. Employees using and sanitary quality, regardless of adversely effect the water in your those bathrooms, in turn, can transport whether you use natural or synthetic physical plant. If the plumbing system those pathogens into your processing components to make dietary ingredients is not adequately installed and areas and contaminate components, and dietary supplements. maintained, it may contaminate your dietary ingredients, dietary Proposed § 111.15(d)(3) would require water supply and, in turn, contaminate supplements, or contact surfaces. that you have documentation or your components, dietary ingredients, Proposed § 111.15(g) would apply to otherwise be able to show that the water and dietary supplements through direct bathrooms. Proposed § 111.15(g) would that contacts components, dietary contact, such as when you use water to require that you have adequate, readily ingredients, dietary supplements, or any make the products, or indirect contact, accessible bathrooms for your contact surface meets the water quality such as when the contaminated water is employees and require that the standard in proposed § 111.15(d)(2). The used on a contact surface. bathrooms be kept clean and not proposal would not prescribe any In addition to the water directly become a potential source of particular type of documentation or contaminating your components, dietary contamination to your components, method for showing water quality, but ingredients, dietary supplements, or dietary ingredients, dietary you should remember that water is used contact surfaces, standing water can supplements, or contact surfaces. The as a component in manufacturing cause contamination by attracting pests proposal would require that you keep dietary ingredients and dietary or becoming a breeding ground for your bathrooms from becoming supplements would fall within the microorganisms. Therefore, the proposal potential sources of contamination. You definition of ‘‘component,’’ so it should would require your plumbing system to would be required to keep the meet whatever specifications you have adequate drainage and would not bathrooms in good repair at all times, establish for component identity, purity, allow backflows or cross-connections in provide self-closing doors, and provide quality, strength, and composition. We your plumbing system because doors that do not open into areas where discuss requirements for the identity, backflows from a nonpotable water components, dietary ingredients, dietary purity, quality, strength, and system to a potable water system under supplements, or contact surfaces are composition of components later in this negative pressure conditions could exposed to airborne contamination, section when we describe proposed contaminate your water system (Ref. except where you have taken other § 111.35, ‘‘What production and process 57). means (such as double doors or positive controls must you use?’’. Proposed A comment to the ANPRM stated that airflow systems) to protect against § 111.15(d)(3) would be similar to a requiring a physical plant’s plumbing to airborne contamination. provision in the drug CGMP regulation carry sufficient amounts of water to Proposed § 111.15(h) applies to hand at 21 CFR 211.48(a) and the proposed required locations throughout the plant washing facilities. The proposal would requirement in the infant formula was too vague. The comment stated the require that you provide adequate and proposed rule (61 FR 36154 at 36211), water is not needed in many operations convenient hand washing facilities that which requires that water meet EPA’s in the plant, and so firms should be able furnish running water at a suitable drinking water requirements in 40 CFR to decide the location and availability of temperature. Proposed § 111.15(h)(1) part 141. water throughout their own physical would require that you have hand Proposed § 111.15(e) is similar to the plants. washing facilities and, where plumbing requirements in the food The comment may have appropriate, hand sanitizing facilities at CGMPs at § 110.37(b). Proposed misinterpreted the ANPRM. Proposed each location in your physical plant

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where good hygienic practices require recontamination of clean, sanitized assert that written procedures are your employees to wash or sanitize (or hands. For example, if sanitized hands necessary, comments should include an to both wash and sanitize) their hands. are necessary at a particular location, explanation of why the requirement is One comment to the ANPRM you might install hand sanitizing necessary to prevent adulteration suggested that, instead of requiring facilities that can be activated by foot including how such a requirement employees to wash ‘‘and/or’’ sanitize pedals or by motion so that your would ensure the identity, purity, their hands, we should require employees do not have to use their quality, strength, and composition of the employees to wash ‘‘or’’ sanitize their hands—and, by doing so, risk dietary ingredient or dietary hands. contaminating their hands—to turn on supplement. Conversely, if comments We disagree with the comments. In the hand sanitizing equipment. assert that written procedures are not some cases, it is necessary to both wash Proposed § 111.15(h)(5) would require necessary, comments should include an and sanitize the hands. Sanitizing that you have easily-understood signs explanation of why the requirement is which generally refers to the removal or and to post them throughout your not necessary including how, in the elimination of living microorganisms, physical plant to direct your employees absence of the requirement, one can may be more effective if the hands are who handle components, dietary prevent adulteration and ensure the washed before they are sanitized, and ingredients, dietary supplements, or identity, purity, quality, strength, and washing, alone, will not sanitize the contact surfaces to wash and, where composition of the dietary ingredient or hands. Therefore, the proposed rule appropriate, sanitize their hands: dietary supplement. would address situations where good • Before they start work, We invite comment on whether • hygienic practices require employees to After each absence from their duty documentation at the time of wash or sanitize their hands or to wash station, and performance of equipment, utensil, and • and sanitize their hands. When their hands may have become contact surface maintenance, cleaning, Proposed § 111.15(h)(2) and (h)(3) soiled or contaminated. and sanitation and keeping such records would require that you provide effective Proposed § 111.15(h)(6) would require should be required in a final rule. This hand-cleaning and sanitizing that you have trash bins that are would give you a record that you would preparations and air driers, sanitary constructed and maintained in a manner be able to consult if any questions towel service, or other suitable drying to protect against recontamination of regarding maintenance, cleaning, and devices. Disposable paper towels would hands and contamination of sanitation of equipment used in be an example of sanitary towel service. components, dietary ingredients, dietary producing the batch arise. We seek One comment to the ANPRM supplements, or any contact surface. comment on whether any of the suggested replacing ‘‘effective hand- The proposal would not specify any proposed requirements in this section cleaning and sanitizing preparation’’ particular type of trash bin to use. are not necessary to prevent with ‘‘commonly available’’ hand- Proposed § 111.15(i) applies to trash adulteration and to ensure the identity, washing and sanitizing preparations. disposal. The proposal would require purity, quality, strength, and We disagree with the comment. The that you convey, store, and dispose of composition of the dietary ingredient or purpose behind proposed § 111.15(h)(2) trash to minimize the development of dietary supplement. If comments assert is to ensure that hand-cleaning and odors; to minimize the potential for that certain provisions are not sanitizing preparations are effective. trash to attract, harbor, or become a necessary, comments should include an While we have objection to the use of breeding place for pests; to protect explanation of why the requirement is ‘‘commonly available’’ hand-washing against contamination of components, not necessary including how, in the and sanitizing preparations if they are dietary ingredients, dietary absence of the requirement, one can ‘‘effective,’’ the effectiveness of the supplements, any contact surface, water prevent adulteration and ensure the hand-washing and sanitizing supplies, and grounds surrounding your identity, purity, quality, strength, and preparation is essential to ensuring that physical plant and to control hazardous composition of the dietary ingredient or the hand-washing and sanitizing waste to prevent contamination of dietary supplement. If comments agree preparation will prevent adulteration of components, dietary supplements, and that the proposed requirements are the product. contact surfaces. necessary for reasons other than those Another comment to the ANPRM Proposed § 111.15(j) would require we have provided, the comments should suggested that a dietary supplement that you assign one or more employees so state and provide an explanation. CGMP rule mention paper towels as a to supervise overall sanitation. Under the proposal, the employee or 2. What Design and Construction hand drying device. Requirements Apply to Your Physical We have drafted proposed employees would have to be qualified Plant? (Proposed § 111.20) § 111.15(h)(3) to identity disposable by training and experience to develop paper towels as an example of sanitary and supervise sanitation procedures. Proposed § 111.20 would describe the towel service. However, under proposed The proposal would give you discretion general requirements for physical plant § 111.15(h)(3), the paper towels must be in deciding how many employees you construction and design that are both sanitary and disposable. need to assign to supervise overall necessary to protect dietary ingredients Another comment to the ANPRM sanitation of your physical plant. As and dietary supplements from becoming suggested that paper towels used in previously discussed, the proposed adulterated during manufacturing, hand-washing facilities should be made requirement does not preclude the packaging, and holding. from recycled paper. possibility of a one-person operation. If Proposed § 111.20(a) would require We take no position regarding the use you are a one-person operation, you any physical plant you use in the of paper towels made from recycled would need to be qualified by training manufacturing, packaging, or holding of paper. The proposal neither requires nor and experience to develop and perform dietary ingredients or dietary prohibits the use of paper towels made all sanitation procedures. supplements to be suitable in size, from recycled paper. We invite comment on whether construction, and design to facilitate Proposed § 111.15(h)(4) would require written procedures for maintenance, maintenance, cleaning, and sanitizing that you provide devices or fixtures that cleaning, and sanitation should be operations. You should note that are constructed to prevent required in a final rule. If comments proposed § 111.20(a) refers to cleaning

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operations and to sanitizing operations. the mixer will contaminate the next However, if your physical plant does Although these terms appear to be batch of ingredients that go into the not allow for physically separate areas, similar, they are distinct in the sense mixer. you would have to develop an that a sanitizing operation usually Proposed § 111.20(c) would require alternative approach for segregating produces a sterile (free of living your physical plant to permit the use of components, dietary ingredients, and microorganisms) environment whereas a proper precautions to reduce the dietary supplements at points when cleaning operation may not. To potential for mixups or contamination they are received, stored, and rejected. illustrate the difference, if you wipe a of components, dietary ingredients, Proposed § 111.20(d) would require contact surface with a wet cloth to dietary supplements, or contact that your physical plant be designed remove any components or dietary surfaces, with microorganisms, and constructed in a manner that ingredients, you would have engaged in chemicals, filth, or other extraneous prevents contamination of components, a cleaning operation. The contact material. The proposal would require dietary ingredients, dietary surface is free of noticeable debris, but the physical plant to have, and require supplements, or contact surfaces. The it might still contain microorganisms. In that you use, separate or defined areas proposal would require that the design contrast, if you used a disinfectant on of adequate size or other control and construction include floors, walls, the contact surface in order to eliminate systems, such as computerized and ceilings that are of smooth and hard any possible microorganisms on that inventory controls or automated systems surfaces that may be adequately cleaned surface, you would have engaged in a of separation, to prevent contamination and kept clean and in good repair. sanitizing operation. and mixups of components, dietary Smooth, hard surfaces are necessary Size, construction, and design of a ingredients, and dietary supplements because they are easier to clean and physical plant are important to during specific operations. The specific sanitize than those surfaces that are not manufacturing, packaging, and holding operations would be listed at proposed smooth and hard. The proposal also dietary ingredients and dietary § 111.20(c)(1) through (c)(7) and are as would require that you use fixtures, supplements that are not adulterated follows: ducts, and pipes that do not because they can help you identify and • Receiving, identifying, holding, and contaminate components, dietary eliminate possible sources of withholding from use, components, ingredients, dietary supplements, or contamination that result in or may lead dietary ingredients, dietary contact surfaces by dripping or to adulteration. For example, supplements, packaging, and labels that condensate. Condensation may contain condensation can occur on water pipes. will be used in or during the microorganisms or contaminants that If these pipes are exposed and run above manufacturing, packaging, or holding of can contaminate your components, a contact surface, condensation from dietary ingredients and dietary dietary ingredients, dietary those pipes may fall onto the contact supplements; supplements, or contact surfaces. surface and adulterate your dietary • Separating, as necessary, Proposed § 111.20(d) also would ingredients or dietary supplements. So, components, dietary ingredients, dietary require your physical plant’s design and if you design your physical plant to supplements, packaging, and labels that construction to: • eliminate exposed pipes or to shield are to be used from components, dietary Use adequate ventilation or your contact surfaces from ingredients, dietary supplements, environmental control equipment, such condensation, you would eliminate a packaging, or labels that are awaiting as air flow systems, including filters, possible source of adulteration. material review and disposition fans, and other air-blowing equipment, As another example, you might find it decision, reprocessing, or are awaiting that minimize odors and vapors more practical to clean certain floors in disposal after rejection; (including steam and noxious fumes) in your physical plant by spraying them • Separating the manufacturing, areas where they may contaminate with water. Obviously, a floor design packaging, and holding of different components, dietary ingredients, dietary that uses floor drains would facilitate product types, including, but not supplements or contact surfaces. the cleaning of those floors. limited to, different types of dietary Adequate ventilation or environmental Proposed § 111.20(b) would require ingredients, dietary supplements, and control equipment is a necessary part of your physical plant to have adequate other foods, cosmetics, and your physical plant’s design and space for the orderly placement of pharmaceutical products; construction because some equipment and holding of materials as • Performing laboratory analyses and contaminants and microorganisms may is necessary for maintenance, cleaning, holding laboratory supplies and be airborne, so a failure to provide and sanitizing operations and to prevent samples; adequate ventilation will increase your contamination and mixups of • Cleaning and sanitizing contact chances of airborne contamination. In components, dietary ingredients, and surfaces; addition, some potentially harmful dietary supplements during • Packaging and label operations; and gases (such as carbon monoxide and manufacturing, packaging, or holding. • Holding dietary ingredients or carbon dioxide) are colorless and Adequate space for the orderly dietary supplements. odorless, so it is important to have a placement of equipment and holding of The proposal would not specify the ventilation or environmental control materials is important because it can types of precautions your physical plant system that minimizes odors and directly affect your ability to maintain, must have to reduce the potential for vapors; clean, or sanitize your equipment or mixups or contamination. The • Use fans and other air-blowing physical plant effectively. For example, precautions may depend on your equipment located and operated in a assume that your manufacturing physical plant and the products you manner that minimizes the potential for operation involves the use of a large make. For example, depending on your microorganisms and particulate matter mixer. However, the mixer is installed physical plant’s size and layout, you to contaminate components, dietary in a small room which makes it difficult may be able to receive components and ingredients, dietary supplements, or to open the mixer fully. This may make dietary ingredients at one location, hold contact surfaces; it difficult for you to maintain and clean them in another location and store • Use equipment to control the mixer properly and, as a result, may rejected components and dietary temperature and humidity. For example, increase the possibility that residues in ingredients in yet another location. high temperatures may stimulate

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reproduction of microorganisms and Proposed § 111.20(g) would require • Equipment using compressed air or pests, and these microorganisms and that your physical plant provide gas; pests may, in turn, contaminate your protection by any effective means • Equipment used to carry out components, dietary ingredients, dietary against contamination of components, processes in closed pipes and vessels; supplements, and contact surfaces; and dietary ingredients, and dietary and • Include aisles or working spaces supplements in bulk fermentation • Equipment used in automatic, between equipment and walls that are vessels. The proposal describes some mechanical, or electronic systems. adequately unobstructed and of means to consider, such as using To show how proposed § 111.25(a)(1) adequate width to permit all persons to protective coverings, placement in areas might apply, assume that you use a perform their duties and to protect where you can eliminate harborages for mixer to blend powdered ingredients. If against contamination of components, pests over and around vessels, placing the mixer blade is too small, it might not dietary ingredients, dietary bulk fermentation vessels in areas where mix the ingredients properly or supplements, or contact surfaces with you can check regularly for pests, pest thoroughly, and the resulting batches clothing or personal contact. For infestation, filth, or other extraneous might be adulterated if the ingredients example, your employees will perform material, and using skimming are not provided at the required levels their duties more efficiently and more equipment. You must protect throughout the batch. In this example, effectively if they have sufficient space components, dietary ingredients, and the mixer was not suited for its intended to perform those duties. The clothing dietary supplements held in bulk use. As another example, if your worn by your employees will be less fermentation vessels because, if the manufacturing equipment is so complex likely to be a source of contamination if contents of a bulk fermentation vessel or designed in a way that makes there is sufficient space between your are contaminated, those contaminated cleaning difficult, any unclean surfaces employees and your components, contents may be used to make many on that equipment could become a dietary ingredients, dietary dietary ingredients or dietary source of contamination in the future. In supplements, or contact surfaces. supplements that, as a result, would be this case, the equipment was not Proposed § 111.20(e) would require adulterated. adequately cleaned and properly your physical plant to provide adequate Proposed § 111.20(h) would require maintained or, alternatively, was not of light in all areas where components, your physical plant to include adequate appropriate design for its intended uses. dietary ingredients, or dietary screening or other protection against Proposed § 111.25(a)(2) would require supplements are examined, processed, pests, where necessary. This provision that you use equipment and utensils of or held and in all areas where contact would be one measure to exclude appropriate design and construction surfaces are cleaned. Proposed certain pests from the physical plant whose use will not result in the § 111.20(e) also would require that you that also may assist you in complying contamination of your components, provide adequate lighting in hand with proposed § 111.15(c). As we dietary ingredients, or dietary washing areas, dressing and locker explained earlier in the discussion of supplements with lubricants, fuel, rooms, and bathrooms. Inadequate proposed § 111.15(c), pests are a coolants, metal or glass fragments, filth lighting in areas where components, potential source of contamination or other extraneous material, dietary ingredients, or dietary because they may carry microorganisms, contaminated water, or any other supplements are examined, processed, shed hair or feathers, leave droppings, contaminants. or held may make it difficult to examine or carry filth or dirt into your physical Proposed § 111.25(a)(3) would require a component or read a label; as a result, plant. your equipment and utensils to be: incorrect ingredients may be used in a • Installed and maintained to dietary supplement. Adequate lighting D. Equipment and Utensils (Proposed facilitate cleaning the equipment, also is important in areas where contact Subpart D) utensils, and all adjacent spaces; surfaces are cleaned to ensure that the Proposed subpart D consists of two • Corrosion-resistant if the equipment contact surfaces have been cleaned provisions. These proposed provisions or utensils contact components, dietary properly. Adequate lighting is important consist of general requirements for ingredients, or dietary supplements; in hand-washing areas, dressing and equipment and utensils and for • Made of nontoxic materials; locker rooms to ensure that personal automatic equipment, including • Designed and constructed to cleanliness is maintained in accordance computerized systems, hardware, and withstand the environment of their with proposed § 111.10(b). software. intended use, the action of components, Proposed § 111.20(f) would require dietary ingredients, or dietary your physical plant to use safety-type 1. What Requirements Apply to the supplements, and, if applicable, light bulbs, fixtures, skylights, or other Equipment and Utensils You Use? cleaning compounds and sanitizing glass that is suspended over exposed (Proposed § 111.25) agents; and components, dietary ingredients, or Proposed § 111.25 would establish • Maintained to protect components, dietary supplements in any step of general requirements pertaining to dietary ingredients, and dietary preparation, unless otherwise equipment design, construction, and supplements from being contaminated constructed in a manner that will sanitation. For example, proposed by any source. protect against contamination in case of § 111.25(a)(1) would require that you Deteriorating equipment can be a glass breakage. These precautions are use equipment and utensils of source of contamination. For example, necessary because glass shards can be appropriate design, construction, and repeated contact between metal surfaces very small and difficult to see, and some workmanship that would enable them to in a grinding or tableting machine can lights may spread their contents if they be suitable for their intended use, result in metal fragments that can burst or explode. So, to protect your adequately cleaned, and properly contaminate your dietary ingredients or components, dietary ingredients, and maintained. The equipment and utensils dietary supplements. So, your dietary supplements, the proposal covered under the proposal would equipment and utensils must be would require your physical plant to include, but not be limited to: designed and constructed to withstand take precautions concerning your • Equipment used to hold or convey; the environment of their intended use lighting and other suspended glass. • Equipment used to measure; and you must maintain your equipment

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and utensils to guard against 100.4 °F, and the variation in would imply strongly a need for contamination. temperature was not significant validation, but that validation is a Proposed § 111.25(a)(4) would require statistically, you could say the standard applicable to drug CGMPs, but your equipment and utensils to have thermometer is precise. The proposed not to food CGMPs. The comment said seams that are smoothly bonded or requirement identifies examples of such that a dietary supplement CGMP rule maintained to minimize accumulation instruments and controls, such as should not require validation of of component, dietary ingredient, or instruments or controls you use to instruments and controls. dietary supplement particles, dirt, filth, measure, regulate, or record: We disagree with the comment’s organic material, or any other • Temperatures; objection to requiring all instrument and extraneous material or contaminants. • pH; controls be accurate because, as we We are proposing this requirement • Water activity; or stated earlier, inaccurate instruments because equipment and utensils • Other conditions that control or and controls may generate inaccurate containing breaks, pits, cuts, or grooves prevent the growth of microorganisms readings, and those readings may can be difficult to clean, and the pores or other contamination. adulterate your dietary ingredients and or crevices in those breaks, pits, cuts, or Instruments or controls that affect the dietary supplements. We believe that all grooves can become a breeding ground environment, such as instruments that instruments and controls used in the for microorganisms and insulate them regulate temperature, pH, and water manufacture, packaging, and holding of from cleaning and sanitizing agents. activity, are important because dietary ingredients and dietary Proposed § 111.25(a)(5) would require environmental factors can influence supplements be accurate and precise, freezers and cold storage compartments microorganism growth and adequately maintained, and adequate in that hold components, dietary deterioration. For example, changes in number for their designated uses. ingredients, or dietary supplements to water activity (aw) can have a dramatic We further disagree that the be fitted with accurate thermometers or impact on microorganism growth. A principles of validation are applicable to other temperature-measuring or population of Salmonella typhimurium drugs, but not to foods. We stated in a temperature-recording devices and is reduced tenfold in 0.18 minutes at 60 previous FDA publication (Ref. 59) that ° would recommend automatic devices C if the aw for the suspending medium the ‘‘computerized system used to for regulating temperature or for is 0.995. If the aw is 0.94, it takes 4.3 control critical functions in food sounding an alarm to indicate minutes (or nearly 24 times as long) at processing should be validated in its significant temperature changes in a 60 °C to achieve the same tenfold entirety.’’ We have no basis to conclude manual operation. These devices are reduction (Ref. 58). that validation of instruments and necessary to ensure that you are able to Adequate maintenance is an controls is a standard applicable to monitor the temperatures where you important part of proposed drugs and not to foods, nor did the hold your components, dietary § 111.25(a)(6). If you fail to properly comment provide a reason for its ingredients, or dietary supplements and maintain your instruments and controls, assertion that validation does not apply to indicate whether they were held at they may produce unreliable readings to foods. We invite comment in this appropriate temperatures to minimize and contribute towards the proposal on whether we should include the growth of pathogens and to prevent contamination and adulteration of your requirements in a final rule, that would deterioration. dietary ingredients and dietary address the same or similar concerns While we patterned proposed supplements. For example, assume that that the principles of validation would § 111.25(a)(5) after a provision in the you refrigerate a particular dietary address. We also invite comment on food CGMPs (§ 110.40(e)), we invite ingredient to prevent microorganism whether there are other procedures that comment on whether we should require growth. If your refrigerator gives you the we should include in a final rule. specific target temperatures for dietary wrong temperature readings so that the Proposed § 111.25(a)(7) would require ingredients or dietary supplements held actual temperature inside your compressed air and other gases that are in freezers or cold storage, and if so, refrigerator is too high, you may be introduced into or onto a component, what those temperatures should be and unaware of microorganism growth that dietary ingredient, dietary supplement, why. has occurred on your dietary ingredient. or contact surface or that are used to Proposed § 111.25(a)(6) would require Similarly, if the actual temperature clean contact surfaces to be treated in a instruments or controls used in the inside your refrigerator is too low so way so that they do not contaminate the manufacturing, packaging, or holding of that you unintentionally froze the component, dietary ingredient, dietary a dietary ingredient or dietary dietary ingredient, the freezing process supplement or contact surface. Air or supplement to be accurate and precise, may have produced a chemical change other gases that are not properly treated adequately maintained, and adequate in in your dietary ingredient that will and filtered, or air that is not of the number for their designated uses. By cause it to be out of specification. proper purity, can introduce using the words, ‘‘accurate and precise,’’ Note, too, that the proposal also contaminants into the dietary we mean that the instruments or would require that your instruments supplement product and adulterate it. controls must be accurate—the recorded and controls be adequate in number for Also, compressed gases can be measurements are equal to the true their designated uses. For example, if contaminated with oil from the value of the thing being measured—and the temperature of a large piece of equipment (such as an air compressor) precise—individual measurements equipment needs to be monitored, or with filth or microbiological should be close to each other when several temperature-indicating devices contaminants from the compression, made under the same conditions. For may be needed to accurately monitor storage, or distribution equipment. So, if example, if the temperature inside a the temperature in all parts of the left untreated, the compressed air can particular piece of equipment is 100 °F, equipment. deposit those contaminants onto your and your thermometer for that piece of A comment to the ANPRM objected to components, dietary ingredients, dietary equipment reads a temperature of 100 requiring all instruments and controls supplements, and contact surfaces. °F, the thermometer is accurate. If used in all aspects of dietary Filtration at the air intake and after multiple temperature readings for that supplement manufacturing be accurate. compression, storage, and distribution thermometer ranged from 99.7 °F to The comment said such a requirement may be an effective means of reducing

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the risk that such contaminants will document that the written procedure also provide information on when and enter the compressed air or other gases. was followed each time a calibration how the instruments and controls were Proposed § 111.25(b)(1) would require was performed or that you must calibrated in case a problem arises with that you calibrate your instruments and document, at the time of performance, a batch of dietary ingredients or dietary controls that you use in manufacturing that the instrument and control supplements. If you examine these or testing components, dietary calibration established in accordance records over time, you also will be able ingredients, or dietary supplements. with this section was performed. The to see how precise your instruments and Proposed § 111.25(b)(2) would require proposed calibration requirement gives controls are and to make any necessary that you calibrate before you first use you discretion in deciding whether to adjustments or repairs. For example, if the instruments and controls and either establish and follow a written your records show that a scale gives a as specified in writing by the calibration procedure. If you establish a particular reading for a standard manufacturer of the instrument and written procedure for calibrating reference weight in January, but then control or at routine intervals or as instruments and controls, you must shows a different reading in June for the otherwise necessary to ensure their document, at the time of calibration same standard reference weight, you accuracy and precision. Calibrating performance, that the written procedure may need to adjust, repair, or even instruments and controls will ensure was performed. If you do not establish replace your scale. that they are accurate and precise and a written calibration procedure then you In fact, proposed § 111.25(d) would that the instrument or control readings must document, at the time of require that you repair or replace are ‘‘true values.’’ We invite comment performance, that the calibration instruments and controls that cannot be on whether we should require, in a final established accordance with this section adjusted to agree with the reference rule, that you establish and follow a was performed. You must identify the standard. You should not trust any written procedure for calibrating following for calibrating instruments instrument or control that cannot be instruments and controls, and whether and controls in any written procedure or adjusted to agree with a reference there are other procedures, that we at the time of performance: standard because an inaccurate should consider including in a final • The instrument or control measurement or reading may result in rule. If comments assert that written calibrated; an adulterated dietary ingredient or procedures are necessary, comments • The date of calibration; dietary supplement. Again, to use a should include an explanation of why • The reference standard used scale as an example, if you have a scale the requirement is necessary to prevent including the certification of accuracy of that you cannot adjust to read the adulteration including how such a the known reference standard and a correct weight, using that scale to weigh requirement would ensure the identity, history of recertification of accuracy. A a dietary ingredient to be added to a purity, quality, strength, and certification of accuracy usually particular mix would cause you to add composition of the dietary ingredient or accompanies a standard reference either too much or too little of the dietary supplement. Conversely, if material and often is valid for a specific dietary ingredient into your mix, thus comments assert that written procedures period of time, but the supplier of the throwing your mix out of specification. are not necessary, comments should reference standard may recertify the So, proposed § 111.25(d) would require include an explanation of why the standard’s accuracy. The recertification that you repair or replace that scale. requirement is not necessary including typically involves testing by the Proposed § 111.25(e) applies to how, in the absence of the requirement, supplier to verify that the material maintenance and sanitation. The word one can prevent adulteration and ensure maintains accuracy as a testing ‘‘maintenance,’’ in this provision, means the identity, purity, quality, strength reference. This information also may the act of keeping your equipment and and composition of the dietary help you trace the source of a problem, utensils in working order as ingredient or dietary supplement. if one arises, in your dietary ingredients recommended by their manufacturer. Further, we seek comment on whether or dietary supplements. For example, if Proposed § 111.25(e)(1) would require any of the proposed requirements in this consumers report an adverse event with that you maintain, clean, and sanitize, section are not necessary to prevent a batch of dietary supplements, records as necessary, all equipment, utensils, adulteration and to ensure the identity, containing a certification of accuracy of and any other contact surfaces that are purity, quality, strength, and the reference standards used and a used to manufacture, package, or hold composition of the dietary ingredient or history of their recertification would components, dietary ingredients, or dietary supplement. If comments assert help you determine if the problem dietary supplements and to take apart that certain provisions are not resulted from using an inaccurate your equipment and utensils as necessary, comments should include an reference standard to calibrate your necessary for thorough maintenance, explanation of why the requirement is instruments; cleaning, and sanitizing. Obviously, if not necessary including how, in the • The calibration method used you fail to keep your equipment, absence of the requirement, one can including appropriate limits for utensils, and contact surfaces clean, you prevent adulteration and ensure the accuracy and precision of instruments risk contaminating them with identity, purity, quality, strength, and and controls when calibrating; microorganisms and other contaminants composition of the dietary ingredient or • The calibration reading or readings and risk transferring those dietary supplement. If comments agree found; microorganisms or other contaminants that the proposed requirements are • The recalibration method used if to anything that touches the equipment, necessary for reasons other than those accuracy or precision or both accuracy utensils, and contact surfaces. we have provided, the comments should and precision limits for instruments and Proposed § 111.25(e)(2) would require so state and provide an explanation. controls were not met; and that you ensure that all contact surfaces Proposed § 111.25(c) would require • The initials of the person who used for manufacturing or holding low- that you must establish a written performed the calibration. moisture components, dietary procedure for calibrating instruments These records will enable you to ingredients, or dietary supplements are and controls you use in manufacturing determine whether the calibration in a dry and sanitary condition at the or testing a component, dietary schedule can maintain the accuracy of time of their use. If the surfaces are wet- ingredient, or dietary supplement and your instruments and controls, and will cleaned, you must sanitize them, when

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necessary, and allow them to dry a contact surface because persons opposed to the planned use, of the thoroughly before you use them again. reaching for those paper towels might equipment. If comments assert that Thoroughly drying equipment before drip contaminated water or other fluids written procedures are necessary, it is used for manufacturing or holding onto the contact surface. Inadvertent comments should include an dry dietary products is essential to reuse of a single-service article also explanation of why the requirement is ensure that the equipment will not could lead to contamination, so necessary to prevent adulteration change the composition of the dry disposing of single-service articles is an including how such a requirement product. For example, if moisture is left important element in proposed would ensure the identity, purity, on equipment, the moisture will become § 111.25(e)(5). quality, strength, and composition of the a part of the product and may change Proposed § 111.25(e)(6) would require dietary ingredient or dietary the composition of the product. Moist your cleaning compounds and supplement. Conversely, if comments surfaces can also promote sanitizing agents to be adequate for their assert that written procedures are not microorganism growth, and intended uses and safe under their necessary, comments should include an microorganisms can adulterate your conditions of use. An adequate cleaning explanation of why the requirement is components, dietary ingredients, or compound is one that will lower the not necessary including how, in the dietary supplements. surface tension of water so that spills absence of the requirement, one can Proposed § 111.25(e)(3) would apply can be lifted and flushed away (Ref. 60). prevent adulteration and ensure the if you use wet processing during Ordinary soap has a limited ability to identity, purity, quality, strength, and manufacturing. Under the proposal, you solubilize fats, oils, and proteins. composition of the dietary ingredient or would have to clean and sanitize all Inorganic alkaline detergents can dietary supplement. contact surfaces as necessary to protect dissolve food solids, such as fats and As discussed later, proposed against the introduction of proteins, but mineral deposits will § 111.50(c)(4) would require that you microorganisms into components, frequently require the use of acid document, in the batch production dietary ingredients, or dietary cleaners (Ref. 60). Proposed record, the date and time of the supplements. Proposed § 111.25(e)(3) § 111.25(e)(6) would not prescribe any maintenance, cleaning, and sanitizing of also would require that, when cleaning particular cleaning compound. Instead, the equipment and processing lines and sanitizing is necessary, you must you may select cleaning compounds used to producing the batch. Records clean and sanitize all contact surfaces that are suited to your particular needs. that document the batch or lot number before use and after any interruption An adequate sanitizing agent is one that of each batch or lot of dietary during which the contact surface may has a bactericidal effect on the types of ingredients or dietary supplements become contaminated. If you use microorganisms normally present in the processed using a particular piece of contact surfaces in a continuous physical plant environment and is safe, equipment or a particular utensil production operation or in back-to-back chemically stable, and convenient for between equipment startup and operations involving different batches of use. However, sanitizing agents can shutdown for maintenance, cleaning, the same dietary ingredient or dietary achieve their intended effect only after and sanitizing will allow you to identify supplement, the proposal would require they are applied to a surface that has all dietary ingredients or dietary that you clean and sanitize the contact been thoroughly cleaned, and if they are supplements that may have been surfaces as necessary. applied at a proper concentration (Ref. manufactured or packaged with a Proposed § 111.25(e)(4) would 61). specific piece of equipment or utensil if complement proposed § 111.25(e)(2) Proposed § 111.25(e)(7) would require you later discover that the equipment or and (e)(3) by requiring that you clean, as that you store cleaned and sanitized utensil was improperly maintained, frequently as necessary, surfaces that do portable equipment and utensils that cleaned, or sanitized. not touch components, dietary have a contact surface in locations and Proposed § 111.25(f) would require ingredients, or dietary supplements to in a manner that protect them from that you keep calibration records as protect against contamination. For contamination. This requirement is required by this section in accordance example, you would not have to clean necessary to ensure that your portable with the recordkeeping requirements in your ceilings as often as you clean your equipment remains clean and sanitized proposed § 111.125. Such records will contact surfaces because your ceilings until used; otherwise, if the contact verify for you and the agency that normally do not touch components, surfaces on the portable equipment or calibrations are performed. More dietary ingredients, or dietary utensils become contaminated, they importantly, these records will help you supplements. However, you would have could lead to adulteration of your ensure that all calibrations are to clean your ceilings as frequently as dietary ingredients or dietary performed. If problems do occur with necessary to prevent dust or other supplements. the production of a product, these contaminants from falling onto your We invite comment on whether we records will help you determine components, dietary ingredients, dietary should require, in a final rule, that you whether those problems are associated supplements, and contact surfaces. establish and follow a written procedure with faulty calibrations. These records Proposed § 111.25(e)(5) would for maintenance, cleaning, and will help you determine which batches establish requirements for single-service sanitizing. Further, we invite comment were produced under these conditions. articles, such as utensils intended for on whether we should require that the Further, these records will help you one-time use, paper cups, and paper person who performs the maintenance, train employees or adjust the calibration towels. Proposed § 111.25(e)(5) would cleaning, and sanitizing described in schedule as needed to avoid further require these articles to be stored in this section document, at the time of problems. appropriate containers and handled, performance that the maintenance, dispensed, used, and disposed of in a cleaning, and sanitizing were 2. What Requirements Apply to manner that protects against performed. Those procedures may be Automatic, Mechanical, or Electronic contamination of components, dietary helpful to inform you that equipment is Equipment? (Proposed § 111.30) ingredients, dietary supplements, or any being maintained, cleaned, and Manufacturers of dietary ingredients contact surface. For example, you would sanitized regularly and as frequently as and dietary supplements often rely on not place a paper towel dispenser over is necessary based on the actual use, as automatic, mechanical, and electronic

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equipment in production. Automated must function as intended. Some production errors or discrepancies and equipment is often used to ensure systems may work properly only within to make necessary corrections. Such proper formulation, mixing, and a narrow range of environmental records will allow you to troubleshoot processing or to test a batch of dietary conditions, such as temperature and and to operate these systems with a ingredient or dietary supplement. Such humidity, and some might be minimum of interruption when automated equipment frequently particularly sensitive to electromagnetic problems occur because the records will consists of a computer or system of interference. The actual conditions of include a copy of all software used and computers that control many or all use of a system should be considered as a backup file of data entered into the stages of production, inprocess early as possible in its design and computer or related system which can sampling, and testing. It is important development. Systems need to be be used to reload the system. The that such systems and equipment installed in a manner that takes into records also will provide information function as expected to ensure that the account the inherent limitations of the that you can use in trying to determine dietary ingredient or dietary supplement system, tested under conditions that why a problem with the system is contains the correct ingredients in the reflect actual conditions of use, and occurring or why the system is not appropriate amounts and is properly maintained to ensure that they producing a dietary ingredient or manufactured according to these CGMP continue to function as expected during dietary supplement that complies with proposed requirements, and thus, is not their lifetime. your specifications for the product. adulterated under section 402(g) of the Moreover, the incorporation of Appropriate controls that you act. software into the operation of automatic establish and use for automated Proposed § 111.30 sets forth equipment has not only increased the measuring, regulating, or recording requirements for automatic, mechanical, complexity of such equipment but also temperatures, pH, acidity, water or electronic equipment. These types of has resulted in a process that may activity, or other conditions will equipment include, for example, operate differently for each execution minimize the potential for growth of mechanical equipment such as a scale because a software-based control system microorganisms, for contamination, or used to weigh bulk components and can be configured at will by the operator for adding too much or too little of a electronic equipment such as a or by the system itself. Therefore, dietary ingredient. Observations, computerized blending machine. proposed § 111.30(a) would require that inspections, and checks of the Proposed § 111.30(a) would allow you you exercise appropriate controls over equipment will help you to determine if to use automatic, mechanical or systems and, in particular, over the critical factors such as revolutions per electronic equipment to manufacture, software used in the systems. minute, temperatures, pressures, package, label, and hold a dietary Proposed § 111.30(b) would require, process times, and automatic ingredient or dietary supplement. Thus, for any automatic, mechanical, or documentation are being controlled by the proposal would let you decide what electronic equipment that you use, that the system. Under proposed § 111.30(b), type of equipment meets your needs. you must: examples of controls to ensure that the Proposed § 111.30(a)(1) would require • Routinely calibrate, inspect, or equipment functions in accordance with that you must design or select check to ensure proper performance. its intended use include: equipment to ensure that dietary • Make and keep written records of • Determining the extent and ingredient or dietary supplement equipment calibrations, inspections, or frequency of calibration, inspections specifications are consistently achieved. checks; and checks to ensure proper • Equipment used in dietary ingredient or Establish and use appropriate performance; dietary supplement manufacturing, controls to ensure that your quality • Determining and using packaging, and label operations must be, control unit approves changes in master predetermined action plans when an for example, of an appropriate size and manufacturing record, batch control alarm sounds indicating an out-of-limits installed properly in order to produce records, packaging operations and label situation or malfunction; an unadulterated product. If not operations, or changes related to the • Checking in-put and out-put on a designed or installed properly, the equipment that you use and that only sufficient basis to provide a high degree equipment can lead to a variety of authorized personnel institute the of assurance that input and output is problems. For example, a mixer for the changes; accurate; blending of powdered ingredients will • Establish and use appropriate • Comparing manual calculations of not properly perform its function if the controls to ensure that the equipment data with the automated calculations on blade is too small relative to the size of functions in accordance with its a sufficient basis to provide a high the mixer or not properly placed inside intended use and have your quality degree of assurance that the automated of the mixer. Such a mixer may produce control unit approve these controls; and calculations are accurate; and an adulterated product because the • Make and keep backup file(s) of • Determining the adequacy of dietary supplement, for example, is not software programs and of data entered automated cleaning and residue of uniform composition and therefore into your computer system. Your elimination. would not be able to meet the backup file may be a hard copy of data We invite comment on whether we specifications for purity, quality, you have entered, diskettes, tapes, should require, in a final rule, that you strength, or composition in the final microfilm, or compact disks but must be establish and follow written procedures product. Thus, equipment design and an exact and complete record of the data for the calibration, inspection, and selection is critical to ensure that you you entered. We also propose to require checking of automatic equipment. In manufacture an unadulterated dietary that you keep your backup software addition, we invite comment on ingredient or dietary supplement. programs and data secure from whether there are procedures, other Proposed § 111.30(a)(2) would require alterations, inadvertent erasures, or loss. than those mentioned, that we should that you determine the suitability of In this way, you have a record of include in a final rule. If comments your equipment. The equipment that changes to your software program and of assert that written procedures are you use must be capable of operating your current software program used in necessary, comments should include an satisfactorily within the operating limits manufacturing. This information is explanation of why the requirement is required by the process. The equipment important to both identify any necessary to prevent adulteration

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including how such a requirement you whether your automatic, E. Production and Process Controls would ensure the identity, purity, mechanical, or electronic processes will (Proposed Subpart E) quality, strength, and composition of the consistently operate as they should. Proposed subpart E contains dietary ingredient or dietary We believe, in general, that scientific production and process controls to help supplement. Conversely, if comments knowledge and industry experience ensure that you have controls covering assert that written procedures are not have defined the basic elements of a all manufacturing, packaging, label, and necessary, comments should include an sound verification system to include; holding operations, and that those explanation of why the requirement is determining whether the capacity of the controls will prevent adulteration of not necessary including how, in the hardware matches its assigned function; your dietary ingredient or dietary absence of the requirement, one can identifying and considering operational supplement. We propose to establish a prevent adulteration and ensure the limits in establishing production framework in which decisions about identity, purity, quality, strength, and procedures; determining whether the producing a dietary ingredient or composition of the dietary ingredient or software matches the assigned dietary supplement are left to you, but dietary supplement. Further, we seek operational function; testing simulated that charges you with incorporating into comment on whether any of the production conditions including ‘‘worst your production process, measures that proposed requirements in this section case’’ conditions; repeating tests enough are designed to ensure that the dietary are not necessary to prevent times to assure a reasonable measure of ingredient or dietary supplement is adulteration and to ensure the identity, consistent reproducible results; manufactured in a manner that will purity, quality, strength, and documenting the verification program; composition of the dietary ingredient or prevent adulteration and misbranding. and initiating reverification when Dietary ingredient and dietary dietary supplement. If comments assert significant changes are made to the supplement manufacturing requires that certain provisions are not system or when errors are noted. necessary, comments should include an technical knowledge and skill (e.g., in Although verification steps would research and development, production explanation of why the requirement is vary according to the nature of the not necessary including how, in the equipment and procedures, and dietary supplement and the complexity analytical equipment and methodology) absence of the requirement, one can of the process, the basic elements of a prevent adulteration and ensure the that a vast majority of companies in the verification system would be generally food processing industry do not have. A identity, purity, quality, strength, and applicable to all dietary ingredients and composition of the dietary ingredient or dietary ingredient or dietary supplement dietary supplements. The primary manufacturer must maintain constant dietary supplement. If comments agree benefit of a verification system would be that the proposed requirements are control because a seemingly innocuous to provide a foundation for building a change in the formulation or necessary for reasons other than those comprehensive approach to ensure that we have provided, the comments should preparation method or in exposure to an the equipment performs in a so state and provide an explanation. unanticipated environmental condition predetermined way, but verification For computerized equipment, you could create a health hazard. Earlier, in should note that we already have issued could impose additional costs on section I.E of this document in our guidance documents that may give you manufacturers. discussion of ‘‘FDA’s Decision to some helpful information. The guidance We invite comment on whether Propose a Rule,’’ we cite several documents are: ‘‘FDA Guide to automatic, mechanical, and electronic examples of problems arising from Inspections of Computerized Systems in equipment verification and poorly controlled manufacturing the Food Processing Industry’’ (Ref. 59), reverification elements that we have practices. For example, we cite and a ‘‘Guide to Inspections of discussed should be done, should be problems of dietary ingredient Computerized Systems in Drug included in the final rule as misidentification; super- and subpotent Processing’’ (Ref. 62). Although we did requirements, which would include dietary supplements; and contamination not draft these guidance documents for requirements to document the including toxic substances, dietary ingredient and dietary verification steps. We invite comment microorganisms of public health supplement firms, they still provide on whether we should regulate significance, and heavy metals. Thus, important advice on establishing and computerized systems separately from we believe that using a production and using computerized systems in dietary other automatic equipment. We seek inprocess control system covering all supplement manufacturing operations. comment on whether any of the stages of processing is necessary to Given the broad range in sophistication, proposed requirements in this section insure that the dietary ingredient or complexity, and computerization in are not necessary to prevent dietary supplement is manufactured in manufacturing equipment, we invite adulteration and to ensure the identity, a manner that will prevent adulteration. comments on whether we should purity, quality, strength, and composition of the dietary ingredient or 1. What Production and Process regulate computerized systems Controls Must You Use? (Proposed separately from other automatic dietary supplement. If comments assert § 111.35) equipment. that certain provisions are not Although we are not proposing necessary, comments should include an Proposed § 111.35(a) would require verification requirements in this explanation of why the requirement is that you implement a system of proposed rule, we are seeking comment not necessary including how, in the production and inprocess controls that on whether such verification should be absence of the requirement, one can covers all stages of manufacturing, included in a final rule. Verification prevent adulteration and ensure the packaging, labeling, and holding of the would be intended to ensure that the identity, purity, quality, strength, and dietary ingredients and dietary processes using automatic, mechanical, composition of the dietary ingredient or supplements. and electronic equipment consistently dietary supplement. If comments agree Proposed § 111.35(b) would require produce an outcome that meets a that the proposed requirements are that your production and inprocess predetermined specification and any necessary for reasons other than those control system must be designed to predetermined quality characteristics. we have provided, the comments should ensure that you manufacture, package, Verification would be intended to show so state and provide an explanation. or hold dietary ingredients or dietary

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supplements in a manner that will section 402(a)(1) of the act. Thus, act) in a dietary ingredient or a dietary prevent their adulteration. The proposal manufacturers have a responsibility to supplement would include the amounts would require that your production and ensure that the dietary ingredients and of the substance that likely would be inprocess control system must include dietary supplements that they produce ingested, based on the amounts all requirements of this subpart and also are not adulterated under section 402(f) recommended or suggested in the label, would require your quality control unit of the act. or under ordinary conditions of use. to review and approve the production However, certain substances are not Such a use may present concerns about and inprocess control system. We ‘‘dietary ingredients’’ within the the safety of exposure to such believe that requiring a production and meaning of section 201(ff) of the act, ingredient, based on the chronic use inprocess control system is necessary to and thus, are not exempt under section suggested or reasonably expected. provide consistency in producing 201(s) from regulation as a food additive Therefore, it is incumbent on the different batches of dietary ingredients under section 409 of the act. Such manufacturer to use ‘‘non-dietary or dietary supplements and to facilitate substances include components that are ingredients,’’ that are safe and lawful preparing each batch. added to provide certain technical under applicable sections of the act for Proposed § 111.35(c) would require effects to the dietary supplement, such such use. that you use your quality control unit in as disintegration, lubrication, or As stated previously, ingredients used your manufacturing, packaging, and binding. In addition, such substances in dietary ingredients or dietary label operations to ensure that these may include color additives that are supplements, other than color additives, operations are performed in a manner used or intended for use to impart color are required to be approved for use as that prevents adulteration and to ensure to the dietary ingredient or dietary a food additive unless excepted from the that the dietary ingredient or dietary supplement. Color additives are exempt definition of a food additive under supplement meets specifications for from the definition of ‘‘food additive’’ section 201(s) of the act. For example, identity, purity, quality, strength, and under section 201(s)(3) of the act and we approved the use of sucralose as a composition. subject to approval and listing under general purpose sweetener in food, Proposed § 111.35(d) establishes section 721 of the act. which would include its use in a dietary requirements for any substance that may Proposed § 111.35(d) would require ingredient or dietary supplement (64 FR be used in a dietary ingredient or a that any substance, other than a ‘‘dietary 43908, August 12, 1999). Some other dietary supplement. This section would ingredient,’’ the intended use of which current food additive listings that would require that any substance that is used results or may reasonably be expected to include uses in certain types of dietary be a ‘‘dietary ingredient’’ within the result, directly or indirectly, in its supplements include, ethyl cellulose (21 meaning of that term in section 201(ff) becoming a component or otherwise CFR 172.868) as a component of of the act, or, if not included with the affecting the characteristics of the protective coatings for vitamin and meaning of that term, must meet the dietary ingredient or dietary mineral tablets, and hydroxypropyl applicable statutory and regulatory supplement, must be: cellulose (21 CFR 172.870) as a binder requirements under section 409 of the • Authorized for use as a food and disintegrator in dietary supplement act, or section 721 of the act (21 U.S.C. additive under section 409 of the act, or vitamin or mineral tablets or wafers. If 379e) if a color additive, to ensure that • Authorized by a prior sanction you have questions about the regulatory the substance is safe and lawful for use consistent with 21 CFR 170.3(l), or status of any substances that you want in a dietary ingredient or a dietary • If used as a color additive, subject to use in a dietary ingredient or a supplement. to a listing that, by the terms of that dietary supplement, you are encouraged A ‘‘dietary ingredient’’ within the listing, includes the use in a dietary to contact CFSAN’s Office of Food meaning of section 201(ff) of the act that supplement, or Additive Safety. is in, or intended for use in, a dietary • Generally recognized as safe We recognize that some ingredients supplement is exempt from the (GRAS) for use in a dietary ingredient or may not be subject to section 409 of the definition of ‘‘food additive’’ in section dietary supplement. Any claim that a act, food additive approval, because 201(s). Such ‘‘dietary ingredients’’ are substance is GRAS, other than a dietary they are GRAS substances. For those not subject to the premarket approval ingredient within the meaning of substances that are GRAS, proposed standard for food additives under section 201(ff) of the act, must be § 111.35(d)(4) would require the section 409 of the act. However, under supported by a citation to the agency’s manufacturer to have documentation for section 402(f)(1) of the act, in order for regulations or by an explanation for why the basis for why such a substance, that a dietary ingredient or a dietary there is general recognition of safety of is not a ‘‘dietary ingredient’’ within the supplement not to be deemed the use of the substance in a dietary meaning of section 201(ff) of the act, is adulterated, substances that are ‘‘dietary ingredient or dietary supplement, and approved for use or is GRAS for use in ingredients’’ that are used in the • Must comply with all other a dietary ingredient or dietary manufacture of a dietary ingredient or a applicable statutory and regulatory supplement. dietary supplement must not present a requirements under the act. The statute, under section 402(g)(2) of significant or unreasonable risk of Thus, if a color additive is used in a the act, provides that the Secretary may illness or injury under the conditions of dietary ingredient or dietary by regulation prescribe good use recommended or suggested in supplement, it must be listed in Title 21 manufacturing practices for dietary labeling or, if no such labeling, under of the Code of Federal Regulations (CFR) supplements. If the good manufacturing ordinary conditions of use. In addition, for use in food and the listing must, by practices are not met, the dietary there must be adequate information to its terms, include such use in a dietary ingredient or dietary supplement would provide reasonable assurance that a new supplement. If the substance is not a be adulterated under section 402(g) of dietary ingredient does not present a color additive, it must be safe under the act. Under proposed § 111.35(d), significant or unreasonable risk of other relevant sections of the act. substances that are not ‘‘dietary illness or injury. Further, under section Relevant considerations about the safety ingredients’’ that are used in dietary 402(f)(1) of the act, dietary ingredients of a substance that may be used as an ingredients and dietary supplements must not be poisonous or deleterious ingredient (other than a ‘‘dietary must be safe and lawful to comply with substances within the meaning of ingredient’’ under section 201(ff) of the CGMPs for such products. Thus, these

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nondietary ingredient substances must use an ingredient based solely on food submitted for review by us in a food be subject to a food additive listing, use of the substance prior to January 1, additive petition. authorized by a prior sanction, included 1958, you would need to support a Proposed § 111.35(e) would require with the terms of a color additive claim that the ingredient is GRAS with that you establish a specification for any listing, or listed as GRAS for such use an explanation of the basis for why the point, step, or stage in the in 21 CFR part 182 or affirmed as GRAS ingredient was in common use in a manufacturing process where control is for such use in 21 CFR part 184. dietary ingredient or a dietary necessary to prevent adulteration. These Alternatively, you can meet the supplement prior to January 1, 1958, points, steps, or stages may include requirements of § 111.35(d) by a and why that use provides the basis for heating steps, cooling steps, points showing that the substance is GRAS general recognition of the safety of the where specific sanitation procedures are within the meaning of § 170.30 (21 CFR substance. needed, product formulation control 170.30). We will view any ingredient, that steps, points where cross contamination Proposed § 111.35(d)(4) would require cannot meet the standard of § 170.30 for may occur, and steps where employee that you have information in your files a GRAS determination, as a food and environmental hygiene are that would substantiate the GRAS status additive, and any dietary ingredient or necessary to prevent adulteration of the of any nondietary ingredient substance dietary supplement that contains a food dietary ingredient or dietary that is not otherwise the subject of a additive that we have not approved for supplement. These specifications are food additive approval, prior sanction, use in the dietary ingredient or dietary regulatory specifications and you would or color additive listing. We believe supplement is subject to regulatory be required to perform testing or that, to implement the act in a way to action. If the safety of such ingredient is examination to confirm such regulatory ensure that the statutory goals are not recognized expressly in an FDA specifications are met. We discuss achieved; that is, to ensure that the regulation, you have the burden to performing testing or examination to manufacturer has the relevant explain why the ingredient is GRAS confirm that a regulatory specification is information to ensure that any asserted under § 170.30. met later in this document. A deviation GRAS ingredient is, in fact, GRAS, it is from such specification would signify In the Federal Register of April 17, appropriate to require that you that the dietary ingredient or dietary 1997, we issued a proposed rule on maintain, in your files, the basis for why supplement could be adulterated. Such GRAS notification (62 FR 18938). We the nondietary substance you assert is deviation would require investigation are currently accepting GRAS GRAS that you use in a dietary and a disposition decision approved by ingredient or dietary supplement is, in notifications under this proposed rule. the quality control unit under proposed fact, GRAS. You must not use unsafe However, we recognized in the GRAS § 111.35(i) (which we also discuss later ingredients in your products. Therefore, notification proposal (62 FR 18938 at in this document). you must have information on 18951) that a failure by us to object to The proposed rule would not prevent ingredients that you intend to use in a a GRAS notification is not equivalent to you from establishing additional dietary ingredient or dietary supplement a GRAS affirmation of GRAS status and specifications that are not at points, to demonstrate that such ingredient is we, as a matter of discretion, may not steps, or stages where control is safe. Otherwise, as a responsible advise a notifier of a problem that we necessary to prevent adulteration if manufacturer, you would not use the have identified that raises no important those additional specifications will help ingredient in your product. public health issues. Therefore, if you you meet your quality control demands, Therefore, under proposed submit a GRAS notification to us under but a failure to meet those nonregulatory § 111.35(d)(4), for any claim that a the April 17, 1997, proposed rule, our specifications will not require that you nondietary ingredient in a dietary failure to object to your determination make a material review and disposition supplement is GRAS, you must support that an ingredient is GRAS in a dietary decision. In other words, you may such claim with a cite to a FDA ingredient or dietary supplement will establish additional specifications regulation or an explanation for why not constitute a GRAS affirmation by us. beyond those that the proposed rule there is general recognition of the safety Further, if we know of no reason to would require, and a material review of the use of the substance in a dietary question the safety and lawfulness of and disposition decision would be ingredient or dietary supplement. If the ingredient that is the subject of a needed only for those specifications if such claim is based on general GRAS notification and that is used in not met, that are required under the recognition of safety based on scientific the manufacture of a dietary ingredient proposed rule. For example, if you procedures, the explanation would be or dietary supplement, we would not determine that a specific heat based on evidence that demonstrates object to your reliance on your temperature is needed at a point, step, that there is common knowledge about determination that the use of the or stage in the manufacturing process to the safety of the substance throughout substance is GRAS. You could not use prevent adulteration, that heat the scientific community knowledgeable our response to your GRAS notification temperature specification is a general about the safety of such substance. as your basis for asserting compliance regulatory specification. If not met, you Under § 170.30(c)(1), if a substance is with the requirements under proposed would need to make a material review GRAS based on common use in food § 111.35(d) because an FDA response and disposition decision. prior to January 1, 1958, this letter to a GRAS notification is not the In addition, proposed § 111.35(e) determination must be based solely on same as your explanation, e.g., a identifies certain points, steps, or stages food use of the substance before January response letter does not provide an where a regulatory specification is 1, 1958, and ordinarily must be based explanation for why an ingredient is required. Regulatory specifications are upon generally available data and GRAS. We encourage any dietary required for materials that you receive, information. Thus, GRAS based on ingredient or dietary supplement at the inprocess stage, and that you common use in food prior to January 1, manufacturer to consult with us on any manufacture, e.g., at the finished 1958, may be determined without the ‘‘nondietary ingredient’’ substance that product stage. Specifically, we are quantity or quality of scientific it intends to use in such product to proposing to require that you establish procedures required for approval of a ascertain whether the use of such specifications at these control points for food additive regulation. If you wish to ingredient may be more appropriately the identity, purity, quality, strength,

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and composition of the components must be safe and suitable for its stages in the manufacturing process (upon receipt only) and for dietary intended use and comply with all other where you determined that a ingredients or dietary supplements (at applicable statutory and regulatory specification is needed to ensure that all of these control points). requirements under the act and must the specification, in fact, is met. For You may establish additional not be reactive or absorptive so as to certain specifications that we would specifications (i.e., those in addition to affect the safety of the dietary ingredient require, i.e., the identity, purity, quality, identity, purity, quality, strength, and and dietary supplement. strength, and composition upon receipt, composition) at these same control Proposed § 111.35(f) would require inprocess, and at the finished product points. For example, you may determine that, for each point, step, or stage, for batch stage, we are providing some that an inprocess specification is which a specification is established flexibility for testing. To illustrate, necessary during the manufacturing under proposed § 111.35(e), you must testing or examination requirements for process to prevent adulteration. That monitor the production and inprocess specifications that you establish (e.g., inprocess specification would be a control points, steps, or stages to ensure those other than the identity, purity, regulatory specification. Specifications that they meet specifications and to quality, strength, and composition of the also are needed for the inprocess detect any unanticipated occurrence dietary ingredients or dietary materials to ensure that inprocess that may result in adulteration. Regular supplements received; inprocess, or materials are not adulterated by the monitoring of these points is necessary finished product), such as for a manufacturing process and are in to ensure that the product meets the botanical extraction process that uses a compliance with the master specifications under proposed specific heat temperature for spray manufacturing record. Additional § 111.35(e) and to ensure that any trend drying, you would be required to ensure specifications also may be needed for toward loss of control is quickly by testing or examination that the the finished product stage. identified. Quick identification of any specified temperature was used. You Specifications are needed for dietary trends that may lead to a deviation from would be required to perform such a test ingredients and dietary supplements a specification could mean that or examination at the inprocess point, you manufacture to ensure that the adjustments may be made to prevent a step, or stages where control is manufacturing process produces the deviation from occurring. In the event necessary. As another example, if a correct dietary ingredient or dietary that a deviation or unexpected specific temperature is used on a supplement and that adulterated and occurrence (such as leakage from a pipe finished batch of dietary ingredient or misbranded dietary supplements do not onto a component) occurs, effective dietary supplement as a heat treatment reach the marketplace. corrective actions can be taken to to inactivate or remove objectionable Containers and closures are a form of remove the adulterated product from the microorganisms that pose a health packaging. The containers and closure system. hazard, and thus, the heat treatment Under proposed § 111.35(g) you must or other packaging, such as blister pack, temperature is a critical control point ensure through testing or examination that comes in contact with dietary specification, then you must perform that each specification that you ingredients or dietary supplements must testing or examination to determine that establish under § 111.35(e) is met. not be reactive or absorptive so as to the specific temperature was used. You Under § 111.35(e), you would have to affect the safety of the dietary ingredient would be required to perform such a test determine the points, steps, or stages or dietary supplement and must be on each finished batch of dietary where control is necessary to prevent composed of substances that are ingredient or dietary supplement that is adulteration. However, there are certain authorized by the agency for use as a manufactured. food additive, the subject of a valid points, steps, or stages in proposed notification under section 409 of the act, § 111.35(e) that we tentatively have For those specifications that we authorized by a prior sanction issued by determined to be those where control is tentatively have determined are the agency, or GRAS for such use. necessary to prevent adulteration. necessary (identity, purity, quality, Thus, under this proposed Specifically, we tentatively have strength, and composition) at receipt, requirement, you would be required to determined that such control points inprocess, and finished product stage, establish specifications for any point, include the receipt of components, we are proposing specific testing step, or stage in the manufacturing dietary ingredients, or dietary requirements that provide some process where control is necessary to supplements, the inprocess stage of flexibility. Under § 111.35(g)(1), we prevent adulteration. Specific manufacturing, and the finished product would require that you test each specifications that would be required for batch stage. Further, we tentatively have finished batch of the dietary ingredient you to establish include: determined that at each of those control or dietary supplement produced before • The identity, purity, quality, points, there need to be specifications releasing for distribution to confirm that strength, and composition of for the identity, purity, quality, strength, specifications are met for the identity, components, dietary ingredients, or and composition of components (only at purity, quality, strength, and dietary supplements that you receive; receipt stage for components), dietary composition intended, provided that • The inprocess controls in the ingredients and dietary supplements (at there are scientifically valid analytical master manufacturing record where all of these control points). In addition, methods available to perform such control is necessary to ensure the we tentatively have determined that testing. We recognize that certain tests identity, purity, quality, strength, and specifications are necessary for dietary for identity, purity, quality, strength, or composition of dietary ingredients or ingredient and dietary supplement composition for certain finished product dietary supplements; labels and packaging. may not be available due to complex • The identity, purity, quality, The testing and examination finished matrices that would make such strength, and composition of the dietary requirements in proposed § 111.35(g) testing impracticable. Further, even ingredient or dietary supplement that would require that you conduct a test or though there may not be a scientifically you manufacture; and examination to ensure that valid analytical method that you could • The packaging that may come in specifications that you established are use to provide you with the information contact with dietary ingredients and met; i.e., that you conduct a test or to evaluate, for example, the identity dietary supplements. The packaging examination at those points, steps, or and composition of the finished

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product, there may be methods available recommend, but would not require, that test is one that is a scientifically valid for testing at the finished product stage you also test materials received for these analytical method. If there is an AOAC for other required specifications of same specifications to ensure that they or FDA method available that is purity, quality, and strength. Under are the right ingredients and so that you appropriate for your purpose, you proposed § 111.35(g)(3), your quality do not end up having to destroy an should use that test method. For control must document that a entire batch of finished product after example, if your dietary supplement scientifically valid analytical method is using an erroneous ingredient that could claims to contain vitamin C, there is a not available to perform finished have otherwise been identified earlier specific test for identifying vitamin C, product testing for any one of the before being added to a batch. and so proposed § 111.35(h) would required specifications for identity, For example, if you manufacture a require that you use that test (Ref. 68). purity, quality, strength or composition. batch of dietary supplements that If an AOAC or FDA method is not If your quality control unit documents contains only one single dietary available, a scientifically valid that a scientifically valid analytical ingredient, St. John’s Wort extract analytical method is one that is based method for testing each batch of dietary (Hypericum perforatum), and there are on scientific data or results published ingredient or dietary supplement is not scientifically valid analytical methods in, for example, scientific journals, available for any one of those required available to test the finished dietary references, text books, or proprietary specifications, then you would be ingredient or supplement to confirm research. While there may not be an required, under § 111.35(g)(2)(i) and that the specifications are met for the AOAC or FDA method available, we are (g)(2)(ii) to test incoming shipment lots identity, purity, quality, strength, and not aware of a situation where an of components, dietary ingredients, or composition intended, then you must appropriate scientifically valid dietary supplements for any such test each batch using such methods. In analytical method is not available. You specification to determine whether it is this example, you would not be required could perform the tests yourself or have met and to test inprocess for any such to perform testing of incoming shipment someone perform these tests for you. specification in accordance with the lots of St. John’s Wort to confirm Proposed § 111.35(i) would require master manufacturing record where identity, purity, quality, strength, and that you must: control is necessary to ensure the composition to confirm that • Establish corrective action plans for identity, purity, quality, strength, and specifications are met nor would you be use when an established specification is composition of dietary ingredients or required to perform testing of inprocess not met. We believe that this dietary supplements. for these same specifications in requirement is necessary because you Using a supplier certification, accordance with the master may need to take corrective action guarantee, or certification in lieu of manufacturing record. As discussed quickly, and the best way to ensure that performing testing on each shipment lot later under proposed § 111.40(b)(2), a corrective action is appropriate is to of components, dietary ingredients, or although testing would not be needed at determine the action in advance. For dietary supplements required in receipt stage for identity, purity, quality, example, if, during the production of a accordance with this section is not strength, and composition, you would specific batch, the temperature specified appropriate because it is possible that a be required under that section, to for tablet coating drying is not met, you supplier’s certification or guarantee may visually compare the label, supplier’s would be able to consult the corrective not ensure the identity, purity, quality, invoice, guarantee, or certification with action plan to see whom you should strength, or composition of a your purchase order for consistency. In contact, what correction to make, and component, dietary ingredient or dietary another example, if you manufacture a when to make the correction. Having supplement. For example, a supplier of dietary supplement that contains corrective action plans in place before a the dietary ingredient plantain provided multiple dietary ingredients (e.g., problem occurs can help you deal with a ‘‘certificate of analysis’’ indicating that Ginkgo Biloba, vitamin C, and folic those problems quickly and efficiently. the plant material was plantain powder, acid) and you do not perform testing on As another example, if during with a description of certain of its the finished dietary supplement because production an operator notes that too physical characteristics (Ref. 6). The there are not scientifically valid low a temperature is used during a plantain was contaminated with D. analytical methods available to confirm tablet coating drying operation, it would lanata (a plant that contains powerful that the specifications for identity, be best for the operator to have an action heart stimulants that can cause life- purity, quality, strength, and plan for immediate implementation, threatening reactions including cardiac composition are met for each dietary rather than having to stop the drying arrest, if ingested) and was distributed ingredient in the finished batch mixture, process to wait for instructions on what to at least 150 manufacturers, then you would be required to perform to do. Quick action may reduce the distributors, and retailers. Thus, if you testing of incoming shipment lots of possibility of diminished changes in do not perform finished product testing each dietary ingredient to confirm that tablet dissolution or an adulterated under § 111.35(g)(1) for identity, purity, such specifications are met and perform product and enable you to avoid having quality, strength, or composition, then inprocess testing in accordance with the to destroy incorrect tablets that are too you would need to test for that master manufacturing record to ensure moist or clump together or to avoid nontested finished product specification that such specifications are met. Thus, recalling a product because it settled upon receipt and inprocess as specified the proposed testing requirements into a clump or became moldy in the in the master manufacturing record to provide flexibility for testing for container; ensure that adulterated dietary identity, purity, quality, strength, and • Review the results of the ingredients or dietary supplements are composition, based on the availability of monitoring required by this section and not distributed to the marketplace. scientifically valid testing methods to conduct a material review of any If you are able to perform testing on perform testing on each batch of dietary component, dietary ingredient, dietary each finished batch of dietary ingredient ingredients or dietary supplements. supplement, packaging or label for or dietary supplement to confirm that Proposed § 111.35(h) would require which you establish a specification that specifications are met for the identity, that you use an appropriate test or is not met, or any unanticipated purity, quality, strength, and examination to determine whether your occurrence that adulterates or could composition intended, then we would specifications are met. An appropriate result in adulteration of the component,

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dietary ingredient, dietary supplement, approves such reprocessing. However, contamination that may adulterate or packaging, or label. This review will the proposal states that you must not may lead to adulteration. reveal whether the monitoring is reprocess any component, dietary The proposal also would require that actually being done and being done ingredient or dietary supplement if it is you use an appropriate scientifically correctly, and whether the rejected because of contamination with valid methodology for the test or specifications are being met; and microorganisms or other contaminants, examination. We discuss analytical • Make a material disposition such as heavy metals. We propose to methods in more detail elsewhere in decision for any component, dietary prohibit reprocessing in such cases this document in our discussion of ingredient, dietary supplement, because it is unlikely that reprocessing laboratory operations, proposed packaging, or label if: will eliminate such forms of § 111.60. The types of contamination 1. A component, dietary ingredient, contamination or will eliminate such covered by proposed § 111.35(k) dietary supplement, packaging, or label contamination without adversely include, but are not limited to, the fails to meet specifications; affecting the component, dietary following: 2. Any step established in the master ingredient, or dietary supplement. • Filth, insects, or other extraneous manufacturing record is not completed; Proposed § 111.35(i)(5) would require material; 3. There is any unanticipated that this review be conducted by an • Microorganisms; and occurrence during the manufacturing individual from the quality control unit. • Toxic substances. operations that adulterates or may lead This is necessary to ensure that the Under this proposed requirement, you to adulteration of the component, review is conducted by a person who is must test or examine for those types of dietary ingredient, dietary supplement, qualified by training and experience to contamination that may adulterate or packaging, or label; or conduct such reviews and who may lead to adulteration. The words, 4. Calibration of an instrument or understands the production and ‘‘for those types of contamination that control suggests a problem that may inprocess control system, understands may adulterate or may lead to have caused batches of a dietary the significance of a processing adulteration,’’ at least in part, mean that ingredient or dietary supplement to deviation, and knows how to respond to you must test a botanical for filth and become adulterated; and a deviation. This will ensure that the microorganisms of public health 5. A dietary ingredient or dietary review that is conducted and the significance. For example, it is highly supplement is returned. likely or certain that botanical • response to any deviation is Have your quality control unit appropriate. The requirements of this components would be contaminated approve any material review and section do not mean that the with filth and undesirable disposition decision. manufacturer needs a large number of microorganisms of public health You should review the public health employees. significance based on the areas in which significance of any deviations from Proposed § 111.35(j) would require they are harvested. Therefore, it would specifications or of any unexpected the person who conducts the material be inappropriate if you did not test occurrences to ensure that dietary review and makes the disposition botanical components for filth and ingredients and dietary supplements decision to document, at the time of microorganisms. The types of tests and that may have been affected adversely performance, every material review and when to test would be left to your by a deviation do not enter the disposition decision in proposed discretion. The proposed rule would not marketplace. A material review and § 111.35(i). The documentation must be specify any particular test or disposition decision would ensure that included in the batch production examination, so you would be able to the disruption of a manufacturer’s record. Proposed § 111.35(j) would decide on the appropriate methods for business is minimized when a deviation require this documentation to: testing or examination that are suited to does occur. For example, if review of a • Identify the specific deviation from your components, dietary ingredients, dietary supplement formulation does the specification or the unanticipated and dietary supplements. not contain the required identity, purity, occurrence; Contamination also can create quality, strength, or composition, you • Describe your investigation into the conditions that promote further can take steps to dispose of the cause of the deviation from the contamination by other organisms. For formulation before it is packaged and specification or the unanticipated example, contamination resulting from labeled. If the monitoring records are occurrence; possible fungal growth on a botanical not reviewed, a dietary supplement • Evaluate whether or not the component can provide the made with a deficient formulation may deviation from the specification or environment for mycotoxin production, be placed on the market, and a costly unanticipated occurrence has resulted especially aflatoxin (Refs. 63 and 64). and embarrassing recall may be in or could lead to adulteration; Therefore, if a toxic substance is a type necessary. • Identify the action(s) taken to of contamination that may adulterate or Proposed § 111.35(i)(4) would require correct and prevent a recurrence of the lead to adulteration of the dietary that for any deviation or unanticipated deviation or the unanticipated ingredient or dietary supplement, you occurrence which resulted in or could occurrence; and must perform an appropriate test to lead to adulteration of the component, • Discuss what you did with the detect the toxic substance. dietary ingredient, dietary supplement, component, dietary ingredient, dietary In other cases, a certain amount of packaging, or label, the proposal would supplement, packaging, or label. For micro flora on a botanical may be require that you reject the component, example, did you segregate the unavoidable. For example, some dietary ingredient, dietary supplement, component? Did you quarantine it until botanical components always will packaging, or label, unless the quality the quality control unit decided whether contain a certain number of control unit determines that inprocess it should be returned to its supplier, microorganisms that live on the plant or adjustments are possible to correct the reprocessed, or destroyed? come from other organisms (micro flora) deviation or occurrence. You would be Proposed § 111.35(k) would require on the plant. Processing these able to reprocess a rejected component, that you test or examine components, components may destroy a substantial dietary ingredient, or dietary dietary ingredients, and dietary number of the microorganisms, but supplement if the quality control unit supplements for those types of some may survive processing (Ref. 65).

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Therefore, for natural products it may be Proposed § 111.35(m) would require steps, such as production, engineering, appropriate to perform tests of finished that you must record the results of all research, and regulatory affairs, may be product to confirm that, of the testing and examinations performed in included in quality control functions. microorganisms present, those of public accordance with this section. If a test or Proposed § 111.37(b) would require health significance did not survive examination is performed on a that your quality control unit must do processing and those that remain that production batch, you must record the the following: are not of public health significance do test or examination result in the batch • Approve or reject all process, not contaminate the dietary ingredient production record in accordance with procedures, specifications, controls, or dietary supplement. § 111.50(c)(10). Your records must tests, and examinations, and deviations Although the proposal does not document whether the testing and from or modifications to them that may specify microbial limits for undesirable examination demonstrates that affect the identity, purity, quality, microorganisms, other non-FDA sources specifications are met. strength, and composition of a dietary have established acceptable, general Proposed § 111.35(n) would require ingredient or dietary supplement; • limits of microbial levels for dietary for any specification that is not met, that Determine whether all components, ingredients and dietary supplements you must conduct a material review and dietary ingredients, dietary (Refs. 66 and 67). These often include disposition decision under § 111.35(i). supplements, packaging, and labels Proposed § 111.35(o) would require conform to their specifications; limits for total aerobic microbial count, • which ranges from 104 to 107 per g, that you make and retain records, in Approve or reject all components, depending on source and nature of accordance with proposed § 111.125, to dietary ingredients, dietary ensure that you follow the requirements supplements, packaging, and labels; components; a total combined yeast and • molds count, which can range from 103 of this section. The proposal would Review and approve all master to 105 per g, again depending on source require these records to include, but manufacturing records and all and nature of components; and the would not limit them to: modifications to the master • absence of Salmonella species, E. coli The specifications established; manufacturing records; • • Review and approve all batch and Staphylococcus aureus. We The actual results obtained during production-related records which establish microbial limits for the monitoring operation; • Any deviation from specifications include, but are not limited to, cross- undesirable microorganisms based on and any unanticipated occurrences; referencing receiving and batch scientific information such as literature • Any corrective actions taken; production records, approval of a surveys and laboratory analyses. At this • The disposition decisions and material review and disposition time, however, we do not have followup; and decision, approval for reprocessing, and sufficient information to support • The identity of the individual approval for releasing for distribution. establishing microbial limits for qualified by training and experience Cross-referencing receiving and batch undesirable microorganisms for dietary who investigated any deviation from production records means that the ingredients. Therefore, the proposed specifications or unanticipated quality control unit must verify that the rule does not establish microbial limits occurrence and the identity of the batch record includes certain for dietary ingredients. However, you individual from the quality control unit documentation of the receiving records must be aware of potential who reviewed the results of that for the components and dietary contamination, regardless of whether it investigation. ingredients such as the unique identifier is due to filth, insects, microorganisms, These records would enable you to assigned to the shipment lot of or toxins, and you must test or examine show, and for us to determine, your components, testing results, a material as appropriate components, dietary compliance with proposed § 111.35. We review and disposition decision, if ingredients, or dietary supplements for generally determine CGMP compliance conducted, and approval for use by the those types of contamination that may by conducting inspections, so records quality control unit. adulterate or may lead to adulteration. play an important role during those • Review and approve all processes Proposed § 111.35(l) would explain inspections in determining CGMP for calibrating instruments or controls; that the tests you use to determine compliance. • Review all records for calibration of whether your components, dietary instruments, apparatus, gauges, and ingredients, and dietary supplements 2. What Requirements Apply to Quality Control? (Proposed § 111.37) recording devices; meet specifications must include at least • Review all records for equipment one of the following tests: Gross Proposed § 111.37(a) would require calibrations, inspections, and checks; organoleptic analysis, microscopic that you use a quality control unit to • Review and approve all laboratory analysis, chemical analysis, or other ensure that your manufacturing, control processes and testing results; appropriate test. These tests may vary in packaging, label, and holding operations • Review and approve all packaging detail or complexity depending on the in the production of dietary ingredients and label records which include, but are purposes of the test and the material and dietary supplements are performed not limited to, cross-referencing being tested. For example, if your in a manner that prevents adulteration receiving and batch production records, component is raw cranberries, and you and misbranding, including ensuring approval for repackaging and relabeling, are trying to verify that a shipment of that dietary ingredients and dietary and approval for releasing for red berries consists of raw cranberries, supplements meet specifications for distribution; an organoleptic (visual test) may be identity, purity, quality, strength, and • Collect representative samples of: sufficient (assuming that you recognize composition. This requirement does not 1. Each shipment lot of components, cranberries). However, if your mean that the manufacturer needs a dietary ingredients, dietary component is a chemical substance, and large number of employees. The supplements, packaging, and labels you are trying to verify that a shipment manufacturing process for an ingredient received for testing or examination, as of bulk powder is that chemical or a dietary supplement can be a needed, to determine whether the substance, chemical analysis may be sophisticated process, and all component, dietary ingredient, dietary more appropriate than an organoleptic organizational units that are involved in supplement, packaging, or labels meet analysis. critical formulation and manufacturing specifications before use or for testing,

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as needed, in consumer complaint manufacturing record where control is should require, in a final rule, written investigations; necessary to prevent adulteration; procedures for the quality control unit 2. Inprocess materials at points, steps, 3. Dietary ingredients and dietary duties required in § 111.37. If comments or stages, in the manufacturing process supplements that you manufacture to assert that written procedures are as specified in the master manufacturing ensure that they meet specifications; necessary, comments should include an record where control is necessary to and explanation of why the requirement is ensure the identity, purity, quality, 4. Packaged and labeled dietary necessary to prevent adulteration strength, and composition of dietary ingredients and dietary supplements to including how such a requirement ingredients or dietary supplements; ensure that you used the packaging would ensure the identity, purity, 3. Each batch of dietary ingredient or specified in the master manufacturing quality, strength, and composition of the dietary supplement that is record and you applied the label dietary ingredient or dietary manufactured to determine, before you specified in the master manufacturing supplement. Conversely, if comments record; assert that written procedures are not release it for distribution, whether it • meets its specifications for identity, Review and approve all material necessary, comments should include an purity, quality, strength, and review and disposition decisions; and explanation of why the requirement is • Approve the reprocessing or composition; and not necessary including how, in the distribution of returned dietary 4. Each batch of packaged and labeled absence of the requirement, one can ingredients or dietary supplements. dietary ingredients or dietary prevent adulteration and ensure the Proposed § 111.37 would impose identity, purity, quality, strength, and supplements to determine that you used duties on your quality control unit that the packaging specified in the master composition of the dietary ingredient or are necessary to the quality control unit. dietary supplement. manufacturing record and applied the The duties proposed in § 111.37 are label specified in the master important in any CGMP standards to 3. What Requirements Apply to manufacturing record; ensure that the dietary ingredient or Components, Dietary Ingredients, • Review and approve all material dietary supplement manufactured has Dietary Supplements, Packaging, and review and dispostion decisions; and the identity, purity, quality, strength, Labels You Receive? (Proposed § 111.40) • Collect representative reserve and composition intended. If a quality Proposed § 111.40 would establish samples of each shipment lot of control unit did not do, that is, lacked requirements to ensure that the components, dietary ingredients, and the responsibility and authority to do, components, dietary ingredients, dietary dietary supplements and each batch of the actions described in proposed supplement, packaging, and labels you dietary ingredient or dietary § 111.37, coordination between various receive are, in fact, what you ordered. supplement. The proposal would parts of your manufacturing, packaging, We are proposing these requirements require that you keep the reserve or holding operation might become because receiving the wrong materials samples for 3 years from the date of haphazard and the product could be can lead to mixups or the use of wrong manufacture for use in appropriate adulterated. For example, if your quality materials and this could result in the investigations, such as, consumer control unit did not make decisions manufacture of an adulterated and complaint investigations to determine, concerning use of components, dietary misbranded dietary ingredient or dietary for example, whether the dietary ingredients, and dietary supplements supplement. ingredient or dietary supplement you receive, you could use the wrong Proposed § 111.40(a)(1) and (a)(2) associated with a consumer complaint component, or a contaminated would apply to components, dietary failed to meet any of its specifications component in manufacturing a dietary ingredients, or dietary supplements you for identity, purity, quality, strength, ingredient or dietary supplement. If receive, and would require that you: and composition. We tentatively decide your quality control unit makes • Visually examine each container or to require that you keep reserve samples decisions concerning releasing dietary grouping of containers in a shipment for for 3 years because we believe that 3 ingredients and dietary supplements for appropriate content label, container years would be a reasonable time period distribution, it will prevent you from damage, or broken seals to determine beyond the date of manufacture for releasing for distribution an adulterated whether the container’s condition has appropriate followup of consumer dietary ingredient or dietary supplement resulted in contamination or complaints received during the before the necessary tests results deterioration of the components, dietary marketing period. Because we have not confirm that the dietary ingredient or ingredients, or dietary supplements; proposed requirements for expiration dietary supplement meets specifications • Visually examine the supplier’s dating of dietary supplements, we for identity, purity, quality, strength, invoice, guarantee, or certification to tentatively conclude that the date of and composition. ensure that the components, dietary manufacture is an appropriate starting Your quality control unit must ingredients, or dietary supplements are time for the retention period. This document, at the time of performance, consistent with your purchase order and requirement in proposed § 111.37(b)(11) that it performed the review, approval, perform testing, as needed, under also would require that the reserve or rejection requirements established in proposed § 111.35(g), to determine samples be identified with the batch or accordance with proposed § 111.37 by whether specifications are met. lot number and consist of at least twice recording the date when the review, We state in proposed § 111.40(a)(2) the quantity necessary for tests; approval, or rejection and requirement that you must perform testing ‘‘as • Perform appropriate tests and/or was performed, and the signature of the needed.’’ This flexibility is necessary, examinations of: person performing the requirement. As given the proposed testing scheme in 1. Components, dietary ingredients, we explained elsewhere in this § 111.35(g). As previously discussed in dietary supplements, packaging, and document, one of the ways we proposed § 111.35(e), you must establish labels received to ensure that they meet determine compliance with CGMP’s is specifications for any points, steps, or specifications; by conducting inspections, so records stages in the manufacturing process 2. Dietary ingredient and dietary enable you to show, and for us to where control is necessary to prevent supplement batch production at points, determine, compliance with CGMP’s. adulteration. In addition, we propose to steps, or stages identified in the master We invite comment on whether we require, under § 111.35(e), certain

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specifications, i.e., identity, purity, supplier’s invoice, guarantee, or deterioration of the packaging and quality, strength, and composition, for certification. labels; components, dietary ingredients, and Under § 111.40(b)(3) through (b)(5), • Quarantine packaging and labels dietary supplements upon receipt. we would require that you: until your quality control unit tests or However, in § 111.35(g), we are • Quarantine components, dietary examines a representative sample to proposing to provide some flexibility for ingredients, or dietary supplements determine that specifications are met. when testing is required for the identity, until your quality control unit reviews You must conduct at least a visual purity, quality, strength, and the supplier’s invoice, guarantee, or identification on the containers and composition specifications. Specifically, certification and performs testing, as closures. If specifications are not met, if you perform finished product testing needed under proposed § 111.35(g), of a the proposal would require that you under § 111.35(g)(1) for identity, purity, representative sample to determine that conduct a material review and make a quality, strength, and composition, then specifications are met. These are the disposition decision and also require under § 111.40(a)(2) we would require specifications that you would set in your quality control unit to approve and that you visually compare the supplier’s accordance with proposed § 111.35(e) release packaging and labels from invoice, guarantee, or certification with and appropriate tests or examinations quarantine before you use them; • your purchase order to confirm used in accordance with proposed Identify each shipment lot of consistency between your order and the § 111.35(g) for materials that you packaging and labels in a manner that supplier’s invoice, guarantee, or receive. If specifications are not met, allows you to trace the shipment lot to certification. You would not need to do proposed § 111.40(a)(3) would require the supplier, the date received, the testing upon receipt. That is why we that you conduct a material review and name of the packaging and label, and have added language to § 111.40(a)(2) make a disposition decision. Your the status (e.g., quarantined, approved, that states, ‘‘and perform testing, as quality control unit must approve and or rejected) and to trace the shipment lot needed, to determine whether release the components, dietary to the dietary ingredient or dietary specifications are met.’’ Alternatively, ingredients, and dietary supplements supplement manufactured and for specifications that you establish from quarantine before you use them; distributed. Like proposed • Identify each lot of components, (e.g., other than the identity, purity, § 111.40(a)(4), proposed § 111.40(b)(3) dietary ingredients, or dietary quality, strength, and composition of the would require that you use this unique supplements in a shipment in a manner components, dietary ingredients or identifier whenever you record the that allows you to trace the shipment to dietary supplements received), such as disposition of each shipment lot the supplier, the date received, the for a holding temperature necessary received; and name of the component or dietary • Hold packaging and labels under during transportation to your physical supplement, and the status (e.g., conditions that will protect against plant to avoid adulteration, you would quarantined, approved, or rejected) and contamination and deterioration and be required to ensure by testing or to trace the shipment lot to the dietary avoid mixups. examination that the specified ingredient or dietary supplement Proposed § 111.40(c) deals with temperature was used. manufactured and distributed. You written documentation and records. If you do not perform finished must use this unique identifier Proposed § 111.40(c)(1) would require product testing under § 111.35(g)(1) for whenever you record the disposition of that the person who performs the identity, purity, quality, strength, or each shipment lot received. Using a requirements established in accordance composition, then you would need to unique identifier throughout the with this section to document, at the test for that nontested finished product manufacturing process will make it time of performance, that he or she specification upon receipt. In that case, possible to track and account for performed the requirements. The testing would be needed under both components, dietary ingredients, and documentation would have to include, proposed §§ 111.35(g)(2) and dietary supplements you receive and is but not be limited to, the date that the 111.40(a)(2). You still would need to necessary to conduct investigations of requirement was performed; the visually compare the supplier’s invoice, consumer complaints; and signature of the person performing the guarantee, or certification with your • Hold components, dietary requirement; any test results; and any purchase order to confirm consistency ingredients, or dietary supplements material review and disposition between your order and the supplier’s under conditions that will protect decision conducted, and the disposition invoice, guarantee, or certification. against contamination, deterioration, of any rejected material. Thus, for those specifications of and avoid mixups. For example, you Proposed § 111.40(c)(2) would require identity, purity, quality, strength, or must segregate components that your that you keep component, dietary composition for which your quality quality control unit has not released for supplement, packaging, and label control unit determines that you cannot use from those components that have receiving records in accordance with test for at the finished product stage been released for use. This provision proposed § 111.125. These records are (because there are no available would require that you refrigerate necessary to be able to determine the scientifically valid methods), then you components that are subject to source of the component, dietary would be required, under contamination or deterioration without ingredient, dietary supplement, § 111.35(g)(2)(i) to test incoming such refrigeration or that otherwise packaging, and labels, so that if shipment lots of components, dietary require storage at a certain temperature. adulteration of dietary ingredient or ingredients, or dietary supplements for Proposed § 111.40(b) would apply to dietary supplement occurs, the records any such specification to determine packaging and labels you receive and will show the source of the material so whether it is met, and such a test also would require that you: that its use can be stopped. In addition, would be considered to be necessary • Visually examine each container or the records will show the basis on under § 111.40(a)(2). As discussed grouping of containers in a shipment for which each component, dietary earlier, you may not rely on a supplier’s appropriate content labels, container ingredient, dietary supplement, certification or guaranty in lieu of such damage, or broken seals to determine packaging, or label was released for use testing, and in addition to such testing, whether the container’s condition has in dietary ingredient or dietary still would need to visually examine the resulted in contamination or supplement production. These records

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are necessary to demonstrate steps, or stages in the master appropriate weight or measure for the compliance with the CGMP and quality manufacturing record where control is component); control procedures. necessary to prevent adulteration, and • The identity and weight or measure We invite comment on whether we establish controls and procedures to of each dietary ingredient that will be should require, in a final rule, that you ensure that each batch of dietary declared on the Supplement Facts label establish and follow written procedures ingredient or dietary supplement and the identity of each ingredient that that implement proposed § 111.40(a) manufactured meets those will be declared on the ingredients list and (b). If comments assert that written specifications. For example, assume that of the dietary supplement in compliance procedures are necessary, comments your manufacturing process blends with section 403(s) of the act. For should include an explanation of why various ingredients in order to make a proposed § 111.45(b)(4), therefore, the the requirement is necessary to prevent dietary supplement. Under proposed master manufacturing record for our adulteration including how such a § 111.45(a), your master manufacturing hypothetical product would state that requirement would ensure the identity, record would establish controls to look the dietary ingredient is Vitamin C at purity, quality, strength, and at specific steps in the manufacturing 250 mg (because Vitamin C would be composition of the dietary ingredient or process and evaluate the blends for the dietary ingredient declared on the dietary supplement. Conversely, if specific ingredients to ensure that you Supplement Facts label) and identify comments assert that written procedures added the correct ingredients at the starch, microcrystalline cellulose, and are not necessary, comments should correct amounts or concentrations that dicalcium phosphate (because those include an explanation of why the meet your specifications before the ingredients would be in the product’s requirement is not necessary including blend proceeds to the next ingredient list, but not on the how, in the absence of the requirement, manufacturing step, in accordance with Supplement Facts label); and one can prevent adulteration and ensure the master production record. • A statement that explains any the identity, purity, quality, strength, Throughout the manufacturing process, intentional excess amount of a dietary and composition of the dietary you would evaluate, as necessary, any ingredient. We recognize that some ingredient or dietary supplement. points, steps, or stages where control is manufacturers intentionally add a 4. What Requirements Apply to necessary to prevent adulteration to specific amount of a dietary ingredient Establishing a Master Manufacturing ensure that specifications established in excess of the declared label amount Record? (Proposed § 111.45) for those points, steps, or stages are met. so that the finished product can meet the label declaration for that dietary Proposed § 111.45 would require that Proposed § 111.45(b) would establish ingredient throughout the product’s you prepare and follow a written master additional requirements for the master shelf life. For our hypothetical vitamin manufacturing record for each type of manufacturing record. These proposed requirements would include: C tablet, if you added an extra 25 mg of dietary ingredient or dietary supplement • that you manufacture and for each batch The name of the dietary ingredient vitamin C to ensure that your product size to ensure uniformity from batch to or dietary supplement to be contains at least 250 mg of vitamin C batch. A master manufacturing record is manufactured and the strength, throughout its shelf life, your master analogous to a recipe that sets forth the concentration, weight, or measure of manufacturing record would state the ingredients to use, the amounts of each dietary ingredient for each batch component and the actual amount of the ingredients to use, the tests to perform, size. For example, assume you have a component as ‘‘Vitamin C, 250 mg, (10 and the instructions for preparing the million tablet batch size of a vitamin C percent excess) 25 mg’’ or ‘‘275 mg of amount the recipe calls for, e.g., 250 mg, product in 250 mg tablets and that the Vitamin C.’’ So, proposed § 111.45(b)(5) 500 mg, vitamin C. This master only other ingredients in your product would require the master manufacturing manufacturing record helps ensure that are starch, microcrystalline cellulose, record to specify the controlled amount you manufacture each ingredient or and dicalcium phosphate. Under of the excess dietary ingredient dietary supplement in a consistent and proposed § 111.45(b)(1), your master necessary to achieve the declared label uniform manner. If you neglect to follow manufacturing record would state, declaration. This provision is not the master manufacturing record, you ‘‘Vitamin C 250 mg, 1,000,000 tablets’’; intended to allow a manufacturer to add would not add all of the necessary • A complete list of components to be excess dietary ingredients in components in the appropriate strength used. Again, to continue using the unspecified amounts that would be in or amount, and this would result in an example immediately above, for excess of the amount actually needed to adulterated ingredient or dietary proposed § 111.45(b)(2), the master meet the label declaration. supplement. manufacturing record also would show The agency considered whether to Therefore, proposed § 111.45(a) is that you used starch, microcrystalline propose requirements in this proposed necessary to ensure that you prepare cellulose, and dicalcium phosphate in rule for expiration dating, shelf-life and follow a written master the product; dating, or best if used by dating manufacturing record for each type of • An accurate statement of the weight (hereinafter referred to as expiration dietary ingredient or dietary supplement or measure of each component to be dating). Although we recognize that to ensure that all the necessary used. For example, under proposed there are current and generally available components as specified, and in the § 111.45(b)(3), the master manufacturing methods to determine the expiration amounts specified, are used to record for our hypothetical vitamin C date of some dietary ingredients, for manufacture each batch to ensure tablet would state the amount of each example vitamin C, we are uncertain uniformity from batch to batch and to component used, such as ‘‘200 lbs. of whether there are current and generally ensure that the dietary ingredient or Vitamin C, 10 lbs. of microcrystalline available methods to determine the dietary supplement is not adulterated. cellulose’’ and the amounts of starch expiration dating of other dietary Proposed § 111.45(a)(1) and (a)(2) and dicalcium phosphate used. (We ingredients, especially botanical dietary describe the proposed contents of the would not require that you show the ingredients. We are not proposing master manufacturing record. The amount using an appropriate English or expiration dating at this time because master manufacturing record would metric standard in a particular way, but we have insufficient scientific identify specifications for the points, we would expect that you use the most information to determine the biological

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activity of certain dietary ingredients depending on the type of material you component and another person used in dietary supplements, and such use, packaging could adulterate your verifying the addition; information would be necessary to dietary ingredients or dietary 4. Special notations and precautions determine an expiration date. Further, supplements. For example, the correct to be followed; and because official validated testing container may protect the dietary 5. Corrective action plans for use methods (i.e., AOAC or FDA) for dietary ingredient or dietary supplement from supplements are evolving, especially for the deteriorating effects of light and if when a specification is not met. botanical dietary ingredients, few an incorrect container is used that does You should think of the written official methods are available to assess not provide this protection, your dietary instructions as being similar to a recipe; the strength of a dietary ingredient in a ingredient or dietary supplement could they should cover the important steps in dietary supplement. Nevertheless, if you deteriorate and could be adulterated. your manufacturing, packaging, or use an expiration date on a product, you The description might consist of holding processes, but they also should should have data to support that date. information such as the type of bottle to tell the reader about any special You should have a written testing be used with your manufacturer’s code directions to follow, tests to perform, program designed to assess the stability number, if available; a description of the precautions to be observed, and characteristics of the dietary cap to be used with the liner specified personnel to use. supplement, and you should use the with a manufacturer’s code number, if Proposed § 111.45(c) would require results of the stability testing to applicable; additional materials needed that you have your quality control unit determine appropriate storage in packaging; and the control number, if review and approve each master conditions and expiration dates. applicable, of the label to be used in manufacturing record and any We invite comment on whether any packaging the dietary ingredient or modifications to a master manufacturing final dietary ingredient and dietary dietary supplement. We are not aware of record. This provision reiterates the supplement CGMP rule should contain evidence of that dietary supplement quality control requirements in provisions regarding expiration dating manufacturers are using unlawful proposed § 111.37. This proposed and the feasibility of conducting tests containers. Section 201(s) of the act requirement is necessary to prevent needed to support such dates. We also defines ‘‘food additive’’ to mean any potential problems that could result invite comments on whether to require substance the intended use of which from changes to the master expiration dating on certain dietary results or may reasonably be expected to manufacturing record made by persons ingredients and not others, for example, result, directly or indirectly, in it’s who are not qualified to assess the require expiration dating of vitamin, becoming a component or otherwise impact of such changes. By having your mineral, and amino acid, but not of affecting the characteristics of any food quality control unit review and approve botanical dietary ingredients. (including any substance intended for the master manufacturing record and Proposed § 111.45(b) also would use in producing, manufacturing, changes to that record, you will reduce require your master manufacturing packing, processing, preparing, treating, your risk of not detecting the inclusion record to contain: packaging, transporting, or holding of an incorrect ingredient in the batch • A statement of theoretical yield of food; and including any source of a manufactured dietary ingredient or radiation intended for any such use). production. The quality control unit dietary supplement expected at each Materials used in packaging that come review will ensure that necessary point, step, or stage of the in contact with food or that react inprocess verifications and testing manufacturing process where control is chemically with food, may be instructions are included in the master necessary to prevent adulteration, and considered to be food contact manufacturing record. Further, any the expected yield when you finish substances or food additives. Foods and changes to the master manufacturing manufacturing the dietary ingredient or dietary ingredients may contain active record will reduce your risk of adding dietary supplement, including the substances that can react with packaging the wrong component, dietary maximum and minimum percentages of materials. Thus, FDA is proposing a ingredient or dietary supplement or the theoretical yield beyond which a CGMP requirement that manufacturer’s wrong amount of a component, dietary deviation investigation of a batch is use containers that are lawful under the ingredient or dietary supplement. For performed and material review is act and that do not impose a risk such example, in one case, a dietary conducted and disposition decision is as leakage or the possibility of physical supplement manufacturer made a made. In this particular instance, when contamination of dietary ingredients or product that had 10 times the labeled we refer to the manufacture of dietary dietary supplements. Information on amount of vitamin D, but did not ingredients, we mean to say that if you packaging and labels materials will also perform any tests for vitamin D use a master manufacturing record to be helpful in case an adverse event concentration as part of its review of its make dietary ingredients (that is, you occurs; and batch records (Ref. 23). The make dietary ingredients rather than • Written instructions including, but manufacturer discovered the dietary supplements), the proposal not limited to: superpotent batches only after State would require the master manufacturing 1. Specifications for each point, step, authorities had contacted them, and had record to contain a theoretical yield at or stage in manufacturing the dietary to recall the product. Had the each point, step, or stage where control ingredient or dietary supplement manufacturer’s quality control unit is necessary to prevent adulteration. necessary to prevent adulteration; reviewed the master manufacturing and Likewise, if you manufacture dietary 2. Sampling and testing procedures; batch production records earlier, the supplements, the proposal would 3. Specific actions necessary to superpotent batches that represented a require your master manufacturing perform and verify points, steps, or change from the master manufacturing record to contain a theoretical yield at stages, necessary to meet specifications record might have been detected before each point, step, or stage where control and otherwise prevent adulteration, the product left the manufacturer, and is necessary to prevent adulteration; including, but not limited to, one person the recall could have been avoided. The • A description of packaging and a weighing or measuring a component manufacturer later took steps to increase copy of the label to be used. We propose and another person verifying the weight its audits of batch records, to require to require such information because, or measure and one person adding the approval of all changes to its master

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formulas, and to perform tests for its record and modifications to that record Further, we seek comment on whether manufacturing activities. properly rests with the quality control any of the proposed requirements in this In another example, several unit because the individuals in the section are not necessary to prevent consumers and employees at spas in quality control unit would have the adulteration and to ensure the identity, Massachusetts and Arizona complained expertise to make a decision whether purity, quality, strength, and of dizziness, vomiting, or the master manufacturing record, if composition of the dietary ingredient or lightheadedness after consuming several followed, will result in an unadulterated dietary supplement. If comments assert dietary supplements. We did an dietary ingredient or dietary supplement that certain provisions are not inspection and found that, in the case of and does not mean that the necessary, comments should include an two products, the manufacturer’s manufacturer needs a large number of explanation of why the requirement is formula called for the use of a product employees. not necessary including how, in the having 0.2 percent selenium by weight, You should note that, while the absence of the requirement, one can but the manufacturer’s records showed quality control unit is responsible for prevent adulteration and ensure the that it used a product that had 5 percent reviewing and approving the master identity, purity, quality, strength, and selenium by weight. This difference manufacturing record and changes to composition of the dietary ingredient or meant that the supplements, instead of that record, this does not mean that the dietary supplement. If comments agree containing 200 µg of selenium, quality control unit must prepare the that the proposed requirements are contained between 400 to 4,699 µg of master manufacturing record itself or act necessary for reasons other than those selenium. After further investigation, we without any involvement from other we have provided, the comments should determined that the error occurred parts of your manufacturing operation. so state and provide an explanation. when the quantity of selenium to be Other individuals or groups may help used was printed in kilograms (kg), prepare, review, and approve drafts of a 5. What Requirements Apply to instead of g. The change in unit master manufacturing record and draft Establishing a Batch Production Record? measurement represents a change from changes to an existing master (Proposed § 111.50) the master manufacturing record. Had manufacturing record, but the quality Proposed § 111.50(a) would require the manufacturer’s quality control unit control unit is responsible for reviewing that you prepare a batch production reviewed the change in the master and approving the final master record every time you manufacture a manufacturing record, it probably manufacturing record and modifications batch of dietary ingredient or dietary would not have approved the change to to that record. supplement. This requirement would include use of the product containing Proposed § 111.45(d) would pertain to apply to any batch, including a batch the higher percent of selenium. written documentation and approved for reprocessing by the quality One comment to the ANPRM opposed recordkeeping. Proposed § 111.45(d) control unit. The proposal also would a requirement that would have a quality would require that you keep your require the batch production record to control unit review and approve the master manufacturing records in include complete information relating to master manufacturing record. The accordance with proposed § 111.125. the production and control of each comment stated that this review and The master manufacturing record in batch. The batch production record is approval process is overly restrictive addition to the batch production records necessary to document that you because other units can perform this will ensure that a complete history of followed the master manufacturing function and only need be audited or each batch of dietary ingredient or record to make each batch of dietary periodically verified by the quality dietary supplement is available for your ingredients or dietary supplements. It is control unit. The comment suggested review in the event that a problem arises important to document such that the quality control unit assure that with a particular batch. These records information for each batch because it a master production and control record also are necessary to demonstrate serves as a check that the master must be prepared for the manufacture of compliance with the CGMP and quality manufacturing record was followed. If each dietary ingredient and dietary control procedures. you later discover problems with a supplement, rather than review and We invite comment on whether a particular batch of dietary ingredients or approve such records. written procedure for preparing the dietary supplements, you could look at We do not agree that the review and master manufacturing record and the batch production record for that approval process is overly restrictive making any modifications to the record, batch, compare it to the master and decline to adopt the comment’s consistent with the requirements in this manufacturing record, and see whether suggestion. The quality control unit can section, should be required in a final the problems occurred because of a be composed of individuals from rule. If comments assert that written failure to follow the master various parts of the organization. procedures are necessary, comments manufacturing record. These records, in Removing this responsibility from the should include an explanation of why conjunction with your master quality control unit would diminish the the requirement is necessary to prevent manufacturing records, will create a quality control unit’s responsibility and adulteration including how such a written system which, when followed, authority. As stated earlier, the requirement would ensure the identity, will result in a reproducible, high- manufacturing process of a dietary purity, quality, strength, and quality, and uniform dietary ingredient ingredient or a dietary supplement can composition of the dietary ingredient or or dietary supplement. be a sophisticated process, and we dietary supplement. Conversely, if Proposed § 111.50(b) would require understand that all organizational units comments assert that written procedures the batch production record to that are involved in critical formulation are not necessary, comments should accurately follow the appropriate master and manufacturing steps, such as include an explanation of why the manufacturing record and also require production, engineering, research, and requirement is not necessary including that you perform each step in producing regulatory affairs, should review and how, in the absence of the requirement, the batch. Even if you have someone approve a master production order and one can prevent adulteration and ensure else (such as a contractor) perform a changes to it. However, the the identity, purity, quality, strength, particular step, you would remain responsibility for reviewing and and composition of the dietary responsible for ensuring that each step approving the master manufacturing ingredient or dietary supplement. is done that complies with the

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requirements in proposed part 111. The record review and any approval for instead of containing 200 µg of contractor, however, is also considered reprocessing or repackaging. selenium, contained between 400 to a manufacturer and must comply with Proposed § 111.50(b) and (c) are 4,699 µg of selenium. As discussed the regulations that apply to the necessary to ensure that you made your earlier, the quality control unit review responsibilities that it has specifically batches correctly under the master and approval of the master contracted to perform. manufacturing record and that you manufacturing record would have noted Proposed § 111.50(c) would specify correctly performed each significant the change in percent selenium by the batch production record’s contents. step in the manufacturing process. If weight and the necessary changes to the The proposal would require that certain you did not create a batch production master manufacturing record could have information be included in the batch record for each batch production that been made. The quality control unit production record including, but not be accurately followed the master review and approval of the batch limited to, the following information: manufacturing record, you would not be production record provides another • The batch, lot, or control number; sure that your dietary ingredient or check to ensure that a mixup has not • Documentation, at the time of dietary supplement was not adulterated. occurred. Had the manufacturer’s performance, showing the date on The master manufacturing record is quality control unit compared the which each step of the master intended to ensure batch to batch master manufacturing record to the manufacturing record was performed, uniformity and to prevent adulteration. batch production record, it would have and the initials of the persons Your batch production record also may noticed the mixup during the performing each step including, but not be valuable in the event of a product manufacturing process and prevented limited to, the person responsible for recall. We seek comment on whether the use of the higher percentage weighing or measuring each component any of the proposed requirements in this selenium dietary ingredient. The used in the batch and the person section are not necessary to prevent information that would be required responsible for adding the components adulteration and to ensure the identity, under proposed § 111.50(c) would help to the batch; purity, quality, strength, and you determine what product was • The identity of equipment and composition of the dietary ingredient or manufactured, when it was processing lines used in producing the dietary supplement. If comments assert manufactured, how it was batch; that certain provisions are not manufactured, and where it was • The date and time of the necessary, comments should include an manufactured. As another example, if explanation of why the requirement is maintenance, cleaning, and sanitizing of your batch production records identify not necessary including how, in the the equipment and processing lines the equipment and processing lines absence of the requirement, one can used in producing the batch; being used, you would be able to go to prevent adulteration and ensure the • The shipment lot unique identifier that piece of equipment or to that identity, purity, quality, strength, and of each component, dietary ingredient, processing line and determine which composition of the dietary ingredient or dietary supplement, packaging, and dietary ingredient or dietary supplement dietary supplement. If comments agree is being manufactured or processed. label used; that the proposed requirements are Further, if your batch records reflect the • The identity and weight or measure necessary for reasons other than those initials of those persons who weighed a of each component used; we have provided, the comments should component, added that specific • The initials at the time of so state and provide an explanation. component, and performed a particular performance or at the completion of the In one case (Ref. 27), we found that a step to prevent adulteration of the batch of the person responsible for manufacturer had produced a subpotent product, you would be able to see who verifying the weight or measure of each folic acid product. When the was responsible for a particular action component used in the batch; manufacturer reviewed the batch • and, if necessary, to consult that person The initials at the time of production records, it discovered that in the event of a problem or to see how performance or at the completion of the the bulk product was not mixed he or she performed a particular task. In batch of the person responsible for properly, and this caused the folic acid addition, if your batch production verifying the addition of components to to be distributed poorly throughout the records contain batch or lot numbers the batch; product. Thus, in this instance, the • and if you later discover a problem with A statement of the actual yield and batch production record helped identify a particular batch, that information will a statement of the percentage of the point in the manufacturing process help you investigate the problem by theoretical yield at appropriate phases when the error occurred, and the reason showing you the manufacturing history of processing; why the error occurred and enabled the • for that particular batch. The actual test results for any manufacturer to correct the problem. A comment to the ANPRM stated that testing performed during the batch Review of batch production records keeping written records of equipment production in accordance with might have prevented another incident cleaning and use, including the date, § 111.35(m); where several persons experienced product, and lot number of each batch • Documentation that the dietary dizziness, vomiting, or lightheadedness processed, would be burdensome ingredient and dietary supplement after consuming vitamin and mineral compared to the benefits it would meets specifications; products. As we mentioned in our provide, particularly when equipment is • Copies of all container labels used discussion of proposed § 111.45, this cleaned after each use. The comment and the results of examinations incident involved a mixup during the added that manufacturers can modify conducted during the label operation to manufacturing process where the their production records to note which ensure that the containers have the manufacturer’s master manufacturing machines they used. correct label; record called for the use of a product We disagree with the comment. • Any documented material review having 0.2 percent selenium by weight, Written records will help you to ensure and disposition decision in accordance but the manufacturer’s batch records that all cleaning operations are with § 111.35(j); and showed that it used a product that had performed correctly and, if problems do • The signature of the quality control 5 percent selenium by weight. This occur with the production of a product, unit to document batch production difference meant that the supplements, will help you determine whether those

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problems are associated with receiving records including review of the correct reserve sample in the event maintenance, cleaning, or sanitizing testing and examination results; that there is a problem with a particular operations. Batch and lot information, • Identification of any deviation from batch. as we stated earlier, will let you identify the master manufacturing record that Proposed § 111.50(i) would require batches or lots that may have been may have caused a batch or any of its that you keep your batch production affected by any equipment or utensil components to fail to meet records in accordance with proposed that was improperly maintained, specifications identified in the master § 111.125. The batch production records cleaned, or sanitized. manufacturing record; in addition to the master manufacturing • Proposed § 111.50(d) and (e) would Records of investigations, records will ensure that a complete set forth your quality control unit’s conclusions, and corrective actions history of each batch of dietary responsibilities regarding batch performed in accordance with proposed ingredient or dietary supplement is § 111.50(d); and available for your review in the event production records. These • responsibilities relate to not only the The identity of the person qualified that a problem arises with a particular review but the documentation of their by training and experience who batch. These records also are necessary review and decisions about whether a performed the investigation in to demonstrate compliance with the batch could be reprocessed. As we accordance with proposed § 111.50(d). CGMP and quality control procedures. Proposed § 111.50(f) would prohibit noted in our discussion of proposed you from reprocessing a batch that 6. What Requirements Apply to § 111.37, the quality control unit has deviates from the master manufacturing Laboratory Operations? (Proposed special knowledge and expertise to record unless your quality control unit § 111.60) determine if a batch is produced approves it for reprocessing. Proposed Proposed § 111.60 would establish correctly, that those records are § 111.50(f) also would prohibit you from various requirements for laboratory complete, and that it is appropriate to reprocessing a dietary ingredient or operations. Proposed § 111.60(a) would reprocess a batch. The quality control dietary supplement if it is rejected require that you use adequate laboratory unit also serves as a quality control because of contamination with facilities to perform any necessary tests check that the batch production record microorganisms of public health or examinations to determine that accurately follows the master significance or other contaminants, such components, dietary ingredients, and manufacturing record. A quality control as heavy metals because you cannot rely dietary supplements you receive meet unit review of batch production records on reprocessing to correct public health specifications; that specifications are could have detected and corrected the concerns that a product with pathogens met during inprocess as specified in the previously discussed manufacturing and/or heavy metals would present. master manufacturing record; and that error caused by use of the dietary Proposed § 111.50(g) would require the dietary ingredients and dietary ingredient with the incorrect selenium. that you meet all specifications supplements you manufacture meet Therefore, the review and established in the master manufacturing their specifications. documentation by the quality control record for any batch of dietary One comment to the ANPRM unit of batch production records ingredient or dietary supplement that is recommended that the regulations provides the necessary quality reprocessed and would require your related to laboratory operations apply to assurance to prevent the production of quality control unit to evaluate and laboratory facilities located and an adulterated dietary ingredient or approve the batch before releasing for operated within a company and those dietary supplement. distribution. This requirement is facilities that a company may contract Specifically, proposed § 111.50(d) intended to ensure that a reprocessed with that are located elsewhere. would require your quality control unit batch is not subject to any lesser Proposed § 111.60(a) would apply to to review in accordance with specifications than are otherwise laboratory facilities generally and is not § 111.37(b)(5) the batch production applicable to a nonreprocessed batch. restricted to laboratory facilities located record. If a batch production record Proposed § 111.50(g) also would require and operated within a company. In deviates from the master manufacturing that you document the results of the other words, even if you hire a private record, including any deviation from quality control unit’s reevaluation in the laboratory to perform various tests for specifications, proposed § 111.50(d)(1) batch production record. you, proposed § 111.60(a) would require would require your quality control unit Proposed § 111.50(h) would require that you make sure that the private to conduct a material review and make that you collect representative reserve laboratory’s facilities are adequate to a disposition decision and record any samples of each batch of dietary perform whatever tests are necessary. decision in the batch production record. ingredient or dietary supplement and to The most important point in proposed Proposed § 111.50(d)(2) would instruct keep the reserve samples for 3 years § 111.60(a), however, is not where the your quality control unit to not approve from the date of manufacture for use in facility is located, but whether the and release for distribution any batch of appropriate investigations including, laboratory facility is adequate for the dietary ingredient or dietary supplement but not limited to, consumer complaint tests and examinations that need to be that does not meet all specifications. investigations to determine whether, for done. Proposed § 111.50(e) would require example, the dietary ingredient or Proposed § 111.60(b)(1) would require your quality control unit to document in dietary supplement associated with a that you establish and follow laboratory accordance with § 111.37(c) the review consumer complaint failed to meet any control processes that the quality performed in accordance with proposed of its specifications for identity, purity, control unit has approved. For example, § 111.50(d). The proposal would require quality, strength, and composition. under proposed § 111.60(b)(1)(i) and the quality control unit to document Reserve samples also may prove helpful (b)(1)(ii), the laboratory control this review at the time it does the review in investigating possible tampering or processes would include use of criteria and would require the review and counterfeiting of your products. We for selecting appropriate testing and documentation to include, but would invite comment on whether we should examination methods and for not limit them to, the following: require, in a final rule, that you identify establishing appropriate specifications. • Review of component, dietary each reserve sample with the batch Specifications play an important role in ingredient, and dietary supplement number so that you can readily identify CGMP’s because they may help

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determine whether a dietary ingredient ingredient is adulterated with another ingredients, or dietary supplements, and or dietary supplement is adulterated. substance or is a poisonous plant that packaging and labels. Your sampling Criteria for establishing appropriate should not be ingested. plans should include reserve samples, specifications must be specific to the Misidentification or a mixup of too, because reserve samples will enable component, dietary ingredient, or botanical ingredients can cause a you to investigate and identify possible dietary supplement. The specifications product to be adulterated (Refs. 6 and 69 manufacturing problems in the future. are the parameters that you must meet. through 73). Heavy metals may The proposal would not specify any For example, for ascorbic acid, your contaminate botanical and natural- particular sampling plan; it would leave specifications would include all the occurring ingredients if a plant is grown such details to your discretion so that criteria that you want your incoming and harvested in an area contaminated you can develop a sampling plan that dietary ingredient or for your finished with heavy metals or even processed in suits your products and your testing product to meet. For example, you a contaminated area (Refs. 74 and 75). needs. might establish criteria for the Pesticides also may contaminate Proposed § 111.60(b)(iv) through appearance, color, odor, identity using botanical ingredients; this occurs in (b)(vi) would require the laboratory one or more tests, heavy metals (e.g., rural areas where the botanical plant control processes to include: lead, arsenic, mercury), and organic grow alongside commercial crops (Ref. • Use of criteria for selecting standard volatile impurities. 64). Therefore, you must consider what reference materials used in performing Similarly, criteria for selecting criteria you need to include for the tests and examinations. An appropriate test and examination types of testing that are needed, for authenticated plant reference material methods include parameters such as example, for heavy metal or pesticide may be used as standard reference type of tests and examinations needed contamination, or identity testing material in performing certain based on the component you receive. criteria for selecting appropriate test organoleptic examinations. An For example, you might use methods, for example, whether to use authenticated plant reference material is morphological characters and organoleptic or chemical analyses for material that has been authenticated as organoleptic characteristics in some identity testing. In addition, you must the correct plant species and correct cases to identify botanical dietary establish criteria for specifications for plant part(s) by a qualified plant ingredients at the time of collection or the tests and examinations used. taxonomist. As described earlier in this for unprocessed botanicals. When Establishing such criteria for document, an organoleptic examination sufficient morphological characters are specifications and appropriate test and may be an appropriate examination to present to separate the plant species examination methods will provide you confirm plant identity when sufficient from other plant species, an accurate with internal processes that will help morphological characters are present to identification can be made since prevent misidentification and separate the plant species from other morphological characters are the sole contamination. plant species. For microscopic and basis of distinguishing most of the Proposed § 111.60(b)(1)(iii) would chemical tests, a reference material is a world’s plant species. However, require your laboratory control highly purified compound that is well unprocessed botanicals that do not processes to include use of sampling characterized, and you would use the contain all the plant parts necessary to plans for obtaining representative reference material to perform tests include adequate morphological samples of: including calibration tests. In general, characters to assure the correct species • Components, dietary ingredients, there are two types of reference should have other identity aids or tests and dietary supplements received; materials: (1) Compendial reference to assure the identity of the botanical. It • Inprocess materials during the standards that do not require is possible to use only a picture as an batch manufacturing when testing or characterization; and (2) noncompendial identity standard for whole fresh Ginkgo examination is required in the master standards. Noncompendial standards leaf from a cultivated field because the manufacturing record; should be of the highest purity that can Ginkgo leaf is not easily confused with • Each batch of dietary ingredient or be obtained by reasonable effort and the leaf shape, venation, and color of dietary supplement manufactured to should be thoroughly characterized to other leaves that could be present in the determine that the dietary ingredient or assure their identity, purity, quality, and field. In contrast, powdered Ginkgo leaf dietary supplement meets strength. Ideally, you should use is a different form of the dietary specifications; compendial reference standards ingredient and would require • Packaging and labels received to whenever possible, but if no microscopic and/or chemical analysis. determine that the materials meet compendial reference standard exists, Ginkgo extracts have no morphological specifications; and you should establish appropriately or anatomical features, and it is possible • Each batch of packaged and labeled characterized inhouse materials that extracts may include a number of dietary ingredients or dietary prepared from representative lots; chemical compounds at different ratios supplements to ensure that the label • Use of appropriate test method and concentrations that would require a specified in the master manufacturing validations. Test method validation different chemical test to assure the record has been applied. determines whether a newly-developed identity of the dietary ingredient. For example, a representative sample or existing test method is accurate, Botanical dietary ingredients that come is important to being able to have an precise, and specific for its intended from wild rather than cultivated sources adequate sample to detect purpose. We have discussed previously may grow among and be unintentionally contamination. Contamination may not the terms ‘‘accurate’’ and ‘‘precise.’’ harvested with ‘‘poisonous’’ plants; be distributed evenly throughout a Validation involves evaluating the test therefore, an identity test also would product and may not be detected method on multiple occasions or in need to show whether a botanical without a representative number of multiple test facilities. Official methods, dietary ingredient is adulterated with units. Determining the size of a such as AOAC International methods, another substance or a poisonous plant. representative sample is important are validated in collaborative studies To illustrate this point, a specification because the sample size must be large using several laboratories under may contain a simple identity test, and enough to meet your testing needs for identical conditions. The AOAC these tests may show whether a dietary specific types of components, dietary International methods that are validated

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in collaborative studies often are often Acceptance Criteria for with proposed § 111.125. Laboratory cited as ‘‘official validated methods.’’ If Biotechnological/Biological Products records are necessary to ensure you modify an officially validated (63 FR 31506, June 9, 1998); and compliance with established method, you should document the • Use of test methods in accordance specifications and to demonstrate reason for the modification and have with established criteria. Your process compliance with the CGMP and quality data to show that the modified method for performing test methods criteria control processes. produced results that are at least as must include sufficient detail, including Proposed § 111.60(c) would require accurate and reliable as the established the material you are testing, the purpose that you verify that the laboratory method for material being tested. of the test, and the test method. The testing methodologies are appropriate Further, you should have complete description of the test method criteria for their intended use. records of any testing and must include any reagents used and Proposed § 111.60(d) would require standardization of laboratory reference preparation instructions, apparatus that you identify and use the standards, reagents, and standard required, any instructions for preparing appropriate validated testing method to solutions that you use in your laboratory the sample to be tested, and instructions use for each established specification for operations. Proposed § 111.25(b)(1) for conducting the examination. For which testing is required to determine would require calibration of laboratory example, if you receive components of whether the specification is met. In instruments, apparatus, gauges, and plant origin from an outside source, other words, the proposal would recording devices. Validated methods your specifications must indicate that recognize that requiring that you have also exist in official compendia for you test those components to verify that testing methods is not sufficient alone; they are not contaminated with vitamins, minerals, and several you must also use those testing methods adulterants of vegetable origin and to botanicals, so you should use validated to prevent the adulteration of dietary determine that the microscopic methods whenever available. You may ingredients or dietary supplements. examination method is appropriate for use validated methods that can be found We invite comment on whether we use. Further, you may decide that the in official references, such as AOAC should require, in a final rule, written AOAC International Official Method International, USP and others. Other procedures for your laboratory 961.01 entitled ‘‘Adulterants in Spices’’ method validations are conducted using operations and should require that the is the appropriate analytical method to two or three laboratories or in a single person who performs the laboratory detect the contaminant which is a processes document, at the time of laboratory by repeating the same test method to detect adulterants of multiple times. Official and nonofficial vegetable origin in spices. Your test performance, that the laboratory method validations use similar methods criteria must specify the processes were performed. If comments performance parameters in conducting component, dietary ingredient, or assert that written procedures are method validations. If an official dietary supplement to be tested, and necessary, comments should include an validated method does not exist in an what specifically to test for, e.g., the explanation of why the requirement is official reference, the method you use identity of the component, dietary necessary to prevent adulteration may be validated by using multiple tests ingredient, or dietary supplement, or a including how such a requirement at your laboratory or multiple specific contaminant. The method would ensure the identity, purity, laboratories performing the same test to criteria must provide detailed quality, strength, and composition of the document that the intended use of the information about performing the dietary ingredient or dietary method is consistently fulfilled. You analysis (i.e., the reagent solutions supplement. Conversely, if comments must validate that the official or needed and their preparation, the type assert that written procedures are not nonofficial method works under your of microscope and other equipment necessary, comments should include an conditions of use in your setting. You required, preparing the sample, and explanation of why the requirement is also should conduct day-to-day examination instructions). The not necessary including how, in the validations of the method that you use, proposed rule would not require that absence of the requirement, one can whether it is an official validated you test for any specific substance and prevent adulteration and ensure the method or a less-formal validated would not require a specific test for a identity, purity, quality, strength, and method, under the conditions of use to substance, so you would be able to composition of the dietary ingredient or ensure that the method will provide the evaluate what the most appropriate test dietary supplement. Further, we seek information you need to ensure that would be for the component, dietary comment on whether any of the your dietary ingredient or dietary ingredient, or dietary supplement and to proposed requirements in this section supplement has the identity, purity, use the test methods that are suited to are not necessary to prevent quality, strength, and composition that your products and your manufacturing adulteration and to ensure the identity, it is supposed to have and is thus not needs. Your test methodology must be purity, quality, strength, and adulterated. Consistent, day-to-day test specific for the component, dietary composition of the dietary ingredient or recoveries for the reference material are ingredient, or dietary supplement and dietary supplement. If comments assert one indicator that the analytical method the specifications you have established. that certain provisions are not is working. There are at least two Proposed § 111.60(b)(2) and (b)(3) necessary, comments should include an references that describe test method would apply to documentation and explanation of why the requirement is validation performance parameters: (1) recordkeeping for your laboratory not necessary including how, in the Performance parameters for operations. Proposed § 111.60(b)(2) absence of the requirement, one can chromatographic methods are described would require the person who conducts prevent adulteration and ensure the in ‘‘Reviewer Guidance, Validation of the testing and examination to identity, purity, quality, strength, and Chromatographic Methods’’ (Center for document, at the time of performance, composition of the dietary ingredient or Drug Evaluation and Research, FDA, that they followed the laboratory dietary supplement. If comments agree November 1994) (Ref. 76); and (2) method and the testing and examination that the proposed requirements are International Conference on results. Proposed § 111.60(b)(3) would necessary for reasons other than those Harmonisation (ICH); Draft Guidance on require that you keep laboratory testing we have provided, the comments should Specifications: Test Procedures and and examination records in accordance so state and provide an explanation.

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7. What Requirements Apply to controls that protect against the or higher sanitary quality water is Manufacturing Operations? (Proposed potential for microorganism growth and necessary for a manufacturing § 111.65) the potential for contamination. This operation. Proposed § 111.65(c)(4) would require Proposed § 111.65 would require that would require that you conduct all that you perform chemical, you take all necessary precautions to operations in receiving, inspecting, microbiological, or other testing, as ensure that, during the manufacturing transporting, segregating, preparing, necessary, to prevent the use of operations, you do not create a source manufacturing, packaging, sorting, and contaminated components, dietary of possible contamination and that packing dietary ingredients and dietary ingredients, and dietary supplements. specifications are consistently achieved. supplements in accordance with You should consider identifying those Under proposed § 111.65(a), you must appropriate and established sanitation areas in the processing and production design or select equipment and procedures. Operations with poor areas where chemical, microbial, or processes to ensure that dietary sanitation in the production and other forms of contamination are most ingredient or dietary supplement processing environment can significantly increase the risk of likely to occur. Chemical, microbial, or specifications are consistently achieved. contaminating components, dietary other testing is necessary to identify Frequently, a computer or system of ingredients, or dietary supplements. areas where sanitation measures have computers may control many or all Pathogenic microorganisms may be not been adequate or where products stages of manufacturing operations such found on the floors and in the drains of may become adulterated. as mixing, producing tablets, and the processing area and on all contact Proposed § 111.65(c)(5) would require packaging. It is important that such surfaces. Without good sanitary that you sterilize, pasteurize, freeze, systems and equipment function as practices, any surface that comes in refrigerate, control hydrogen-ion expected to ensure that the dietary contact with components, dietary concentration (pH), control humidity, ingredient or dietary supplement ingredients, and dietary supplements control water activity, or use any other contains a homogenous mixture, a tablet could be a potential source of microbial effective means to remove, destroy, or that is neither too hard or too friable, contamination. Thus, using appropriate prevent the growth of microorganisms and that the packaging contains the sanitation procedures would provide and to prevent decomposition. The correct dietary ingredient or dietary conditions and controls to protect measures you decide to use to remove, supplement. Equipment used in dietary against potential contamination and destroy or prevent the growth of ingredient or dietary supplement microbial growth. microorganisms on or in your manufacture, packaging, and label Proposed § 111.65(c)(2) would require components, dietary ingredients, or operations must be, for example, of an that you wash or clean components that dietary supplements must be appropriate size and installed properly contain soil or other contaminants. This appropriate under the conditions of in order to produce an unadulterated is a basic sanitation procedure to protect manufacture, handling, and product. If not designed or installed against contamination and microbial distribution. Such measures are properly, the equipment can result in a growth. Raw agricultural materials and necessary to prevent their adulteration variety of problems. For example, a other components that contain soil or and misbranding. Microorganisms mixer for the blending of powdered other contaminants must be washed or include pathogenic bacteria that, if ingredients will not properly perform its cleaned as necessary. Water quality present would adulterate the product. In function if the blade is too small relative used for washing, rinsing, or conveying addition, decomposition may result in a to the size of the mixer or not properly raw agricultural materials must be change in the component, dietary placed inside of the mixer. Such a mixer adequate for its intended use, both at ingredient, or dietary supplement may produce an adulterated product the start and at the end of the processing strength; the consequence of not using because the dietary supplement, for operation, and should not contribute to the appropriate measure may be that the example, is not of uniform composition the contamination of such materials. dietary ingredient or dietary supplement and therefore would not be able to meet Proposed § 111.65(c)(3) would require no longer meets specifications, and the specifications for purity, quality, that you use water that meets the EPA’s thus, would be adulterated under strength, or composition in the final NPDW regulations or, where necessary, section 402(g) of the act and misbranded product. Thus, equipment design and higher sanitary quality and that under section 403 of the act. By selection is critical to ensure that you complies with all applicable Federal, including the phrase, ‘‘any other manufacture an unadulterated dietary State, and local regulations for water effective means,’’ we provide you with ingredient or dietary supplement. that is used in the manufacturing discretion to decide which measures to Proposed § 111.65(b) would require operation. If you reuse water that was use to destroy or prevent the growth of that you conduct all manufacturing used to remove soil or contaminants microorganisms and to prevent operations in accordance with adequate from components, the proposal would decomposition. sanitation principles. We discussed the require that the reused water be safe and Proposed § 111.65(c)(6) would require importance of having adequate of adequate sanitary quality so that it that you hold components, dietary sanitation earlier and related it to the does not become a source of ingredients, and dietary supplements use of sanitary practices for employees, contamination. Some manufacturing that can support the rapid growth of physical plant, and equipment. operations may require water of a higher microorganisms of public health Proposed § 111.65(c)(1) through sanitary quality than water that meets significance in a manner that prevents (c)(11) would require that you take all the NPDW regulations. For example, the them from becoming adulterated. the necessary precautions during the fluoride or chloride levels in water Proposed § 111.65(c)(7) would require manufacture of dietary ingredients and meeting the NPDW regulations may that you identify and hold any dietary supplements to prevent interfere with certain capsule or tablet components, dietary ingredients, and contamination of components, dietary operations and a higher quality water dietary supplements, that require a ingredients, and dietary supplements. such as distilled water may be material review and disposition Proposed § 111.65(c)(1) would require necessary. This proposed requirement decision, in a manner that protects the that you perform manufacturing allows the manufacturer discretion in components, dietary ingredients, and operations under conditions and determining whether NPDW regulations dietary supplements against

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contamination and mixups. A dietary stated that manufacturers typically are make a disposition decision in ingredient or dietary supplement under able to identify the particular piece of accordance with proposed § 111.35(i) this proposed rule would require a equipment that is the source of the for any component, dietary ingredient, material review and disposition metal contamination. or dietary supplement that fails to meet decision when the components, dietary We disagree with the comment. The specifications or that is, or may be, ingredients, or dietary supplements purpose behind proposed § 111.65(c)(9) adulterated. If the material review and deviate from specifications. As is to ensure that no metal or foreign disposition decision allows you to previously explained, the specifications material becomes a source of possible reprocess the component, dietary contamination and not to establish established as production and process ingredient, or dietary supplement, mechanisms to be used after controls under proposed subpart E of proposed § 111.65(d) would require that part 111, are regulatory specifications. contamination has or is suspected to you retest or reexamine it to ensure that Thus, a deviation from such a have occurred. We believe that the most specification means that the practical way to protect against the it meets specifications and is approved components, dietary ingredients, or inclusion of metal and foreign material by the quality control unit. dietary supplements may be is to require that you use effective The person who performs the material adulterated. Any component, dietary measures during the manufacturing review and disposition review required ingredient, or dietary supplement that operations. The source of metal in accordance with this section would may be adulterated must be segregated contamination is not limited to be required to document at the time of from such material that meets equipment and we previously performance the results of the material specifications so that it does not become emphasize the need to maintain review and disposition decision. In a source of contamination. The proposal equipment to prevent such accordance with § 111.50(d), such would require that you hold these contamination. Metal contamination documentation must be maintained components, dietary ingredients, and also may occur during harvesting of with the batch production record. dietary supplements in a manner that natural products and use of utensils protects against contamination and such as metal brushes. Therefore, We invite comment on whether we mixups. because we believe that it is not possible should require, in a final rule, that you Proposed § 111.65(c)(8) would require to identify and eliminate all possible establish and follow written procedures that you perform mechanical sources of metal contamination or to to implement the manufacturing manufacturing steps (such as cutting, determine when measures would be operations required in proposed sorting, inspecting, shredding, drying, necessary to eliminate such § 111.65. If comments assert that written grinding, blending, and sifting) by any contamination, proposed § 111.65(c)(9) procedures are necessary, comments effective means to protect the dietary would require that you use effective should include an explanation of why ingredients or dietary supplements measures to protect against the the requirement is necessary to prevent against contamination. Such steps must inclusion of metal and foreign material adulteration including how such a include consideration of cleaning and for all your manufacturing operations. requirement would ensure the identity, sanitizing contact surfaces, using Proposed § 111.65(c)(10) would purity, quality, strength, and temperature controls, and using time require that you segregate and identify composition of the dietary ingredient or all containers for a specific batch of controls. For example, when blending dietary supplement. Conversely, if components, if you use a mixer that has dietary ingredients or dietary comments assert that written procedures not been cleaned and sanitized, your supplements to identify their contents are not necessary, comments should blended material may become and, where necessary, the phase of contaminated with microorganisms, manufacturing. This proposed include an explanation of why the including microbial pathogens. Thus, it requirement is intended to protect requirement is not necessary including is important to clean and sanitize your ingredients or dietary supplements from how, in the absence of the requirement, mixer before use. potential contamination or misuse one can prevent adulteration and ensure Proposed § 111.65(c)(9) would require during manufacturing or storage. the identity, purity, quality, strength, that you use effective measures, such as Identifications of these items will enable and composition of the dietary filters, traps, magnets, or electronic you to determine accurately the status of ingredient or dietary supplement. metal detectors, to protect against the all batches of dietary ingredients or Further, we seek comment on whether inclusion of metal or other foreign dietary supplements during all stages of any of the proposed requirements in this material in your components, dietary the manufacturing process, will help to section are not necessary to prevent ingredients, or dietary supplements. prevent mixups in the addition of adulteration and to ensure the identity, This proposed requirement is intended components or dietary ingredients to the purity, quality, strength, and to exclude foreign and extraneous dietary supplement and will facilitate composition of the dietary ingredient or matter that would contaminate prompt action if any problems in dietary supplement. If comments assert components, dietary ingredients, or processing are identified. that certain provisions are not dietary supplements. The purpose of Proposed § 111.65(c)(11) would necessary, comments should include an this proposed requirement is not to require that you identify all processing explanation of why the requirement is exclude dietary ingredients that are lines and major equipment used during not necessary including how, in the intended to be used and that are of manufacturing and to indicate their absence of the requirement, one can mineral origin. contents, including the name of the One comment to the ANPRM dietary ingredient or dietary supplement prevent adulteration and ensure the suggested that we require the use of and the specific batch or lot number identity, purity, quality, strength, and effective measures to protect against the and, when necessary, the phase of composition of the dietary ingredient or inclusion of metal or other extraneous manufacturing. The same reasons given dietary supplement. If comments agree material in dietary products when there for proposed § 111.65(c)(10) apply to that the proposed requirements are is reason to suspect that the product is this proposed requirement. necessary for reasons other than those contaminated by metal or other Proposed § 111.65(d) would require we have provided, the comments should extraneous material. The comment that you conduct a material review and so state and provide an explanation.

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8. What Requirements Apply to equipment can help you avoid some • Identifying, by any effective means, Packaging and Label Operations? common mistakes that can adulterate filled dietary ingredient or dietary (Proposed § 111.70) your products. For example, in one case, supplement containers that are set aside Proposed § 111.70 would establish a consumer complained about receiving and held in unlabeled condition for requirements for your packaging and two different sized capsules in a bottle future label operations, to prevent label operations. The correct use of labeled as containing acidophilus mixups; • Identifying the dietary ingredient or packaging and labels can affect whether capsules. We conducted an dietary supplement with a batch, lot, or your product is adulterated. For investigation and found that the control number that can be used to example, if a packaging material, manufacturer had received a similar determine the manufacturing history intended only for use with a dry report from a different consumer (Ref. and control of the batch. Using a unique product, is used to package a liquid, 77). We analyzed the capsules and identifier for each batch or lot is unsafe substances could migrate from found that the smaller capsules were not necessary for you to trace the the packaging to the liquid, and acidophilus capsules but contained levels of stannous fluoride that would manufacturing history for a particular adulterate your dietary ingredients or batch, and thus help you investigate and dietary supplements. In addition, if you cause convulsions in certain persons and even exceeded the lethal dose in correct any safety problems for a batch apply the wrong label, your product or to recall a dietary ingredient or would be adulterated under section small children. We also collected unopened bottles of the acidophilus dietary supplement batch. For example, 402(g) of the act because your label must if you discovered a particular batch had be that which is specified in the master product and, after opening the product, found different sized capsules. The a safety problem, you could recall the manufacturing record. In addition, your batch by identifying the batch number product would be misbranded under presence of smaller capsules containing stannous fluoride mixed in with the for the problem product. If you did not section 403 of the act. have a unique identifier, consumers Proposed § 111.70(a) would require larger acidophilus capsules adulterated the product. The fact that these small would be unable to determine which that you take necessary actions to product was the subject of a recall, and ensure each packaging container for stannous fluroride capsules mixed in with the larger acidophilus capsules they may not stop using the product or holding dietary ingredients or dietary you will have to recall more of the supplements meets its specifications so indicated that the manufacturer had not cleaned the filling equipment properly. product. that the packaging container’s condition • Examining a representative sample In another case, consumer complaints will not contaminate your dietary of the packaged and labeled dietary about a vitamin C product prompted us ingredients or dietary supplements or ingredient or dietary supplement to and the product’s manufacturer to cause them to deteriorate. As previously ensure that it meets specifications and investigate the product (Ref. 78). We stated in the discussion of proposed that the label specified in the master both discovered that the products § 111.35(e)(4), you must establish manufacturing record has been applied; contained niacin instead of vitamin C, specifications for packaging materials and that may come in contact with dietary and the problem was the result of a • Suitably disposing of labels and ingredients or dietary supplements. failure to clean out the packaging other packaging for dietary ingredients Meeting such specifications would equipment so that niacin that had been or dietary supplements that are obsolete ensure that the packaging that is used is left in the packaging equipment was put or incorrect to ensure that they are not safe and suitable for the intended use into the capsules during the used in any future packaging and label and meets all of the statutory and manufacturing operation for the vitamin operations. The use of any obsolete or regulatory requirements under the act. C product. The manufacturer reviewed incorrect label would adulterate the In that way, the packaging materials will its packing operations and instructed its product because it would not comply not adulterate the dietary ingredient or personnel at the manufacturing plant to with the requirement that the correct dietary supplement. This proposed prevent this problem from reoccurring. label as specified in the master • requirement would give you the Protecting manufactured dietary manufacturing record be used. discretion to establish the specifications ingredients and dietary supplements Proposed § 111.70(c) would require for each packaging container, and would from contamination, particularly that you conduct a material review and require that these specifications are airborne particulates such as dust, dirt, make a disposition decision of any routinely met. For example, if your or microbes that may contaminate your packaged and labeled dietary product is sensitive to light, you would product when your product is exposed ingredients or dietary supplements that choose a container that protects the to the environment. do not meet specifications. If packaged product from the light so that it does not • Using sanitary handling procedures. and labeled dietary ingredients or deteriorate. • Establishing physical or spatial dietary supplements do not meet Proposed § 111.70(b) would require separation of packaging and labels from specifications, it means that there is a that you fill, assemble, package, and operations on other dietary ingredients problem and that the dietary ingredient perform other related operations in a and dietary supplements to prevent or dietary supplement may be or is way that protects your dietary mixups. It is important to keep adulterated and this step is needed to ingredients or dietary supplements inprocess material separate from determine what to do and how to against adulteration and misbranding. finished product that is ready to be handle the product to ensure that it does The proposal would require that you packaged and labeled so that inprocess not get distributed. use any effective means to do this, material is not inadvertently packaged Sometimes problems arise because a which would include: and labeled as finished product. In manufacturer used the wrong label on a • Cleaning and sanitizing all filling addition, this proposed requirement particular ingredient. For example, in and packaging equipment, utensils, and would prevent mixup of one type of one case, an ingredient manufacturer dietary ingredient or dietary supplement dietary ingredient with another type of put the wrong label on its product so containers, as appropriate. This is dietary ingredient during packaging and that a product labeled as containing zinc important because cleaning and label operations such as the vitamin C picolinate actually contained zinc sanitizing all filling and packaging and niacin mixup described earlier. polynicotinate (Ref. 79). The dietary

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ingredient went to another manufacturer As another example, controlling written procedures for packaging and who, believing that the product was access of labels can help identify label operations that implement the zinc picolinate, used the dietary instances when mislabeling may have requirements of this section. If ingredient to make its dietary occurred. If you issue only the necessary comments assert that written procedures supplement. The error was discovered number of labels to cover a particular are necessary, comments should include after consumers who used the product production run but use fewer labels an explanation of why the requirement started complaining of adverse reactions than expected even though you labeled is necessary to prevent adulteration that are associated with niacin the expected number of containers for including how such a requirement supplements, but the problem could the production run, this discrepancy would ensure the identity, purity, have been avoided if the dietary would suggest that you used some quality, strength, and composition of the ingredient manufacturer had taken steps wrong labels during the run and that dietary ingredient or dietary to ensure that the correct labels were you should conduct an investigation to supplement. Conversely, if comments used. determine the cause of, or reconcile the assert that written procedures are not Proposed § 111.70(d) would require discrepancy. necessary, comments should include an that you repackage or relabel dietary Proposed § 111.70(f)(2) would require explanation of why the requirement is ingredients or dietary supplements if that you must examine carefully, before not necessary including how, in the approved and appropriately packaging operations, packaging and absence of the requirement, one can documented by your quality control labels for each batch of dietary prevent adulteration and ensure the unit. The quality control unit would ingredient or dietary supplement to identity, purity, quality, strength and need to decide whether the improperly ensure that the label and packaging composition of the dietary ingredient or packaged product was adulterated by conform to the master manufacturing dietary supplement. Further, we seek the incorrect package and could be record. comment on whether any of the repackaged and relabeled without Proposed § 111.70(g) would require proposed requirements in this section reprocessing of the dietary ingredient or that the person who performs the are not necessary to prevent dietary supplement. requirement established in accordance adulteration and to ensure the identity, Proposed § 111.70(e) would require with this section document, at the time purity, quality, strength, and that you retest or reexamine any of performance, that he or she composition of the dietary ingredient or repackaged or relabeled dietary performed the requirement. This would dietary supplement. If comments assert ingredients or dietary supplements. include, but not be limited to, that certain provisions are not They must meet all specifications and documentation in the batch production necessary, comments should include an the quality control unit must approve or record of: explanation of why the requirement is reject their release for distribution. The • The identity and quantity of the not necessary including how, in the reason this is necessary is to ensure for packaging and labels used and absence of the requirement, one can example, by testing or examination, that reconciliation of any discrepancies prevent adulteration and ensure the the repackaged or relabeled product between issuance and use; identity, purity, quality, strength, and meets specifications and that the • The examination of a representative composition of the dietary ingredient or container in which the product is sample (as proposed § 111.70(b)(7) dietary supplement. If comments agree repackaged meets specifications. would require); that the proposed requirements are • Proposed § 111.70(f)(1) would require The conclusions you reached from necessary for reasons other than those that you control the issuance and use of retests conducted under proposed we have provided, the comments should packaging and labels and reconcile the § 111.70(e); and so state and provide an explanation. issuance and use of discrepancies. It is • Any material reviews and important to control access to the disposition decisions for packaging and 9. What Requirements Apply to Rejected storage of packaging and labels; for labels. Components, Dietary Ingredients, example, only the labels that are Proposed § 111.70(h) would require Dietary Supplements, Packaging, and required for current label operations that you keep the packaging and label Labels? (Proposed § 111.74) should be issued to prevent issuance of operations records required under this Proposed § 111.74 is intended to any incorrect labels during the label section established in accordance with ensure that you do not mistakenly use operation. Using batch or lot numbers proposed § 111.125. These records are rejected materials that are determined on your labels may be one control necessary to ensure that the correct by the quality control unit to be method. Batch or lot numbers also help packaging and label, i.e., the packaging unsuitable for use to make a dietary you (and us) to identify a particular and label specified by the master ingredient or dietary supplement. product and to trace that product’s manufacturing record, were used in and Proposed § 111.74(a) would require manufacturing history through your applied to the batch of dietary that you clearly identify, hold, and CGMP records. They can help identify ingredient or dietary supplement. These control, under a quarantine system any which products are affected by a records together with the master component, dietary ingredient, dietary product recall, if a recall is necessary, manufacturing records and batch supplement, packaging, and label that is and this can help preserve consumer production records will ensure that a rejected and unsuitable for use in confidence in your product. complete history of each batch of manufacturing, packaging, or label For example, if a recall covers batch dietary ingredient or dietary supplement operations. The term ‘‘control under a A123, and a particular consumer has a including use of the correct packaging quarantine system’’ indicates that you product whose batch number is C456, and label is available for your review in must prevent the use of any rejected he or she will know that the product is the event that a problem arises with a component, dietary ingredient, dietary not covered by the recall. In contrast, if particular batch. These records also are supplement, packaging, or label because no batch numbers appear on the product necessary to demonstrate compliance such rejected product is unsuitable for label, the consumer would not be able with the CGMP and quality control use. For example, under this proposed to tell whether his or her product is procedures. We invite comment on rule, if a component, dietary ingredient, covered by the recall and may continue whether we should require, in a final or dietary supplement is rejected and to use it. rule, that you establish and follow determined by the quality control unit

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to be unsuitable for use, such material the components, dietary ingredients, or explanation of why the requirement is would be adulterated and not be dietary supplements. For example, dried necessary to prevent adulteration suitable for reprocessing. Therefore, to plants stored in a hot, humid warehouse including how such a requirement prevent contamination of nonrejected may become moldy. Mold would ensure the identity, purity, material, you must quarantine the contamination could adversely affect quality, strength, and composition of the rejected material before disposal. The the purity of the dietary ingredients and dietary ingredient or dietary proposed rule would not specify any dietary supplements you manufacturer. supplement. Conversely, if comments particular mechanism for how you You will decrease the chances of mold assert that written procedures are not quarantine the material, instead, you contaminating your dried plants if you necessary, comments should include an control temperature and humidity. would have discretion in deciding what explanation of why the requirement is Proposed § 111.80(b) would require actions to take or what process to use. not necessary including how, in the You also should note that, by referring that you hold packaging and labels absence of the requirement, one can to items that are rejected and unsuitable under appropriate conditions of prevent adulteration and ensure the for use, proposed § 111.74(a) excludes temperature, humidity, and light so that items that can be reprocessed and made the quality of the packaging and labels identity, purity, quality, strength, and suitable for use. Those items that can be are not affected. For example, some composition of the dietary ingredient or reprocessed and made suitable for use plastics become brittle when exposed to dietary supplement. are dealt with in proposed § 111.82. extreme temperatures. If brittle plastic 2. What Requirements Apply to Holding containers are used to hold dietary Inprocess Material? (Proposed § 111.82) F. Holding and Distributing (Proposed ingredients or dietary supplements, they Subpart F) could crack or break, thereby losing Proposed § 111.82 discusses proposed 1. What Requirements Apply to Holding their protective qualities, and lead to requirements for holding inprocess Components, Dietary Ingredients, contamination or deterioration of the material. Proposed § 111.82 would Dietary Supplements, Packaging, and dietary ingredient or dietary require that you segregate any inprocess Labels? (Proposed § 111.80) supplement. You need to know the material that does not meet your conditions of temperature, humidity, specifications, is awaiting further Proposed § 111.80 would require that and light that are appropriate for your processing, or needs further evaluation you hold dietary ingredients and dietary packaging and labels and you need to by the quality control unit (e.g., because supplements under conditions that will hold the packaging and labels under protect them against contamination and such conditions. the inprocess material does not meet deterioration. Proposed § 111.80(a) Proposed § 111.80(c) would require specifications, or because of an would require that you hold that you hold components, dietary unexpected occurrence) to determine if components, dietary ingredients, and ingredients, dietary supplements, it is suitable for reprocessing. dietary supplements under appropriate packaging, and labels under conditions Proposed § 111.82(a), therefore, would conditions of temperature, humidity, that do not lead to mixup, require that you identify and hold and light so that the identity, purity, contamination, or deterioration of the inprocess material under conditions that quality, strength, and composition of the components, dietary ingredients, dietary will protect such material against components, dietary ingredients, and supplements, packaging, and labels. For mixup, contamination, and dietary supplements are not affected. example, your holding conditions must deterioration. This proposed provision includes the include a system for identifying holding of components, dietary container contents and its status (e.g., Proposed § 111.82(b) would require ingredients, dietary supplements in segregated, approved for use) in a that you hold inprocess material under your physical plant and at any point in manner that prevents mixup or use of appropriate conditions of temperature, the distribution process, however, we unsuitable materials in manufacturing. humidity, and light. The intent here is would not extend the holding Further, the presence of rodents in your to prevent any contamination or requirements under this proposed holding area may cause contamination deterioration of that inprocess material. CGMP regulation to retail or deterioration of components, dietary We invite comment on whether we establishments, but would defer to State ingredients, dietary supplements, should require, in a final rule, that you and local governments for regulating packaging, and labels. Therefore, your establish and follow written procedures operations that provide dietary holding conditions must be rodent-free. for holding inprocess material. If supplements to retail for sale to the Moreover, rodents in your holding area comments assert that written procedures consumer. However, if a retail holding would adulterate your dietary are necessary, comments should include area is filthy, we would not be ingredient or dietary supplement under an explanation of why the requirement prevented from taking an enforcement section 402(g) of the act. Holding is necessary to prevent adulteration action under a legal authority other than conditions that prevent mixup, including how such a requirement section 402(g) of the act. contamination, or deterioration of would ensure the identity, purity, This requirement would ensure that components, dietary ingredients, dietary products are not contaminated while supplements, packaging, or labels are quality, strength, and composition of the they are held by the manufacturer, the necessary to prevent the production of dietary ingredient or dietary wholesaler, or while being held at a an adulterated dietary ingredient or supplement. Conversely, if comments warehouse. This would increase the dietary supplement. assert that written procedures are not likelihood that the products consumers We invite comment on whether we necessary, comments should include an purchase have the same quality as when should require, in a final rule, that you explanation of why the requirement is they left the manufacturer. Note that establish and follow written procedures not necessary including how, in the proposed § 111.80(a) uses the words for holding components, dietary absence of the requirement, one can ‘‘not affected;’’ this means that the ingredients, dietary supplements, prevent adulteration and ensure the conditions under which you hold packaging, and labels. If comments identity, purity, quality, strength, and components, dietary ingredients, and assert that written procedures are composition of the dietary ingredient or dietary supplements must not adulterate necessary, comments should include an dietary supplement.

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3. What Requirements Apply to Holding dietary supplement to show that it is your manufacturing processes and those Reserve Samples of Components, ‘‘returned.’’ We would require that you other batches if the reason for a dietary Dietary Ingredients, and Dietary identify and quarantine (not just ingredient or a dietary supplement Supplements? (Proposed § 111.83) identify and segregate) returned dietary being returned implicates other batches. Earlier, we discussed a provision ingredients or dietary supplements so The point of the investigation would be concerning the collection of reserve that they cannot be used. We propose to to determine whether, for example, the samples. Proposed § 111.50(h) would require that you quarantine returned other implicated batches may have the require that you collect representative products because you must assume that same problem or have been subject to the returned product is adulterated until the same problematic manufacturing reserve samples of each batch of dietary tests show otherwise. Thus, the product process for which the dietary ingredient ingredient or dietary supplement. should not have physical closeness or or dietary supplement was returned. Proposed § 111.83 would set forth contact with nonreturned product to Other batches may be implicated if the requirements for holding any reserve ensure that it will not be mixed up component or dietary ingredient used in samples collected. mistakenly with nonreturned product, Proposed § 111.83(a) would require the returned product also was used in redistributed or reused in that you hold any reserve samples of additional batches or if your manufacturing. investigation indicates that there was a components or dietary ingredients Proposed § 111.85(b)(1) states that you collected in a manner that protects problem with a step in the may salvage returned dietary manufacturing process that affected against contamination and deterioration. ingredients and dietary supplements Proposed § 111.83(b) would require additional batches. The proposal also only if: would require that you document the that you hold such reserve samples of • Evidence from their packaging (or, investigation and include your dietary supplements in a manner that if possible, an inspection of the protects against contamination and conclusions and followup. premises where the dietary ingredients Proposed § 111.85(e) would require deterioration. Further, this provision and dietary supplements were held) you to establish and keep records for would require that you hold the reserve indicates that the dietary ingredients any material review and disposition samples under conditions of use and dietary supplements were not decision and any required testing to recommended or suggested in the label subjected to improper storage determine compliance with of the dietary supplement and, if no conditions. This would require that you specifications done for any returned conditions of use are recommended or have personal knowledge of the exact dietary ingredient or dietary suggested in the label, then under conditions under which the returned supplement. You should include the ordinary conditions of use. This dietary ingredients or dietary following information in your records: proposed requirement also would supplements were held. Normally, for • The name of the person or company require that you use the same container- most types of packaging, simply or both the name of the person and closure system in which the dietary examining the packaging will not tell company who returned the dietary supplement is marketed or one that you about the storage conditions that ingredients or dietary supplements; provides the same level of protection existed. However, we are aware of some • A description of the returned against contamination or deterioration technologies that are being used, such as dietary ingredient or dietary as the marketed container-closure temperature-sensitive materials that supplement; system. It is necessary to hold the change colors, that could provide some • The batch or lot number of the reserve sample of a dietary supplement information about storage conditions; returned dietary ingredient or dietary under the same conditions and in the and supplement and any reprocessed batch same packaging as you would expect a • Tests demonstrate that the dietary or batch manufactured using the consumer to hold that dietary ingredients or dietary supplements meet returned dietary ingredient or dietary supplement so that, if you need to later all specifications for identity, purity, supplement; test that reserve sample, the testing quality, strength, and composition. This • The reason for the return; would reflect current conditions under requirement will ensure that you do not • The quantity returned; which the dietary supplement is held by return to distribution a dietary • The disposition of the dietary the consumer prior to being consumed. ingredient or dietary supplement that ingredient or dietary supplement; and • The date of disposition. 4. What Requirements Apply to does not meet specifications. Salvage is available for only those products for Proposed § 111.85(f) would require Returned Dietary Ingredients or Dietary that you make and keep records for Supplements? (Proposed § 111.85) which testing can be performed on finished product. returned dietary ingredients and dietary Proposed § 111.85 would establish For purposes of this discussion, supplements in accordance with requirements for returned dietary ‘‘salvage’’ means to return to § 111.125. These records are necessary ingredients or dietary supplements. distribution without reprocessing the to ensure that returned products that ‘‘Returned’’ dietary ingredients or dietary ingredient or dietary could be adulterated are not dietary supplements are those products supplement. inadvertently redistributed or that a distributor, wholesaler, or retailer Proposed § 111.85(c) would require inadvertently used in manufacturing. returns to a manufacturer. Proposed that you destroy or suitably dispose of Further, records of any reprocessed § 111.85(a) would require that you the returned dietary ingredients or batch or batch manufactured using the identify returned dietary ingredients or dietary supplements if they do not meet returned product will be useful in the dietary supplements and to quarantine specifications for identity, purity, event that a problem arises with a them until your quality control unit quality, strength, and composition, particular batch that is manufactured conducts a material review and makes a unless the quality control unit conducts with returned product. These records disposition decision. (Your quality a material review and makes a also are necessary to demonstrate control unit would do this under disposition decision to allow compliance with the CGMP and quality proposed § 111.37.) For example, you reprocessing. control procedures. We invite comment could attach a tag or other identifier on Proposed § 111.85(d) would require on whether we should require, in a final the returned dietary ingredient or that you conduct an investigation of rule, that you establish and follow

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written procedures for identifying, dietary supplements should take steps determine whether an investigation of quarantining, and salvaging returned to ensure that their shipments are the complaint is necessary. dietary ingredients and dietary obtained from manufacturers that follow Proposed § 111.95(a) would require supplements. If comments assert that these proposed CGMP requirements. that you have a qualified person review written procedures are necessary, In addition, these proposed CGMPs all consumer complaints to determine comments should include an would apply to manufacturers who whether the consumer complaint explanation of why the requirement is export their dietary ingredient or dietary involves a possible failure of a dietary necessary to prevent adulteration supplement, unless exported in ingredient or dietary supplement to including how such a requirement compliance with section 801(e) of the meet any of its specifications, or any would ensure the identity, purity, act. Section 801(e)(1) of the act states other requirements of this part, quality, strength, and composition of the that a food intended for export must not including those specifications and other dietary ingredient or dietary be deemed to be adulterated or requirements that, if not met, may result supplement. Conversely, if comments misbranded under the act if it: in a possible risk of illness or injury. A assert that written procedures are not • Accords to the foreign purchaser’s ‘‘qualified person’’ would be a person necessary, comments should include an specifications; who has the training and experience to explanation of why the requirement is • Is not in conflict with the laws of determine whether a complaint not necessary including how, in the the country to which it is intended for represents a possible failure of a dietary absence of the requirement, one can export; ingredient or dietary supplement to prevent adulteration and ensure the • Is labeled on the outside of the meet any of the requirements in this identity, purity, quality, strength, and shipping package that it is intended for part, or represents a possible risk of composition of the dietary ingredient or export; and illness or injury that is unrelated to such dietary supplement. • Is not sold or offered for sale in failure. The qualified person’s review is domestic commerce. important for distinguishing between 5. What Requirements Apply to Dietary ingredients and dietary those consumer complaints that your Distributing Dietary Ingredients or supplements for export are subject to quality control unit must review and Dietary Supplements? (Proposed section 801(e)(1) of the act and would be those consumer complaints that § 111.90) subject to the notification and represent a consumer’s dissatisfaction Proposed § 111.90 would establish recordkeeping requirements of § 1.101 with a dietary ingredient or dietary requirements concerning the (21 CFR 1.101) and you would be supplement that is unrelated to a distribution of dietary ingredients and required to comply with the export possible failure to meet specifications dietary supplements. Proposed requirements of § 1.101. that would be required by this proposal, § 111.90(a) would require any We invite comment on whether we or any other requirement in this part. distribution of dietary ingredients or should require, in a final rule, that you For example, some consumer dietary supplements to be under make and keep records on the complaints about quality may simply conditions that will protect them from distribution of dietary ingredients and express a personal dislike of the taste, contamination and deterioration. This is dietary supplements that you color, odor, or size of tablet, which to protect dietary ingredients and manufacture, package, or hold. would probably not require your quality dietary supplements from distribution G. Consumer Complaints—What control unit to review them. As stated practices that may adulterate them. Requirements Apply to Consumer earlier, consumer complaints related to As discussed previously, proposed an illness or injury related to a part 111 also would apply to foreign Complaints? (Proposed Subpart G, § 111.95) pharmacologically active substance of a firms that manufacture, package, or hold particular dietary ingredient, such as dietary ingredients and dietary Proposed § 111.95 would establish aristolochic acid, would not be a supplements that are imported or requirements for receiving and handling consumer complaint within the offered for import into the United consumer complaints. Consumer meaning of that term in this proposal States, unless imported for further complaints can be helpful in alerting and thus would not be of the type that processing and export under section you to possible manufacturing and the quality control unit must review 801(d)(3) of the act. It also would apply safety problems associated with your under this proposed rule. to persons who distribute imported dietary ingredients or dietary Proposed § 111.95(b) would require dietary ingredients and dietary supplements. that your quality control unit review all supplements, and to persons who export As stated in § 111.3, consumer consumer complaints involving the dietary ingredients and dietary complaint refers to a possible failure of possible failure of a dietary ingredient supplements from the United States a dietary ingredient or dietary or dietary supplement to meet any of its unless exported in compliance with supplement to meet any of the specifications, or any of the other section 801(e) of the act. requirements of this part, including requirements in this part, including We recognize that the safety of dietary those that, if not met, may result in a those specifications and other supplements cannot be adequately possible risk of illness or injury. requirements that, if not met, may result ensured if the imports are not subject to Proposed § 111.95(e) would require that in a possible risk of illness or injury, to the same controls as domestic products. you keep a written record of every determine whether there is a need to In addition, we believe that the importer consumer complaint that is related to investigate the consumer complaint. who distributes a foreign product good manufacturing practices. Thus, When there is a reasonable possibility of should share responsibility with the whether the complaint was sent by a relationship between the quality of a foreign manufacturer for safety. More regular mail, electronic mail, or any dietary supplement and an adverse often than not, it is a U.S. importer, other form of written communication, or event, such as a report of an illness or rather than the foreign manufacturer, whether received orally, you would be injury that may be due to a wrong who actually distributes imported required to keep a written record of each ingredient or wrong label, then the dietary supplements for sale in the consumer complaint. You should manufacturer would be required to do United States. Thus, we believe that include all information that would an investigation that includes both importers of dietary ingredients or allow your quality control unit to batch records associated with the

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dietary ingredient or dietary supplement health. However, a consumer complaint complaint because the manufacturer involved in the consumer complaint. does not include an adverse event, may not be aware of possible problems However, if the quality control unit illness, or injury related to the safety of associated with its products. determines that an investigation is a particular dietary ingredient Proposed § 111.95(f) addresses unnecessary, it would be helpful to you independent of whether the product is documentation and recordkeeping. if your quality control unit documents produced under good manufacturing Consumer complaints can alert you (and why an investigation was not necessary. practices. The consumer complaint us) to potential quality problems with a This information would be useful to you written record must include, but is not product that is related to good because it could save time if you receive limited to, the following: manufacturing practices, such as cases additional similar consumer complaints • The name and description of the where the manufacturer used the wrong about a particular product. dietary ingredient or dietary ingredient or put the wrong label on a Proposed § 111.95(c) would require supplement; product. A prudent manufacturer, that your quality control unit investigate • The batch or lot number of the therefore, must investigate any a consumer complaint when there is a dietary supplement, if available; complaints regarding its products reasonable possibility of a relationship • The complainant’s name, if because the results of its investigations between the quality of a dietary available; might lead to solutions or improvements supplement and an adverse event. For • The nature of the complaint, that will make the product or example, if a manufacturer uses too including how the consumer used the manufacturing process better and much of a dietary ingredient in a dietary product; benefit the manufacturer and • supplement (e.g., 400 to 4,699 µg of The reply to the complainant, if consumers. µ any; and Proposed § 111.95(f)(1) would require selenium instead of 200 g of selenium), • it is a manufacturing error that may Findings of the investigation and the person who performs the result in an adverse event. Further, if a followup action taken when an requirement established in accordance communication alleges consumer investigation is performed. with this section to document, at the dizziness, vomiting, or lightheadedness We suggest that you report the time of performance, that he or she after consuming several dietary consumer complaint and the performed the requirement. supplements, it is a adverse event report investigation results to us when there is Finally, proposed § 111.95(f)(2) would that is worthy of quality control unit a possibility of a relationship between require that you keep consumer investigation. the consumption of a dietary complaint records established in Proposed § 111.95(d) would describe supplement and a serious adverse event. accordance with proposed § 111.125. what the quality control unit’s While the proposal would not require These records are necessary for investigation must include. In brief, the that you submit these reports, we handling consumer complaints in a quality control unit’s investigation of a strongly suggest that you do so because manner that ensures that an consumer complaint must include the we may have additional expertise or unanticipated problem with a dietary batch records associated with the data that may be helpful in investigating ingredient or dietary supplement is dietary ingredient or dietary supplement the complaint or determining whether reviewed and investigated. These involved in the consumer complaint. the problem applies to more than one records also are necessary to The quality control unit must extend the product. We suggest that you submit demonstrate compliance with the investigation to other batches of dietary these reports within 15 days after you CGMP. ingredients or dietary supplements that receive such information to the FDA We invite comment on whether we may have been associated with a failure MedWatch program by calling our should require, in a final rule, that you to meet a specification or any other ‘‘MedWatch’’ program (our database for establish and follow a written procedure requirements of this part. When there is reporting possible adverse events) at 1– for receiving, reviewing, and a possible product defect or failure, we 800–FDA–1088 (1–800–332–1088) to investigating consumer complaints. If recommend that the investigation request that a reporting form (one-page, comments assert that written procedures include laboratory testing of the dietary return postage paid) and instructions on are necessary, comments should include ingredient or dietary supplement how to complete the form be mailed to an explanation of why the requirement because you will need the test results to you, downloading a form and is necessary to prevent adulteration determine if specifications or instructions from the MedWatch including how such a requirement requirements for the dietary ingredient Internet site at http://www.fda.gov, or would ensure the identity, purity, or dietary supplement were not met. using the interactive form available on quality, strength, and composition of the Complaints such as those that involve the MedWatch Internet site at http:// dietary ingredient or dietary serious adverse events should include www.fda.gov. supplement. Conversely, if comments followup by a health care provider. For Further, we suggest that you report a assert that written procedures are not other types of complaints, neither consumer complaint even if you are not necessary, comments should include an laboratory nor medical investigation the manufacturer of a dietary ingredient explanation of why the requirement is may be necessary because the product or dietary supplement and only package not necessary including how, in the defect or failure may be identified by or distribute a dietary ingredient or absence of the requirement, one can reviewing batch documents or the dietary supplement if you receive a prevent adulteration and ensure the consumer complaint may not involve a consumer complaint that may be related identity, purity, quality, strength, and serious adverse event. to the manufacture of the dietary composition of the dietary ingredient or Proposed § 111.95(e) would require ingredient or dietary supplement. dietary supplement. that you make and keep a written record Sometimes consumers submit of every consumer complaint that is complaints to the person who H. Records and Recordkeeping—What related to good manufacturing practices. distributes a product or the person who Requirements Apply to Recordkeeping? For the purposes of this regulation, a is listed on the package label. If this (Proposed Subpart H, § 111.125) consumer complaint about product happens, you should notify the Throughout this discussion of the quality may or may not include manufacturer of the dietary ingredient proposed rule, some provisions have concerns about a possible hazard to or dietary supplement of the consumer included a paragraph that would require

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that you keep records established in • Sections as questions and answers ‘‘prescribe good manufacturing practices accordance with proposed § 111.125. to focus sections better; and for dietary supplements.’’ Other relevant Proposed § 111.125 would establish • Personal pronouns to reduce legal authority is discussed in section II general recordkeeping requirements and passive voice and draw readers into the of this document. tell you how long you must keep certain text. For this proposed CGMP rule for records. As we have stated several times In some cases, we modeled a dietary ingredients and dietary in this document, we determine CGMP proposed provision after an existing supplements, recordkeeping is compliance by conducting inspections. regulation, but wrote the proposed rule necessary to provide the type of Records, therefore, enable you to show, using plain language techniques. We documentation that would demonstrate and for us to determine, how you invite the public to comment on the that dietary ingredients and dietary complied with the CGMP requirements. plain language techniques used in this supplements are manufactured, Proposed § 111.125(a) would apply to proposed rule. In developing your packaged, and held under the all records covered by the proposed rule comments, please consider addressing conditions that would be required under and would require that you keep those the following points: the proposed CGMP regulations. Under • Do you like the proposed rule’s records for 3 years beyond the date of section 701(a) of the act, we may issue manufacture of the last batch of dietary appearance? • Do plain language techniques make regulations necessary for the efficient ingredients or dietary supplements the document easier to read and enforcement of the act. If you did not associated with those records. Retention understand? and keep records, for example, documenting for 3 years beyond the date of • Do you have other suggestions to practices performed during previous manufacture would be appropriate for improve the format? production runs, it would be difficult followup of consumer complaints for us to determine whether, as stated received during the marketing period. V. Paperwork Reduction Act of 1995 under section 402(g)(1) of the act, the Proposed § 111.125(b) would deal This proposed rule contains dietary supplement had been with the form in which you keep information collection requirements that manufactured, packaged, and held records. The proposal would allow you are subject to review by the Office of under CGMPs. By requiring records, we to keep records required under this part Management and Budget (OMB) under will be able to ensure that you follow as original records, as true copies (such the Paperwork Reduction Act of 1995 CGMPs and that your dietary as photocopies, microfilm, microfiche, (44 U.S.C. 3501–3520). A description of supplements are not adulterated and or other accurate reproductions of the these requirements is given below with misbranded during manufacturing, original records), or as electronic an estimate of the annual recordkeeping packaging, or holding operations. records. If you use reduction burden. Included in the estimate is the The proposed rule would establish techniques, such as microfilming, the time for reviewing instructions, the minimum manufacturing practices proposal would require that you make searching existing data sources, necessary to ensure that dietary suitable reader and photocopying gathering and maintaining the data supplements are manufactured, equipment readily available to us. If you needed, and completing and reviewing packaged, or held in a manner that will use electronic records, the proposal each collection of information. not adulterate and misbrand the dietary would require that you comply with We invite comments on: (1) Whether ingredients or dietary supplements. part 11 (our requirements for electronic the proposed collection of information The proposed regulations would records). is necessary for the proper performance impose requirements for: (1) Personnel, Proposed § 111.125(c) would require of our functions, including whether the (2) physical plants, (3) equipment and that you make your records available for information will have practical utility; utensils, (4) production and process inspection and copying by us when (2) the accuracy of our estimate of the controls, (5) holding and distributing, requested. We sometimes need to copy burden of the proposed collection of (6) consumer complaints, and (7) records when our field inspectors need information, including the validity of records and recordkeeping. guidance or additional expertise from the methodology and assumptions used; We are proposing recordkeeping our headquarters staff; if we were (3) ways to enhance the quality, utility, requirements that include records unable to copy records, our inspections and clarity of the information to be pertaining to: (1) Calibration of would become more complicated and collected; and (4) ways to minimize the instruments and controls; (2) automatic, longer in duration, particularly if the burden of the collection of information mechanical, or electronic equipment inspection involved a complex scientific on respondents, including the use of calibration, inspection, or checks; (3) or technical issue that normally would automated collection techniques, when production and process controls; (4) be handled at FDA headquarters. appropriate, and other forms of quality control; (5) receiving IV. Statement Concerning the Use of information technology. Title: Current Good Manufacturing components, dietary supplements, Plain Language Practice in Recordkeeping and packaging, and labels; (6) master In response to the June 1, 1998, White Reporting for Dietary Ingredients and manufacturing and batch production; (7) House Presidential Memorandum on Dietary Supplements. packaging and label operations; (8) Plain Language, we drafted this Description: Section 402(g) of the act returned dietary ingredients or dietary proposed rule in plain language. Plain gives us explicit authority to issue a rule supplements; and (9) consumer language is intended to help readers regulating conditions for manufacturing, complaints. find requirements quickly and packaging, and holding dietary Description of Respondents: Dietary understand them easily. To do that, we supplements. Section 402(g)(1) of the ingredient manufacturers, dietary have reorganized sections modeled after act states that a dietary supplement is supplement manufacturers, packagers existing regulations and reworded the adulterated if ‘‘it has been prepared, and repackagers, distributors, paragraphs using: packed, or held under conditions that warehousers, exporters, importers, large • Short sections, paragraphs, do not meet current good manufacturing businesses, and small businesses. sentences, and words to speed up practice regulations.’’ Section 402(g)(2) We estimate the burden of this reading and enhance understanding; of the act authorizes us to, by regulation, collection of information as follows:

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TABLE 1.—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1

Annual fre- 21 CFR Section Number of quency of Total annual Hours per Total hours recordkeepers recordkeeping records record

111.15(b)(3) ...... 231 12 2,772 0.1 277 111.15(d)(3) ...... 231 260 60,060 0.25 15,015 111.25(d) ...... 213 365 77,745 0.5 38,873 111.30(b)(2) and (b)(5) ...... 707 260 183,820 0.5 91,910 111.35(d) ...... 10 1 10 10 100 111.35(e) ...... 367 260 95,420 0.25 23,855 111.35(f) ...... 367 260 95,420 0.1 9,542 111.35(i)(1) ...... 367 10 3,670 0.25 918 111.35(j) ...... 367 260 95,420 .25 23,855 111.35(m) ...... 367 365 133,955 0.1 13,396 111.37(b)(1), (b)(3) through (b)(5), (b)(7) through (b)(10), and (b)(12)(i) ...... 286 260 74,360 0.5 37,180 111.37(c) ...... 286 365 104,390 0.5 52,195 111.40(a)(3), (a)(4), (b)(2), and (b)(3) ...... 449 365 163,885 0.1 16,389 111.40(c)(1) ...... 218 365 79,570 0.5 39,785 111.45(a) 2 and (b) 2 ...... 200 1 200 30 6,000 111.50(a) through (c), (d)(1), and (e) ...... 68 260 17,680 1 17,680 111.50(g) ...... 68 260 17,680 0.5 8,840 111.60(b)(2) ...... 133 365 48,545 1 48,545 111.60(d) 2 ...... 133 1 133 3 399 111.65(c)(7), (c)(10), and (c)(11) ...... 133 365 48,545 0.1 4,855 111.70(b)(5) through (b)(6), (d), and (e) ...... 245 260 63,700 0.1 6,370 111.70(g) ...... 245 260 63,700 0.50 31,850 111.74(a) ...... 200 12 2,400 0.1 240 111.82(a) ...... 53 52 2,756 0.1 276 111.85(a) ...... 53 260 13,780 0.1 1,378 111.85(d) and (e) ...... 53 260 13,780 0.5 6,890 111.95(e) ...... 53 75 3,975 0.1 398 111.95(f)(1) ...... 93 75 6,975 0.5 3,488 111.125 ...... 220 4 880 0.1 88

Total ...... 500,587 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 One time burden.

The burden estimates above are based are performed and in recordkeeping. We would require that the batch production on our institutional experience with used an estimated annual batch records be prepared every time a batch CGMP requirements for drugs and on production of 260 batches per year to is manufactured and § 111.50(i) would data provided by Research Triangle estimate the burden of requirements that require that batch production records be Institute (RTI) in the ‘‘Survey of are related to the number of batches kept in accordance with proposed Manufacturing Practices in the Dietary produced annually, e.g., proposed § 111.125. The estimated burden for Supplement Industry’’ (Refs. E1 and E2). § 111.50, ‘‘What requirements apply to establishing the batch production We tentatively conclude that there are establishing a batch production record?’’ records is counted in proposed no capital costs or operating costs The estimate of 260 batches per year is § 111.50(a) and the estimated burden for associated with this proposed rule. near the midpoint of the number of keeping the batch production records as However, we invite comments on annual batches reported by RTI survey would be required in accordance with information provided in table 1 of this firms. § 111.50(i) is counted in proposed document or on any anticipated costs. Proposed § 111.125 prescribes the § 111.125. The estimates for number of firms length of time for which CGMP records In compliance with the Paperwork affected by each provision of the rule must be maintained. The burden chart Reduction Act of 1995 (44 U.S.C. are based on the percentage of reflects the estimated annual burden for 3507(d)), the agency has submitted a manufacturers, ingredient suppliers, record maintenance, for periodically copy of this proposed rule to OMB for repacker/relabelers, distributors, and reviewing records to determine if they its review. Interested persons are warehousers that reported to RTI that may be discarded, and for any requested to send comments regarding they have not established or do not associated documentation for that information collection to the Office of maintain records that would be required activity for records that would be Information and Regulatory Affairs, or recommended under the proposed required under part 111. To avoid OMB (see ADDRESSES). rule. The RTI survey estimated that double-counting, we have not included VI. Environmental Impact 1,566 firms would be covered by this a separate estimate of burden for those Considerations rule including manufacturers, dietary sections that would require maintaining ingredient suppliers, repacker/ records in accordance with proposed The agency has determined under 21 relabelers, distributors, and § 111.125, but have included a single CFR 25.30(j) that this action is of a type warehousers. The time estimates burden estimate for all such records that does not individually or include the burden involved in maintenance under proposed § 111.125. cumulatively have a significant effect on documenting that certain requirements For example, proposed § 111.50(a) the human environment. Therefore,

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neither an environmental assessment Preliminary Regulatory Impact Analysis, Brand names convey some information nor an environmental impact statement in section VII.B of this document. We to consumers about a firm’s is required. perform the Initial Regulatory manufacturing practices. Some private Flexibility Analysis of the effects on the organizations, such as the National VII. Analysis of Impacts proposed rule on small businesses in Nutritional Foods Association and the A. Introduction section VII.C of this document. USP design minimum product FDA has examined the economic standards or manufacturing B. Preliminary Regulatory Impact requirements. The current act contains implications of this proposed rule as Analysis required by Executive Order 12866. some provisions that prevent using Executive Order 12866 directs agencies 1. The Need for the Proposed CGMP putrid substances and insanitary manufacturing practices. In addition, to assess all costs and benefits of Regulations either the threat of litigation or available regulatory alternatives and, The proposed CGMP regulations are consumers seeking compensation for when regulation is necessary, to select needed because establishments that defective products and adverse health regulatory approaches that maximize manufacture, package, and hold dietary events may create incentives for net benefits (including potential ingredients and dietary supplements establishments to adopt good economic, environmental, public health may not have sufficient market manufacturing practices. and safety, and other advantages; incentives to use controls to prevent the Actions by manufacturers, primarily distributive impacts; and equity). adulteration and misbranding of dietary voluntary quality controls, do not Executive Order 12866 classifies a rule ingredients or dietary supplements, provide sufficiently protective industry- as significant if it meets anyone of a including incentives to ensure their wide minimum requirements for number of specified conditions, identity, purity, quality, strength, and manufacturing, packaging, and holding including: Having an annual effect on composition (product quality). of dietary ingredients and dietary the economy of $100 million, adversely Manufacturing, packaging, and holding supplements. Without the proposed affecting a sector of the economy in a practices that ensure product quality regulations, survey evidence shows that material way, adversely affecting can be costly, so establishments may not products in the dietary supplement competition, or adversely affecting jobs. adopt them unless required to do so by market are sorted somewhere between A regulation is also considered a regulation. Without the proposed two types: significant regulatory action if it raises regulations consumers of dietary • Higher-priced products with brand novel legal or policy issues. FDA has supplements cannot be assured that all names or industry certification that determined that this proposed rule, if it establishments are manufacturing follow several of the good were to become a final rule, would be dietary supplements in a way that manufacturing practices proposed here; a significant regulatory action as defined ensures that these products are not • Lower-priced products that contain by Executive Order 12866. adulterated or misbranded. no private certification or respected The Small Business Regulatory Manufacturing, packaging, and brand name and that follow few of the Enforcement Fairness Act of 1996 (Pub. holding practices can compromise good manufacturing practices that are L. 104–121) defines a major rule for the safety if they fail to prevent biological, proposed here. purpose of congressional review as chemical, and physical contamination, Without the proposed rule, the being likely to cause one or more of the or if the wrong dietary ingredients are current practices do not provide all following: an annual effect on the used that present an unreasonable risk consumers with safe manufacturing economy of $100 million; a major of illness or injury. Strength (which is practices or reliable product quality increase in costs or prices; significant the amount of a specific dietary throughout the industry. adverse effects on competition, supplement or dietary ingredient in The market for dietary supplements is employment, productivity, or each tablet or capsule) that differs from full of information; consumers of dietary innovation; or significant adverse effects label statements, missing or extra supplements must sort through on the ability of U. S.-based enterprises ingredients, and inconsistency across information and misinformation about to compete with foreign-based units of the product are other problems the properties of these products from enterprises in domestic or export caused by poor manufacturing practices. magazines, brochures, popular books, markets. In accordance with the Small Products may also be held in insanitary television, and a host of other sources. Business Regulatory Enforcement or environmentally inappropriate However, the information from these Fairness Act, OMB has determined that conditions, or may be physically sources deals most often with the claims this proposed rule, when final, will be damaged if stored improperly. Some for the products themselves, not with a major rule for the purpose of poor manufacturing practices, such as the steps taken by establishments to congressional review. the use of ingredients that are protect against contamination or to FDA has examined the economic undeclared, of incorrect strength, or ensure quality. Private quality control implications of this proposed rule as missing altogether result in a fails to provide industry-wide minimum required by the Regulatory Flexibility misbranded product. The proposed good manufacturing practices for the Act (5 U.S.C. 601–612). If a rule has a CGMP regulations would establish following reasons: significant economic impact on a minimum requirements to ensure that • Establishments do not have substantial number of small entities, the manufacturing, packaging, and holding incentives to disclose information about Regulatory Flexibility Act requires practices ensure the identity and quality their own practices, because disclosure agencies to analyze regulatory options of components, dietary ingredients, and that some consumers may perceive to be that would lessen the economic effect of dietary supplements. harmful or undesirable would reduce the rule on small entities. FDA finds Consumers today rely on the demand for their products. that this proposed rule would have a manufacturer’s assurances, existing Establishments therefore have significant economic impact on a regulations and statutes (for example, incentives to withhold information from substantial number of small entities. section 402(a)(3) and (a)(4) of the act), consumers. We carry out the cost-benefit analyses and recourse to the legal system to • Businesses normally do not required for significant rules in the ensure that products are not defective. advertise differences in manufacturing

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practices. They seldom have access to adulterated foods that consist of filthy, percent of small firms and 11 percent of competitors’ proprietary information, putrid, or decomposed substances or large firms do not follow a good and they may fear that advertising based foods that have been prepared, packed, manufacturing practice model. The on differences in practices would or held under insanitary conditions so survey results also show that 32 percent discredit the entire industry. that they may become contaminated or of vitamins and mineral establishments, • Without public disclosure of may be rendered injurious to health; 39 percent of amino acid/protein/animal product quality and adverse health • Publicity from private consumer extract establishments, 41 percent of events, the link between manufacturing groups or health agencies on the risks herbal and botanical establishments, practice and health hazard is difficult to from products not manufactured using and 59 percent of establishments not establish. The link is probabilistic, CGMP regulations, manufacturers already classified, do not follow a good requires data pooling across products assurances, and the voluntary adoption manufacturing practice model. and establishments (in order to establish of some or all provisions of the Without industry-wide uniform cross sectional variation), and can be proposed regulations; requirements, some establishments may interpreted in a variety of ways. • Current or enhanced State and local follow different practices but convey the • Because many consumers already enforcement activity to bring about a message that they follow good mistakenly believe that the Federal reduction of potential harm from manufacturing practices. In short, Government guarantees safety, contaminated or poor quality dietary people who want to discriminate businesses have weak incentives to supplements; or between establishments that use good adopt good manufacturing practices, • Litigation or the threat of litigation practices and those that do not would which are costly. In one recent survey by consumers who allege harm from not have sufficient information to do so. of the nation’s consumers, 34 percent consumption of the dietary supplement. Another reason for our skepticism about report that they believe that the We believe that there are compelling universal voluntary adoption of good government regulates dietary reasons not to rely on these alternatives manufacturing practices is that good supplements to ensure safety and that alone. practices appear to be taken for granted products do what they claim to do. (For If public and private health agencies, by many consumers. Indeed, some details of the survey, see Ref. E3.) If consumer groups, competitors, trade consumers already believe that the people believe that good manufacturing organizations or other third parties Federal Government regulates the practices are already followed, publicized the risks from products not manufacturing practices of the industry, manufacturers may believe they gain manufactured using private good so firms lack an incentive to provide little from voluntarily adopting them. manufacturing practices, then additional assurance (Ref. E3). Information about manufacturing consumers would decide for themselves Current or enhanced State and local practices for dietary supplements is on the risks of contaminated or poor regulations could bring about a imperfect and costly to produce, so quality products. The weakness of this reduction of potential harm from well-informed people should be willing alternative is that third-party contaminated supplements. This to pay for improvements in the quality organizations cannot easily discover alternative has the advantage that State of information. An important benefit of many of the problems caused by poor and local governments can exercise the proposed regulations will be to manufacturing practices because more discretion when responding to reduce variation in manufacturing manufacturers are reluctant to local manufacturing conditions or practices and ensure minimum quality voluntarily share information to third consumer health practices than the for dietary supplement products. parties about their manufacturing Federal Government. Because most of Reducing the variation in product practices. the industry engages in interstate quality by creating industry-wide Actions by manufacturers, such as by commerce, however, Federal regulations minimum requirements reduces the voluntarily introducing good are appropriate. Also, Federal information consumers now attempt to manufacturing practices, occur when regulations would apply uniformly get through costly and uncertain sources the expected private economic benefits across the country, whereas State and in order to make purchasing decisions. of the actions exceed the private costs. local regulations might impose different Voluntary adoption of good standards on establishments that supply 2. Regulatory Options manufacturing practices will occur supplements across State and local FDA considered several regulatory when it is profitable to do so. Many boundaries. options for dealing with current establishments appear to be adopting Litigation or the threat of litigation manufacturing, packaging, and holding some publicly available good may help to bring about the goals of the practices that may not ensure product manufacturing practice models in order proposed rule. The potential of costly quality. The options considered include: to meet the demand for safer and more litigation from the harm caused by (a) No new regulatory action, (b) fewer uniform products. NNFA is deficient manufacturing practices requirements for vitamins and minerals, implementing a good manufacturing creates an incentive for manufacturers (c) more restrictive regulations than the practice certification program. The USP to reduce the risks from defective proposed CGMP regulations, (d) HACCP sets standards for strength, purity, products. However, we do not believe without the other elements of CGMP disintegration, and dissolution for that litigation or the threat of litigation regulations, (e) final product testing individual and combination vitamins has created the incentives for all only, (f) regulations for high-risk and minerals. Also, Consumerlab.com is manufacturers to implement the products or hazards only, and (g) the introducing a certification label, CL, to manufacturing practices that we believe proposed rule. show when ingredients meet their are necessary to avoid adulterated or a. No new regulatory action. Under minimum requirements. However, 36 misbranded products. As discussed this option, consumers would probably percent of recently surveyed dietary earlier, not all surveyed dietary rely on the following as protection supplement establishments do not supplement manufacturers reported that against defective products: follow any good manufacturing practice they followed good manufacturing • Possible enforcement action by FDA models for their products (Ref. E2). The practices. Furthermore, in some cases it under, for example, section 402(a)(3) breakdown of survey results shows that is difficult and costly to demonstrate to and (a)(4) of the act, regarding 48 percent of very small firms, 27 the courts that the harm to plaintiffs was

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actually the result of poor be reduced. Moreover, if dietary propose a requirement that manufacturing practices, making supplements contain too little of a manufacturers implement a HACCP (or recourse to the courts sometimes vitamin or mineral consumers may not HACCP like) system for the impractical. receive the intended health benefits, manufacturing of dietary supplements In the absence of the proposed CGMP and if the dietary supplements contain without the other elements of the regulations, the burden of monitoring too much of a vitamin or mineral they proposed CGMP regulations. A critical manufacturing practices would fall may experience illness or injury. control point is where production more heavily on consumers, despite the We estimate that the benefits of this controls can be applied to reduce or difficulties consumers face in option would be approximately eliminate hazards (including biological, monitoring manufacturers. Moreover, proportional to the ratio of recalled chemical, or physical contamination) the proposed CGMP regulations are products that were classified as that may make dietary supplements preventative and should ensure that vitamins and minerals to all recalled unsafe. problems are identified and dealt with dietary supplements products. The advantage of an industry-wide during manufacturing, packaging, and Approximately 50 percent of the HACCP program is that HACCP does not holding, rather than after someone has recalled products were vitamins and require manufacturers to follow detailed consumed an unsafe product and minerals so we estimate that this option uniform requirements in order to experienced an adverse effect. would generate no more than $109 achieve desirable outcomes. b. Fewer requirements for vitamins million in benefits. We assumed that the Manufacturers themselves determine for and minerals. FDA could require more costs of this option would be their specific products and processes controls from establishments that proportional to the fraction of how they will best eliminate, reduce, or manufacture, package, or hold plant or establishments that would be required control hazards in the manufacturing of animal derived dietary ingredients such to follow all of the proposed provisions dietary supplements. as amino acids, proteins, herbals, and those that follow the reduced We have not designed a hypothetical botanicals and other products not requirements with the total costs HACCP system for the dietary classified as vitamin and mineral estimated for this proposal as shown in supplement industry. For the purpose of manufacturers, packagers, or holders. table 17 of this document. The generating estimates of costs and The plant or animal derived dietary estimated mean cost of the proposed benefits, we assumed that a HACCP ingredients are probably characterized regulation is $86 million (see table 19 of regulation for a dietary supplement by greater variation in product quality this document). The fraction of manufacturer would be likely to than synthetically derived dietary establishments required to follow all the encompass sanitation prerequisites that ingredients. Under this option, the provisions is .46 (= 723/1566). The are met, writing a HACCP plan, and segment of the industry that fraction of establishments that would monitoring critical control points. The manufacture, package, or hold products have reduced testing is .54 (= 843/1566). benefits and costs of the HACCP plan that are the most likely to have Testing is approximately 36 percent of would be generated by controls for a difficulty manufacturing or maintaining the total costs. We estimate the total narrower set of hazards in the uniform product quality dietary costs from this option to be $69 million manufacturing, packaging, and holding ingredients would be required to follow ($86 million × .46 + $86 million × .54 processes than those covered by this the proposed testing and other × (1¥.36)). proposal, and would not include the production and process control c. More restrictive CGMP regulations other benefits and costs generated by the requirements. Manufacturers of than the proposed regulations. One proposed rule especially the reduced vitamins and minerals would be option is to propose (or finalize) more consumer search costs, because uniform required to follow the sanitation, restrictive rules than the proposed product quality would not necessarily holding, and consumer complaint CGMP regulations. Under this option, be assured. The advantage of HACCP as provisions only, they would not have to CGMP regulations could provide an option to prevent product adopt manufacturing controls to ensure consumers with additional safeguards. contamination is that it does not specify that products did not contain too much Several of the largest manufacturers of detailed manufacturing requirements. or too little of a vitamin or mineral. dietary supplements now voluntarily The disadvantage is that in the absence Plant or animal ingredients are likely comply with some of these additional of uniform controls there would not be to experience greater natural variation safeguards (Ref. E2). The most uniform minimum product quality in product quality than synthetic significant additional provisions that across the industry and consumers compounds, so they may require the would be required under this option are would not derive the same benefits from higher minimum standard of regulation product quality testing for each lower search costs. contained in the proposed regulation. incoming shipment lot of components e. Require final product testing only. The advantage of this option is that and dietary ingredients, inprocess FDA could propose that manufacturers fewer establishments will be affected as testing for contaminates at critical test their finished products for identity, much; approximately 723 control points and mandatory written purity, quality, strength, and establishments classified as procedures for all of the various composition but not include any of the manufacturers, packagers or holders of provisions of the proposed regulation. other mandatory provisions of the products other than vitamins and The advantage of this option is that proposed regulation. The advantage of minerals, rather than the 1,566 the additional requirements provide this option is that it would be the least establishments estimated to be covered safeguards that the essential safety and costly option of those considered. Many by the proposed regulation (see table 2 quality provisions are being followed. firms already test some of their finished of this document). The compliance costs The disadvantage of this option is that products, reducing the impact of this would therefore be lower. The it is more costly than the proposed rule, option. Approximately 69 percent of disadvantage is that vitamin and and we are not aware of any information manufacturing plants conduct finished mineral manufacturers also potentially that would show any additional product testing and almost 65 percent of manufacture products of variable verifiable health benefits. all finished batches in the industry are quality, so the expected benefits from d. HACCP without the other elements already tested using physical, chemical, more consistent product quality would of CGMP regulations. The agency could microbiological, visual or organoleptic

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testing techniques (Ref. E2). The options, but it does not generate the full supplements. We therefore have no problem with this option is that finished range of benefits provided by the basis upon which to begin a full product testing alone cannot ensure proposed rule. evaluation of what the high-risk product quality for some types of f. Regulate only high-risk products. products are or may be. products. Not every finished product FDA could propose CGMP regulations 3. Coverage of the Proposed Rule currently has a test that confirms that would cover only high-risk products. The advantage of this option identity, purity, quality, strength, or The proposed rule would cover is that it would impose lower costs than composition, especially for establishments that manufacture, the proposed rule, but (if all risky multiingredient products. Tests may not package, hold dietary ingredients or products could be identified and have been developed, or they may not dietary supplements. Tables 2, 3, and 4 be completely reliable, or they may not regulated) generate the same level of benefits. Only those establishments that of this document list the estimated be capable of evaluating every type of number of covered manufacturers, product defect. Also, potentially lower manufacture high-risk products or have high-risk hazards would incur the costs packagers, dietary ingredient suppliers, cost alternatives to finished product of adopting CGMP regulations. High-risk holders, and other establishments. Table testing—such as incoming component might be defined as those products most 2 of this document shows the number of lot testing, inprocess testing, or both— likely to be contaminated, or suffer covered establishments by product type might be available and desirable to firms other product defects. There are two and size. A small business, based on the as a means to protect the public. problems with this option. Adverse Small Business Administration Moreover, finished product testing event reporting is not mandatory, so definition, is any firm with 500 or fewer alone is not sufficient to prevent significant underreporting is expected. employees. For purposes of analysis, we products with microbiological or Also, it is possible that the confirmed defined very small establishments as chemical contamination from being illnesses and other problems linked to having fewer than 20 employees. Table discovered because it is possible that particular dietary supplements may be 3 of this document shows the number of false negatives might occur, as when those most easily traced, rather than establishments categorized as there is ‘‘hotspot’’ contamination within those with the highest risk. High levels manufacturers, ingredient suppliers, a batch. Preventative controls must be of identified problems may not be repackers or relabelers, holders whose imposed to achieve that goal. Finally, closely correlated with high levels of primary business is dietary ingredients finished product testing alone also will risk. In other words, problems or dietary supplements, and other not facilitate trace backs when defective associated with the known defective (although not including other holders products are discovered in the products may or may not be correlated and distributors). Table 4 of this marketplace, nor will it facilitate with the highest risk. Without more data document shows our estimate of the responsible investigations of consumer and risk assessments, it would be number of general warehouses and complaints. The estimated cost of this difficult to distinguish what risks may wholesalers that hold dietary option is lower than that of the other be associated with particular dietary supplements.

TABLE 2.—COVERED ESTABLISHMENTS BY PRODUCT TYPE AND SIZE FROM DIETARY SUPPLEMENT ENHANCED ESTABLISHMENT DATABASE (DS–EED)

Very Product type small % Small % Large % Unknown % Total

Vitamins and Minerals...... 252 29.8 223 26.5 78 9.2 290 34.5 843 Amino Acids, Proteins ...... 21 31.0 16 23.0 6 6.9 27 39.1 69 Herbals and botanicals ...... 148 42.6 46 13.2 5 1.1 150 43.1 348 Supplements not already classified ...... 93 30.4 66 21.6 20 6.5 127 41.6 306

Total ...... 514 32.8 351 22.4 106 6.8 594 38.0 1,566

TABLE 3.—COVERED ESTABLISHMENTS BY TYPE OF OPERATION FROM DS–EED

Number of Percent of Establishment type establishments establishments

Manufacturer ...... 1,228 78.4 Dietary ingredient supplier ...... 106 6.7 Repacker; relabeler ...... 26 1.7 Holder ...... 114 7.3 Establishments not already classified ...... 92 5.9

Total ...... 1,566 100.0

TABLE 4.—COVERED ESTABLISHMENTS THAT HOLD DIETARY SUPPLEMENTS

Number of Type of holders Source and SIC code establishments

Grocery Wholesalers or Drug Wholesalers ...... Dunn and Bradstreet: 5122, 5141 ...... 25,527 Food or Drug Warehouse ...... Dunn and Bradstreet: N/A ...... 738 Miscellaneous Food or Drug Warehouse ...... Dunn and Bradstreet: 4225, 4226, 5912, 5499, 5411, 5122, 238 5141, 5149, 5399, 5311, and 5331.

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TABLE 4.—COVERED ESTABLISHMENTS THAT HOLD DIETARY SUPPLEMENTS—Continued

Number of Type of holders Source and SIC code establishments

Dietary Supplement ...... DS–EED ...... 114

Total ...... 26,617

We consulted several sources to requirements do not apply to retailers supplements that were neither vitamins estimate the number of establishments and transporters. We believe that and minerals nor herbals and botanicals reported in tables 2, 3, and 4 of this retailers and transporters may increased less, averaging 11 percent per document. The number shown in tables voluntarily adopt provisions related to year. The lowest annual sales increases 2 and 3 of this document, 1,566, is the the holding of these products and thus were for vitamins and minerals, estimated number of establishments in there may be changes in the marketplace averaging 8 percent per year. For all the DS–EED that manufacture, with accompanying costs and benefits. dietary supplements combined, sales repackage, supply dietary ingredients, However, we expect that the only increased an average of 12 percent a or hold dietary supplement products in retailers and transporters that will year since 1994 (not shown on the the United States. RTI developed the voluntarily adopt the proposed table). DS–EED using FDA’s Official requirements are those that expect the Establishment Inventory (OEI) and private benefits of adoption will exceed While the sales growth shown in table supplemented that source with the private costs. 5 of this document, Panel A, is information from trade organizations, impressive, only part of this apparent trade shows, and electronic databases 4. Baseline Practices growth represents increased use. (Refs. E1 and E2). a. Consumer baseline practices. Population growth and rising prices also The number of establishments in the Baseline consumer and manufacturer contributed to the apparent growth. The DS–EED that hold dietary supplements practices, governed by current market real (growth inflation-adjusted) increase is not the total number of holders forces and existing government in dietary supplement prices is covered by the proposed regulation. The regulations, give rise to the current risks estimated by subtracting the inflation holding establishments in the DS–EED associated with the manufacturing of rate from the rate of price increases of identified holding dietary supplements dietary supplements. When determining dietary supplements (Ref. E4). As shown as their primary business. To estimate baseline manufacturing practices, it is in table 5 of this document, Panel B, the total number of establishments that necessary to estimate both the practices between 1995 and 1997 the real price of could hold dietary ingredients or dietary that are used now, as well as the likely vitamins and minerals and supplements supplements but do not consider dietary changes in manufacturing practices that other than vitamins and minerals all supplements as their primary business, will occur even in the absence of new increased. Rising real price indicates we performed three searches of firms regulations. The risks to consumers that demand is growing rapidly. that are listed with Dun and Bradstreet’s from these products can be associated Dialog database. We first looked for a with a combination of consumption Table 5 of this document, Panel C, count of firms that had standard habits, the contamination of the shows estimated annual increases in per industrial classification (SIC) codes for products, or both. Contamination may capita consumption of dietary wholesalers of groceries or drugs. Next be caused by current manufacturing supplements.1 As shown in table 5 of we looked for a count of firms that met practices. Consumption is influenced by this document, Panel C, the estimated the description of warehouses of the price and quality of dietary per capita consumption of the different groceries or drugs (no SIC codes were supplements, set by the interaction of categories of dietary supplements has used). Finally, we looked for a count of market participants. Finally, changes in increased since 1994. any firms that had both warehouse SIC practices of either consumers or For the consumption estimates in codes and miscellaneous drug stores, manufacturers caused by new regulatory table 5 of this document, we averaged food stores, sundries, and general requirements will give rise to changes in dietary supplement use over the entire merchandise (SIC 4225, 4226, 5912, risks, as estimated by changes in costs U.S. population, 275 million. In table 6 5499, 5411, 5122, 5141, 5149, 5399, and benefits. of this document, we included 5311, and 5331). The results are shown The consumption of dietary estimated average supplement use for in table 4 of this document. We supplements has grown in recent years. the population of supplement users, 160 concluded that the total number of Consumers report that they are using a million (Ref. E13). The three panels in establishments in this category that wider range of product types, and that table 6 of this document show the could hold dietary ingredients or dietary they are using dietary supplements for supplements and would be covered by more reasons than they were in the past. annual consumption per supplement the regulation was approximately the Table 5 of this document illustrates user and the annual change in sum of the numbers counted in the three the rapid sales growth of the dietary consumption per supplement user for searches, or 26,617. supplement industry from 1994 to 2000. The number of establishments that Panel A of table 5 of this document 1 An index measuring per capita consumption of hold dietary ingredients or dietary shows annual sales of three general dietary supplements can be derived using the following equation: PCCt = [1,000 × Salest]/[POP × supplements includes retailers that sell categories of dietary supplements, a Pt ], where, t = year index; PCCt = per capita dietary supplements to consumers, and measure of the market size of the consumption (# of unit sales); Sales = millions of transporters of dietary ingredients and supplement industry. Annual increases dollars of sales; POPt = thousands of U.S. residents; Pt = average price of supplement. In the formula, dietary supplements. We made no effort in sales of herbals and botanicals were we measure consumption as the number of dietary to determine the number of such the greatest, averaging 18 percent per supplement units (bottles, packages, etc.) sold per holders, because the proposed year, while annual increases in sales of U.S. resident for a given year.

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vitamins and minerals, herbals and user has apparently declined since that the estimated trend in consumption botanicals, and supplements other than 1994. per user is biased. This trend, expressed vitamins and minerals and herbals and One limitation of the estimates in as the percentage change in botanicals. Table 6 of this document table 6 of this document is that consumption per user, is negative for all also shows that during this period the prevalence of supplement use is based segments of the dietary supplement proportion of consumers using on the proportion of U.S. adults industry since 1994. The large and supplements increased faster than the consuming supplements, while the per rising number of consumers accounts average consumption for the total capita consumption figures are based on for the growing size of the dietary population. The surprising implication the entire U.S. population. Nonetheless, supplement industry. of this result is that consumption per we do not have any reason to believe

TABLE 5.—GROWTH IN MARKET SIZE AND PER CAPITA CONSUMPTION OF DIETARY SUPPLEMENTS, 1994–2000

1994 1995 1996 1997 1998 1999 2000

Panel A—Nominal Market (Millions of Current Dollars)

Vitamins ...... 3,960 4,220 4,780 5,190 5,550 5,940 6,360 Growth rate (percent) ...... 6.57 13.27 8.58 6.94 7.03 7.07 Minerals ...... 700 800 900 1,070 1,160 1,250 1,350 Growth rate (percent) ...... 14.0 13.0 19.0 8.0 8.0 8.0 Herbals and Botanicals...... 2,070 2,530 2,990 3,530 4,170 4,840 5,520 Growth rate (percent)...... 22.22 18.18 18.06 18.13 16.07 14.05 Supplements other than vitamins/min- erals and botanicals...... 2,070 2,290 2,620 2,890 3,180 3,490 3,840 Growth rate (percent) ...... 10.63 14.41 10.31 10.03 9.75 10.03 Total ...... 8,080 9,840 11,290 12,680 14,060 15,520 17,070 Growth rate (percent) ...... 12.0 15.0 12.0 11.0 10.0 10.0

Panel B—Prices

Consumer price index-units (percent) ..... 148.5 152.5 157.0 160.5 163.2 166.7 ...... Inflation rate (percent) ...... 2.56 2.76 2.957 2.23 1.68 2.14 2.39 Vitamins and minerals ...... Average nominal price (IRI) ...... $6.20 $6.50 $6.87 $7.34 $7.54 $7.78 $8.05 Nominal price increase (percent) ...... 2.69 4.84 5.69 6.84 2.72 3.18 3.43 Real price increase (percent) ...... 5.25 2.08 2.74 4.61 1.04 1.04 1.04 Supplements other than vitamins and minerals: Average nominal price...... $6.20 $6.50 $6.87 $7.34 $7.70 $8.11 $8.56 Nominal price increase (percent) ..... 5.80 4.84 5.69 6.84 4.85 5.31 5.56 Real price increase (percent) ...... 3.24 2.08 2.74 4.61 3.17 3.17 3.17

Panel C—Per Capita Consumption (Number of Units Sold Per U.S. Resident)

Vitamin/mineral sales...... 2.45 2.47 2.62 2.64 2.72 2.80 2.87 Growth (percent)...... 0.69 6.19 0.66 3.12 2.74 2.55 Herbals sales...... 1.28 1.48 1.64 1.80 2.00 2.19 2.34 Growth (percent) ...... 15.48 10.79 9.45 11.60 9.17 7.03 Supplements other than vitamins and minerals and herbals sales ...... 1.28 1.34 1.44 1.47 1.53 1.58 1.63 Growth (percent)...... 4.53 7.26 2.26 3.95 3.23 3.25

TABLE 6.—COMPARISON OF CONSUMPTION PER PERSON WITH CONSUMPTION PER USER: EVIDENCE THAT THE DIETARY SUPPLEMENT MARKET IS BECOMING BROADER NOT DEEPER

Average Growth 1994 1995 1996 1997 1998 1999 1994–2000

A. Vitamins and Minerals

Per capita consumption (units per U.S. resident) ...... 2.45 2.47 2.62 2.64 2.72 2.80 ...... % Growth ...... 0.69 6.19 0.66 3.12 2.74% 2.68% Consumption prevalence (percent) ...... 47.70 54.0 61.0 70.0 79.0 ...... Reference ...... Ref. E6 Ref. E6 Ref. E6 Ref. E6 Ref. E7 ...... % Growth ...... 13.44 13.44 13.44 13.44 13.44 Consumption per user (units) ...... 5.18 4.85 4.30 3.91 3.54 ...... % Growth ...... ¥6.39 ¥11.27 ¥9.10 ¥9.43 ¥9.05

1994 1995 1996 1997 1998 1999 1994–1999

B. Herbals and Botanicals

Per capita consumption (units per U.S. resident) ...... 1.28 1.48 1.64 1.80 2.00 2.19 ......

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TABLE 6.—COMPARISON OF CONSUMPTION PER PERSON WITH CONSUMPTION PER USER: EVIDENCE THAT THE DIETARY SUPPLEMENT MARKET IS BECOMING BROADER NOT DEEPER—Continued

Average Growth 1994 1995 1996 1997 1998 1999 1994–2000

% Growth ...... 15.48 10.79 9.45 11.60 9.17 11.30 Consumption prevalence (percent) ...... 8.20 12.10 12.10 12.10 28 49 ...... Reference ...... Ref. E8 Ref. E8 Ref. E8 Ref. E9 Ref. E10 Ref. E7 ...... % Growth ...... 47.56 0.00 0.00 131.40 75.00 50.79 Consumption per user (units) ...... 15.64 12.24 13.56 14.84 7.16 4.47 ...... % Growth ...... ¥21.74 10.79 9.45 ¥51.77 ¥37.62 ¥18.18%

C. Supplements Other than Vitamins and Minerals and Herbals and Botanicals

Per capita consumption (units per U.S. resident) ...... 1.28 1.34 1.44 1.47 1.53 1.58 ...... % Growth ...... 4.53 7.26 2.26 3.95 3.23 4.24 Consumption prevalence (percent) ...... 5.1 8.8 11.2 14.2 18.1 23.0 ...... Reference ...... Ref. E8 Ref. E8 Ref. E8 Ref. E8 Ref. E8 Ref. E7 ...... % Growth ...... 72.55 27.15 27.15 27.15 27.14 36.23 Consumption per user (units) ...... 25.15 15.24 12.85 10.34 8.45 6.86 ...... % Growth ...... ¥39.42 ¥15.64 ¥19.58 ¥18.25 ¥18.81 ¥22.34

b. Manufacturer’s baseline practices. establishments sampled were not includes the establishments discussed FDA contracted with RTI to conduct a eligible for the survey because they were in section VII.B.3 of this document. If survey of the dietary supplement no longer in operation at the listed firms start good manufacturing practices industry to learn about both baseline address or did not handle any dietary in the absence of this rule, both the (existing) manufacturing practices and supplements or ingredients for human costs and benefits of the rule would be the existing standards used for consumption. less than we estimate. If firms were to manufacturing dietary ingredients and To achieve the highest possible stop in the absence of the rule, both the dietary supplements (Ref. E2). A sample response rate, RTI operated a toll-free costs and benefits would be more than of 966 dietary supplement help line and attempted to contact each we estimate. We lack information about establishments from the DS–EED establishment up to eight times before the trend in the industry, so we database was selected from an estimated assigning a disposition of nonresponse. assumed that the survey reflects both eligible population of 1,566 firms in the RTI also attempted up to two refusals the current and future practices in the industry. The sample was stratified by conversions, which are attempts to industry. We request comment or manufacturer’s product type and the persuade firms that declined to answer information about the industry trend in size of firm in the industry. the survey to respond. The survey was adopting good manufacturing practices. Stratification helps ensure that conducted over a 10-week period, i. Stratification. The survey was estimates of the subpopulations are November 29, 1999, to February 4, 2000. stratified by product type and more precise. Establishments that were There were a total of 238 completed establishment size. Stratification stratified by manufacturer’s product surveys, resulting in a final disposition ensures that samples are representative type were classified as primarily: (1) of: (1) An overall eligibility rate of close of the industry population.2 The Vitamins and minerals; (2) amino acids, to 50 percent, and (2) a response rate of subdivisions of the population of proteins, or animal extracts; (3) herbals 50 percent. interest here were establishment size (by and botanicals; or (4) all other product Determining baseline practices is the number of employees) and product types not already classified. The necessary in order to determine the new type, because these characteristics are product type strata were further activities that are likely to take place as likely to influence whether an stratified by four size categories: (1) a result of implementation of this establishment already has adopted the Very small, (2) small, (3) large, and (4) proposed rule. Each of the new practices that would be required by the unknown. This categorization generated activities potentially brought about by regulation. The DS–EED includes nine 16 sampling strata. the proposed rule has both a marginal product types: (1) Vitamins and The contractor, RTI, sent each of the (or incremental) cost and a marginal (or minerals; (2) herbals and botanicals; (3) 966 firms in the sample a lead letter on incremental) benefit. These incremental herbal and botanical extracts; (4) amino FDA letterhead and a one-page brochure costs and benefits of likely new acids; (5) proteins; (6) animal extracts; to explain the purpose of the survey, the activities form the basis of our economic (7) tea like products; (8) concentrates, value of the establishment’s analysis of the proposed rule. metabolites, or constituents; and (9) participation, and the agency’s The survey asked establishments a supplements not already classified (all confidentiality procedures. Following series of questions about existing other supplements). Establishments may the mailing, RTI placed telephone calls practices; we used the responses to produce more than one product type; to each establishment to screen for estimate how many establishments in establishments with multiple product eligibility and to recruit eligible the industry already operated in types were, however, only classified in establishments for the mail survey. To accordance with the requirements of the one category. For stratification and be eligible for the survey, proposed regulation. One key reporting purposes, we defined the establishments had to currently assumption in this analysis is that no manufacture, repackage, supply dietary firms are expected to stop CGMPs and 2 Stratification is a subdivision of the population ingredients, hold, import or export no firms are expected to start good of establishments in the dietary supplement dietary supplements for human manufacturing practices in the absence industry by a unique characteristic such as product consumption. Almost 50 percent of the of this rule. The universe for the survey type or number of employees.

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following four mutually exclusive as part of a small or large company. To (if data on employment were not categories of dietary supplements: obtain parent company data for available), then the establishment was 1. Vitamins and minerals (includes establishments in the survey universe, classified as small. An establishment establishments that may also we sent InfoUSA 3 the DS–EED data was classified as very small if the manufacture, package, or hold herbals records (N = 2,004) and requested the number of employees was less than 20. and botanicals, amino acids, proteins, or name, address, primary SIC, iii. Survey response. Table 7 of this animal extracts but predominately employment size (in ranges), and manufacture vitamins and minerals); document presents the number of revenue (in ranges) of parent company establishments surveyed, stratified by 2. Amino acids, proteins, and animal firms with establishments in the survey the four product types and by size. extracts (includes establishments that universe. InfoUSA matched 1,219 of the Although the sample allocation was also manufacture, package or hold 2,004 records in the DS–EED to their designed to yield 400 completed herbals and botanicals, including U.S. database of 10.3 million businesses. surveys, we received only 238 extracts; excludes establishments Of the 1,219 matched records, 31 completed mail surveys. The number of already classified as vitamins and records were found to be duplicates of minerals); another record and were removed, respondents was fewer than expected 3. Herbals and botanicals, including leaving 1,188 matched records and because the number of establishments extracts (excludes establishments 1,566 total records in the sampling that were ineligible was greater than we already classified as ‘‘vitamins and frame. The nonmatched records did not expected and because some minerals’’ or ‘‘amino acids, proteins, or match because: (1) They were recently establishments did not respond to the animal extracts’’); and established businesses, (2) they were out survey after agreeing to participate. 4. Supplements not already classified of business, or (3) they had recently Ineligible establishments are those that (all other product types). no longer produce dietary supplements We further stratified each of the four changed their names or addresses. Because data on revenue or employment because they have gone out of business product categories into four size or changed product lines, or they have categories, very small, small, large, and size were not available for the nonmatched records, we created an moved and could not be located. unknown—resulting in 16 sampling Despite receiving fewer responses than strata. We classified each establishment ‘‘unknown’’ stratum for these establishments. The survey of practices planned, the confidence level for the into one mutually exclusive industry final results allowed us to make category (manufacturer, dietary collected information on employment meaningful inferences regarding the ingredient supplier, repacker/relabeler, that allowed us to classify some of these industry. For example, 65 percent of the holder, or establishment not already establishments by size for the analysis. establishments surveyed responded that classified). Establishments that Of the 1,188 matched records, 180 manufacture supplements and also were linked to parents. The parent they followed published good supply, repack, or hold dietary company data for these 180 manufacturing practice models; the 95 supplements or ingredients were establishments were merged with the percent confidence interval was 56 to 72 classified as manufacturers. survey universe. The remaining 1,008 percent. By size category, 52 percent of ii. Size stratification. The Small records did not link to an ultimate very small, 73 percent of small, and 89 Business Administration classifies parent company. For these records, the percent of large establishments companies as ‘‘small’’ based on the size establishment and parent company were responded that they followed published of the entire company, including both the same entity, so we used good manufacturing practice models parent and subsidiaries. If firms that establishment level data to classify size. (Ref. E2). Although we do not suggest manufacture dietary supplements have We classified each of the establishments that these percentages are precise, they 500 or fewer employees, they are in the survey universe as part of very do tell a plausible story of the current classified as small. Because the DS–EED small, small, or large businesses based use of good manufacturing practice data on size are only for specific on the employment size or annual models in the supplement industry: The establishments and not parent firms, we revenues of each establishment’s parent use of good manufacturing practice had to obtain parent company company. If an establishment or its models appears to be widespread but far information on employment or revenue parent company had 500 or fewer from universal, with use more likely the to correctly classify each establishment employees or sales less than $20 million larger the establishment.

TABLE 7.—NUMBER OF COMPLETED SURVEYS BY SAMPLING STRATA

Size Product type Very small Small Large Unknown Total

Vitamins and minerals ...... 19 39 13 1 72 Amino acids, proteins ...... 8 7 0 5 20 Herbals and botanicals, including extracts ...... 58 25 0 30 113 Supplements not already classified ...... 14 13 2 4 33

Total ...... 99 84 15 40 238

The mean survey results reflect the each practice. The use of a survey for the use of the survey answers from more degree of uncertainty associated with this economic analysis often required than one question to assess the impact

3 InfoUSA is a publicly held company that creates address, phone number, fax number, estimated business (SIC code or yellow page heading), key proprietary business databases. Their database sales, volume, number of employees, type of contact names, and titles. includes such information as: Company name,

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of each proposed provision. For • We could take the number of avoidable manufacturing mistakes. We example, answers to questions about reported cases and multiply by a factor have recall data that show that testing herbals might have been to account for underreporting. manufacturing mistakes exist, so we can combined with questions about whether • We could take the number of construct a possible link between the firms manufactured herbals. Some defective products and multiply by the manufacturing mistakes and potential highlights of the survey are: probability of illness for the given illnesses or injuries. The number of • Plant characteristics: Manufacturers defect. illnesses associated with a recall is both account for 62 percent of the total firms In an ideal analysis, we would variable and uncertain, and could be and 36 percent of manufacturers estimate the baseline both ways and anything from zero to quite large. We produce vitamins and minerals as their then compare them. For the analysis of concluded that one illness would not be primary product. illnesses from poor manufacturing an implausibly high average for a recall, • Use of published good practices, however, we did not have so we assumed that a recalled product manufacturing practice model: 65 sufficient data to perform either type of could be a proxy for a single reported percent of all firms follow some type of baseline estimate. illness associated with a defective We looked at many sources for good manufacturing practice model, product. We ask for comments on this information, including medical and primarily food good manufacturing assumption. other literature on adverse events, practices; 28 percent follow the NNFA Because there are no well established information from poison control centers, good manufacturing practices and 31 systems for the notification of adverse reports to the agency, popular percent follow FDA’s drug good health events related to dietary newspaper and magazine articles, and manufacturing practice requirements. supplements, and some significant • surveys of users. The literature review barriers to reporting, we assume that Personnel: 67 percent of all was conducted using Medline, establishments maintain records of unreported illnesses caused by poor Healthstar, Aidsline, Cancerlit, and manufacturing practices are personnel education, training, or OldMedline (Ref. E12). We found experience. substantially greater than reported evidence of many adverse events illnesses. We relied on Ref. E16 to • Quality control: 85 percent of all associated with dietary supplements. estimate a more precise relationship establishments have a unit or person For example, one recent survey found between reported and unreported rates. responsible for quality control. Almost that 12 percent of consumers (about 11.9 Based on empirical data for drug and 80 percent of all manufacturers conduct million) who have used an herbal vaccine reporting rates among other at least some type of identity tests on remedy claim to have suffered from side studies, the author of Ref. E16 incoming components and dietary effects or other adverse reactions (Ref. determined that for dietary ingredients and 96 percent of these E13). The American Association of supplements, reported illnesses firms also conduct some type of Poison Control Centers received 6,914 represent at best approximately 1 contamination test; 63 percent conduct reports on dietary supplements in 1998 percent of total illnesses (Ref. E16). A some type of potency test. Nearly 70 (Ref. E14). In a recent survey, 46 percent similar multiplier of 100 linking known percent conduct tests on inprocess of respondents answered that people get cases of foodborne illness to total materials or finished products. Of these sick from dietary supplements ‘‘often’’ incidence is often used. We assume that firms, 97 percent conduct identity tests, or ‘‘sometimes’’ (Ref. E3). In addition, reporting adverse health events due to 94 percent conduct contamination tests the agency has received many voluntary poorly manufactured dietary and 72 percent conduct potency tests. reports of illnesses caused by dietary supplements would occur at the same Asked whether firms hold reserve supplements (Ref. E15). The vast proportion as adverse health events samples of each finished batch, 75 majority of the illnesses described in the caused for other reasons by dietary percent answered yes. Of the plants that sources we consulted, however, are supplements. We show the sensitivity of have production processes, 70 percent reported as associated with the benefits to the choice of multiplier use production and process controls ingredients used in the products below, in the uncertainty and sensitivity that identify the points, steps, or stages themselves, not with poor analysis of our results. in the manufacturing process to prevent manufacturing processes. We have no The outbreak of eosinophilia-myalgia adulteration. Almost 68 percent of all direct evidence on what fraction of syndrome (EMS) resulting from incoming ingredient or component lots illnesses can be attributed to contaminated L–Tryptophan resulted in are tested now and almost 70 percent of manufacturing processes. The anecdotal the recall of the contaminated products. inprocess or finished product batches evidence implies that many illnesses In part based on this example, we are tested in some manner. could have been caused by poor assume that product recalls can indicate • Warehousing: 70 percent of manufacturing processes, but with a few when there are adverse health events. warehouses have temperature controls exceptions, no evidence explicitly links We also assume that the reported class and 22 percent have humidity controls. illnesses to these manufacturing 1 and class 2 recalls that have occurred • Consumer complaints: Only 19 processes. over the last 10 years represent the percent report incidents to FDA. The agency’s recall records are more number and type of recalls that will useful than the reports on illnesses, occur in the future but for the 5. Baseline Risk because the class 1 and class 2 recalls implementation of this regulation. From The current number of illnesses all involve defective products that could 1990 through 1999, the agency received caused by poor manufacturing practices have caused illness if ingested. The reports on an annual average of 13 class requires data linking illnesses directly major public health events that have 1 and class 2 recalls of dietary to poor practices. Without direct been linked to poor manufacturing supplements. If each recall is a proxy for evidence on the number of illnesses processes show up in the list of dietary a reported illness, then the total number caused by poor manufacturing practices, supplements recalled. Although the of unreported illnesses per year is we had to use an indirect approach. recall data cannot be linked directly to approximately 1,300. Obviously, to the There are two indirect ways to estimate illness data, we have found anecdotes, extent that products are successfully the number of illnesses caused by surveys, and some medical literature on recalled, illnesses will be avoided. Our defective products: illnesses that could be caused by assumption is that the recall occurs

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because at best one person on average the reduction in pain and suffering, and suffering (as measured by the symptom- has been made ill. We recognize that our (3) the reduction in expenditures on problem index 5). These losses per day procedure generated highly uncertain medical treatment. We measured lost can be interpreted as the difference estimates of the number of illnesses. productivity indirectly with measures of between a day of normal health, where The use of recalls to estimate reported functional state, which includes normal is defined as the population’s and unreported illnesses probably measures of physical function. We health not affected by these products, generated a distribution of illnesses estimated the losses caused by pain and and a day of suffering from the health below the ‘‘true’’ distribution, because suffering with a symptom-problem conditions caused by these defective many illnesses occur that are not linked index. We used direct measures of products. The numerical scale is a to recalls and are never reported. We medical costs, such as payments to relative baseline that rests on the notion were not able to determine even the physicians and hospitals.4 of a quality-adjusted life day (QALD). approximate size of the underestimation Table 8 of this document contains from this procedure. summaries of our measures of the health The QALD for a day of normal health We estimated the monetary value of effects potentially caused by known equals 1; the QALD for death equals 0. the health benefits from CGMP instances of defective products The loss of QALDs per illness equals the regulations by multiplying the number associated with poor manufacturing daily loss multiplied by the number of of illnesses prevented by the health processes. We estimated the health loss days the illness lasts. We converted costs associated with an illness. The per day for the different levels of illness QALDs to dollars by multiplying the health benefits associated with severity by summing the lost index numbers by the value of a preventing an illness come from: (1) productivity (as measured by functional statistical life day and adding the direct Preventing the loss of productivity, (2) state) and the loss from pain and medical costs.

TABLE 8.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990 AND 1999

Number Frequency of Quality ad- Duration of Medical cost Health cost Problem Class of of Outcomes illness justed life illness ($) per ($) per recall recalls (percent) day (days) event event

Hypervitaminosis A ... 1 2 ...... 100 0.472 3 84 936 Salmonella ...... 1 4 Mild ...... 93.8 0.473 2 0 534 Moderate ...... 5 0.473 5 800 2,223 Severe ...... 1.2 0.563 17 9,100 14,859 Reactive arthritis 2 0.42 25 100 6,438 (short term). Reactive arthritis 1 0.42 5,223 400 1,320,252 (long term). 2 4 Death ...... 0.04 ...... 9,100 5,009,100 Klebsiella pneumonia 1 1 Severe ...... 85 ...... 6,235 10,650 Death ...... 15 ...... 6,235 5,006,325 Selenium poisoning ... 1 1 Low doses ...... 50 0.482 3 84 954 Severe ...... 35 0.482 3 2,578 4,448 Death ...... 15 ...... 2,578 5,002,578 Stannous fluoride ...... 1 1 Acute ...... 100 0.473 3 84 938 2 1 ...... 0.473 3 84 938 Eosinophilia-myalgia 1 7 Mild ...... 47 0.482 5,223 1,176 1,515,863 syndrome. Moderate ...... 50 0.482 60 84 17,484 2 41 Severe ...... 10 ...... 14,964 27,394 Glass fragments ...... 2 1 Dental injury, simple 50 0.231 1 139 ...... Dental injury, com- 12 ...... 3,741 ...... plicated. Oral emergency ...... 12 ...... 3,741 6,428 Tracheo-esophageal 25 ...... 290 obstruction. Esophageal 1 ...... 14,964 23,343 performation. Hypervitaminosis D ... 2 1 ...... 100 0.473 3 168 1,022 Pyridoxine (vitamin 2 2 ...... 100 0.482 30 168 8,868 B6). Super-potent zinc ...... 2 1 Mild ...... 50 ...... 285 Moderate ...... 40 ...... 596 Severe ...... 10 ...... 1,247 3,347 Niacin ...... 2 1 ...... 100 ...... 84 4,258 Yellow #5 2 5 Mild allergic reaction 90 0.44 2 0 529 (undeclared). Severe allergic reac- 10 ...... 2,494 3,346 tion.

4 The cost of a hospital day is from the Health 5 Functional Status Code is a measure of lost is not possible. Symptom-problem health utility Care Financing Agency’s Indicator Tables. It is the mobility (MOB), physical activity (PAC) and social index is a weighted measure of the cost of each amount per patient day in 1997, adjusted to 1999 activity (SOC). Lost MOB might mean an inability symptom. For example, a sick or upset stomach has dollars. See Ref. E17. to drive a car. Lost PAC might mean walking with a utility weight of .290. physical limitations. Lost SOC might mean self-care

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TABLE 8.—SUMMARY OF HEALTH EFFECTS BASED ON POTENTIAL ILLNESS ASSOCIATED WITH RECALLS BETWEEN 1990 AND 1999—Continued

Number Frequency of Quality ad- Duration of Medical cost Health cost Problem Class of of Outcomes illness justed life illness ($) per ($) per recall recalls (percent) day (days) event event

Contact dermatitis .... 50 ...... 84 1,205 Yellow #6, red #40, 2 1 Abdominal cramps .... 10 0.473 3 84 938 blue #2 (undeclared). Contact dermatitis .... 90 ...... 84 1,205 Copper salts ...... 2 1 ...... 100 0.473 1 84 369 Digitalis ...... 1 33 Mild ...... 94.9 0.473 3 84 938 Severe (heart block) 5 ...... 1,247 455,883 Death ...... 0.1 ...... 5,000,000 Ephedra (undeclared) 1 1 Cardiovascular ...... 14 ...... 1,415 3,530 CVS w/chronic ...... 2 ...... 2,591 457,227 Nervous system ...... 14 0.47 2 1,331 1,900 NS w/chronic ...... 2 ...... 2,507 455,597 Liver impairment ...... 4 ...... 168 4,342 Exfoliative dermatitis 7 ...... 84 1,206 Other ...... 54 0.29 1 0 174 Death ...... 3 ...... 2,507 5,002,507 Lactose (undeclared) 2 1 Mild ...... 100 0.48 1 0 290 intolerance. Iron poisoning ...... 2 1 Mild ...... 100 0.48 1 84 374 Sulfites (undeclared) 1 1 Mild allergic reaction 100 0.44 2 0 529

We used the transformed value of is $5 million/7,968, which is expenditures, reflect the foregone statistical life to estimate the value of approximately $630. We use this value benefits from alternative investments. QALD. For the most likely value of a to estimate the public health benefits The pure social rate of time preference statistical life day, we used $630. We from preventing illness. can differ from the return on private derived this value from a widely-used In addition to lost productivity and investments. pain and suffering, illness caused by estimate of the value of a statistical life: 6. Benefits and Costs $5 million. The $5 million estimate is supplement contamination leads to based on calculations matching labor direct medical costs. Direct medical Changes in current practices by market risks with wages for risky jobs. costs include the cost of medicine, manufacturers, or consumers, or both, Workers in risky jobs tend to receive hospitalization, and visits to physicians cause incremental (marginal) benefits increased wages to compensate them for and other professionals. We included all and costs. There are several possible (usually) small increases in the estimated medical costs, not just out-of- reactions manufacturers might have to pocket expenses. These full medical the proposed regulatory requirements: probability of death. The implicit value • of a statistical life is the increased wage costs often are missed because most Stop producing dietary divided by the increased probability of medical care is covered by health supplements and possibly go out of death. The advantage of valuing insurance that separates the bearer of business. • Move production to a foreign statistical lives with this method is that the medical cost (society) from the country where compliance with these it reflects the observed willingness of bearer of the utility losses (the ill regulations is more difficult to enforce. workers, and by inference, of the whole person). The total costs of illnesses caused by • Comply with part or all of the population of adults, to accept small the contamination of dietary proposed regulation. Consumers will risks to their lives in a real world risk- supplements from poor manufacturing likely be confronted with higher priced dollar tradeoff. practices would be the costs per illness dietary supplements but also products We turn the estimated value of a (classified by severity) multiplied by the that are, on average, more uniform and statistical life into a value of a statistical number of illnesses (classified by higher quality. To the extent that the life day by first assuming that the severity). For chronic illnesses, the latter is unknown to consumers, they workers have a remaining life utility losses and medical costs stretch will probably reduce consumption of expectancy of 36 years (Ref. E18). Using indefinitely into the future. We used a dietary supplements, perhaps in some a 3 percent social rate of time real discount rate of 7 percent to cases substituting them with alternative preference, the present value of 36 years calculate the present value of chronic products such as foods. is 21.83 years. The social rate of time medical expenditures and utility losses. The benefits from the proposed preference is the average long-term real OMB suggests using a real discount rate regulation and the regulatory options rate of interest, with no premiums for of 7 percent to analyze the costs and result from reducing contamination and risk and other factors that affect interest benefits of regulations. This rate adopting practices that will result in rates. Most analysts use the average real approximates the marginal rate of return consistently high quality dietary rate on long-term treasury bonds (3 to 5 on an average investment in the private supplements. Creating industry-wide percent in recent years) to represent the sector in recent years. We used a minimum requirements for good social rate of time preference. The different discount rate for the social rate manufacturing practices should reduce discounted expected days lost for a of time preference (3 percent) and the the occurrence of product defects, statistical death is 21.83 x 365 = 7,968. discount rate of future medical costs (7 which in turn should reduce the Therefore, the value of a statistical day percent). Medical costs, like all number of illnesses and deaths.

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Defective products can cause isolated dietary supplements, which would $healthij = health costs of severity level cases of illnesses, but also rare reduce the number of illnesses and the i of illness j; catastrophic events such as the outbreak probability of deaths caused by QALD = quality adjusted life day; of eosinophilia myalgia syndrome manufacturing problems. The proposed $ per QALD = dollar value of a (EMS) that resulted from the rule would also improve product safety statistical day; consumption of contaminated L- through the provisions requiring records $ medical = direct medical costs; Tryptophan. That outbreak caused 38 and investigations of consumer Eb = expected health benefit from deaths and over 1,500 illnesses. complaints related to manufacturing j The provisions that require practices. We assumed that the preventing a single case of illness j; establishments to maintain consumer proposed rule would reduce both fij = frequency of severity i of illness j complaint files related to manufacturing sporadic illnesses and catastrophic (S fij = 1); practices will generate additional health outbreaks. We estimated the reduction m = number of levels severity for illness benefits. The use of these files by of sporadic or annual illnesses by using j; manufacturers and the agency will help the agency’s recall records as evidence EB [c1], EB [c2] = expected benefits identify dietary supplements that were of possible illnesses; class 1 and class 2 from preventing an average illness manufactured or contaminated in ways recalls of dietary supplements all associated with a class 1 recall or a that could cause a significant or involved adulterated products that class 2 recall; unreasonable risk of illness or injury. could have caused illness if ingested. wj = weight of illness j; We estimated the reduction of illnesses These records may reduce the rj = number of product recalls for hazard likelihood of catastrophic events, from preventing catastrophic events by j; using the public health effects of the because a cluster of illness complaints n = number of hazards or potential types outbreak of EMS that resulted from could be identified, and preventive of illness. action taken before the number of consumption of contaminated L- illnesses reached catastrophic levels. Tryptophan. We then repeated the procedure for Improved product quality will also i. Reduced illnesses estimated from class 2 recalls and the associated reduce the number of products recalled. recall data. For annual illnesses, we illnesses in table 8 of this document. Certain manufacturing practices, such as used this formula for estimating the Table 9 of this document shows the more frequent finished product quality benefits from fewer illnesses: average value of preventing a single testing, help establishments to identify Marginal health benefits = baseline (or illness associated with class 1 and class problems before the products are current) number of illnesses caused 2 recalls. × released for consumption. If defective by poor manufacturing practices We estimated the annual marginal products are caught before they are expected reduction in the number health benefits as the health benefits per of illnesses brought about by the illness for each class of recall multiplied released, they will not be recalled. × Creating minimum requirements proposed regulation health cost by the estimated number of recalls. saved per prevented illness. should also generate benefits for Health Benefits = (EB[c1] × estimated consumers by reducing the variation in We estimated the annual expected annual number of class 1 illnesses product quality. Creating verifiable health benefits for the proposed rule by prevented) + (EB[c2] × estimated minimum manufacturing requirements taking the values in table 8 of this annual number of class 2 illnesses reduces the private effort necessary to document and weighing them by their prevented). distinguish products manufactured, incidence in the table. We computed the packaged, and held using good practices expected health benefits from To estimate the number of illnesses from those using poor practices. preventing a single illness (of any type) prevented, we started with the average Reducing the effort needed to find associated with a class 1 recall as a annual number of products recalled for products with the identity, purity, weighted average of all potential the decade 1990 to 1999—six class 1 strength, quality, and composition, illnesses (see table 8 of this document), and seven class 2. As discussed above, among other characteristics, creates a with the potential illness divided by the we then assumed that these recalled potentially substantial, though implicit, total number of class recalls. products represented proxies for about 1 benefit for consumers. The following formulas show how we percent of all illnesses caused by these The benefits from the proposed rule, calculated the average health benefits of problems leading to the recalls. With then, are from: preventing a single illness associated that assumption, we get 600 illnesses • Reduced health costs caused by the with a class 1 recall. from class 1 recalls and 700 illnesses reduced number of illness; $healthij = (QALD × days × $ per from class 2 recalls (see table 9 of this 6 • Fewer product recalls, and; QALD)ij + $ medicalij document). • Greater assurance of consistent and EBj = Si (fij x $healthij) Table 9 of this document shows the better quality products. EB [c1] = Sj (wj × EBj) estimated value of the health benefits a. Reduced illnesses. The proposed wj = rj/(Sj rj) from the proposed rule using class 1 and regulation would improve the safety of Where: 2 recall data.

TABLE 9.—HEALTH BENEFITS USING RECALL DATA

Total number of illnesses prevented, recall base ...... 1,300 Total number of illnesses associated with class 1 recalls ...... 600 Total number of illnesses associated with class 2 recalls ...... 700

6 We used a probability distribution to represent negative binomial distribution estimates the the probability of reporting equaled 1 percent (Ref. the uncertainty associated with the number of number of failures (unknown cases) that will occur E16). The result is that the mean estimated number illnesses. We modeled the number of illnesses before some number of successes (known cases) for of illnesses is 100 times the reported number of prevented for each class as the average number of a given probability of success. In the negative recalls. recalled products plus a negative binomial binomial distribution, we assumed that the number distribution representing unknown cases. The of recalled products were reported cases and that

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TABLE 9.—HEALTH BENEFITS USING RECALL DATA—Continued Dollar estimate of health benefit for preventing an illness associated with a class 1 recall ...... $60,000 Dollar estimate of health benefit for preventing an illness associated with a class 2 recall ...... $5,000 Dollar estimate of annual health benefits, recall base (million) ...... $39

ii. Health benefits from preventing a health event; the defective products percent of EMS patients were still rare catastrophic event. We estimated could be identified and withdrawn well symptomatic 21 to 64 months after the marginal health benefits from before the event claimed as many onset. The symptoms associated with reducing the probability of a victims as L-Tryptophan. EMS also frequently lead to activity catastrophic event as follows: To estimate the benefits from limitations. Another study of victims Marginal health benefits = Change in preventing reduction in the probability (Ref. E22) found that 74 percent of probability of rare catastrophic of a rare catastrophic event occurring, symptomatic EMS sufferers were event caused by poor we first estimated the period between limited in their functions 12 months manufacturing practices brought now and the last rare catastrophic event, after the onset of illness. about by the proposed regulation × 1989, and we needed to make baseline assumptions about the likely time To find the health cost of the the number of illnesses caused by outbreak, we estimated the cost of the the rare event × health cost saved interval between events. The last following health outcomes: Death, acute per illness. catastrophic event occurred over 13 years ago, so we assumed that the lower illness only, chronic illness with no In 1989, there was a widespread activity limitation, chronic illness with outbreak of EMS resulting from bound would be 50 years. For lack of data, we then assumed a uniform mild activity limitation, chronic illness consumption of contaminated L- with moderate limitation, and chronic Tryptophan. More than 1,500 cases (175 probability distribution between these two bounds, which leads to a rough illness with severe limitations. To acute illnesses and 1,287 chronic determine the cost for each of these illnesses) and 38 deaths were identified estimate of once in 30 years. We do not health outcomes, we multiplied the lost in 50 states (Refs. E21 and E22). The know how likely rare events are, nor do quality-adjusted life days over the outbreak prompted a recall of all dietary we actually know the likelihood of duration of the illness by the value of supplements that contained more than reducing these events by the proposed a life day. For medical costs, we 100 mg per daily dose, which later was regulation. There can be no conclusive expanded to almost all products empirical support for the likelihood of estimated the cost of hospitalization for containing L-Tryptophan. We used the a future event because the past may not the EMS patients who required public health cost of this event as an predict the future in the absence of a hospitalization (32 percent of all estimate of the cost of a future rare stable frequency distribution that victims), by assuming 3 days per catastrophic event associated with reflects a statistically significant number hospital stay. We used $1,284 as the dietary supplements. of similar events. All we know is that cost per day of time spent in a hospital EMS is characterized by severe such an event occurred at least once in (Ref. E17). We assumed that chronic myalgia and elevated eosinophils the recent past, and remains a sufferers visited the doctor once a year counts. Some of the most common possibility. We recognize that our lack at a cost of $84 per visit. We estimated symptoms are fatigue, weakness, fever, of information about such events creates the total cost of the event to be about $2 and arthralgia. Although a repeat of the significant uncertainty about the social billion. Most of the cost of the outbreak EMS outbreak is not expected, it is an costs of these events and the health comes from the deaths and severe example of the rare, catastrophic events benefits from reducing their impact. Our chronic illnesses. Table 10 of this that should be prevented or mitigated by estimate is meant to convey the document shows the values used in the the proposed CGMP regulation. The potential or hypothetical enormity of calculation. Note that the categories are testing provisions of the proposed such an event, not the certainty of such not mutually exclusive. The average age regulation should reduce the probability an event. We would like comments of victims was about 50, so the value of that contaminated ingredients would be regarding our estimate of such an event. statistical life was adjusted accordingly. released to the public. The provisions The health cost of the EMS outbreak If the event occurs about once in 30 for keeping complaint files and was large because of the number, years in the absence of the proposed investigating complaints would allow severity, and duration of the cases. One rule, then the expected average annual more rapid identification of a major followup study (Ref. E21) found 88 cost would be about $66 million.

TABLE 10.—HEALTH BENEFITS FROM PREVENTING RARE CATASTROPHIC EVENT

Costs per Number case

Hospitalization ...... 480 $3,741 Death ...... 38 4,214,301 Acute Illness ...... 175 8,760 Chronic illness not limited ...... 380 1,091,849 Mild chronic illness, limited ...... 190 1,349,002 Moderate chronic illness, limited ...... 307 1,601,539 Severe chronic illness, limited ...... 409 1,602,844 Visits to physicians ...... 1,287 1,539

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The benefits attributable to this catastrophic number of illnesses and the assume consumers expect some proposed rule from preventing a rare public health system accurately unknown number of their products may catastrophic event are highly uncertain. recorded the full number of both not meet their expectations but We do not know if such an event would, sporadic and catastrophic illnesses. purchase them anyway. In other words, in the absence of the proposed b. Fewer products recalled. we cannot rule out the possibility that regulation, ever occur again. The EMS Implementation of the proposed the purchase price already incorporates outbreak may have been a unique event, regulation would reduce the number of the expectations of consumers that some although the recent severe public health adulterated products distributed to the products will be ‘‘lemons.’’ Because we effects associated with aristolochic acid public, which would reduce the number cannot look into the minds of in Europe show that such similar events of products recalled. Manufacturing consumers to determine their remain possible (Ref. E23). We also do practices, such as testing of finished expectations or their willingness to pay not know that if another catastrophic products and better recordkeeping, will for these products, we can only estimate event occurred, the health effects would increase the ability of establishments to the benefits from more uniform quality be as large as for L-Tryptophan. Some of identify problems before products are by estimating the changes in behavior the smaller clusters associated with released for distribution. If adulterated that would occur if consumers were dietary supplements could represent products are caught before they are aware of the change in quality brought small events potentially prevented by distributed, they will not be recalled. about by the proposed rule. In other the proposed CGMP regulations (Ref. To estimate the direct benefits from words, we assume that if the quality E15). fewer recalled adulterated dietary attributes of dietary supplements were We included reducing the likelihood supplements, we estimated the baseline observable, then consumers would of a catastrophic public health event as number of annual recalls of dietary spend time searching for those a benefit of the rule because the battery supplements due to contamination attributes, as they do for other goods. of checks and controls that would be before the proposed regulation. From We measured this benefit as a reduction required under the proposed regulation 1990 to 1999, FDA received reports on in the hypothetical search costs for would reduce the likelihood of such an an average of 20 recalls per year (Ref. product quality, meaning the identity, event occurring again. In particular, the E12). The average figure reported here quality, purity, strength, and requirement that establishments keep includes class 3 recalls. The number of composition claimed on the label. records of consumer complaints should units of dietary supplements for each The hypothetical measure of quality lead to early identification and recalled product varied, so we used a starts by assuming the existence of a prevention of potential catastrophic distribution per recalled product of baseline amount of search necessitated events related to manufacturing 1,000 units to 34,000 units (Ref. E12). by the existence of poor manufacturing practices. Product price also varied, with most practices. Our hypothetical consumers Our estimate of the health benefits prices falling between $5 per unit and must search for products made with associated with this proposal is based $9 per unit; we used a most likely price good manufacturing practices, because on two models that estimate future of $7.70 per unit. We also included an they cannot take such practices for illnesses and deaths prevented by this adjustment for the goodwill lost by the granted when purchasing dietary proposed rule: Illnesses caused by establishment as a result of the recall. supplements. Although the search we sporadically adulterated products and Studies of changes in market valuations use as a measure of the benefits from predicted by recall data; and rare of firms after recalls indicate that the improved quality is hypothetical, the catastrophic outbreaks of illnesses, as value of lost customer goodwill, based values we use in estimating our search predicted by one previous event in the on the decline of the share price of model are based on data and inferences United States and corroborated by one publicly traded stocks from recalls is about real searches for other products. in Europe. The frequency and often as large as the cost of the recall To get the products they want, people magnitude of a rare catastrophic event is itself (Ref. E24). We multiplied the search across the range of market largely hypothetical. In contrast, direct cost of the recall by two in order alternatives. Several recent articles have sporadic illnesses are small but frequent to include the lost goodwill. The result noted the large variation in product events that happen routinely. Small is an estimated savings of about $3 quality for different goods and services sporadic events are characterized by million per year. (Refs. E25, E26, and E27). Searching significant underreporting primarily We based the estimated benefits from takes time and resources that could be because of the difficulty linking an fewer recalled products on our recall used for other purposes, so a regulation illness with the cause of an illness. data. If there were private recalls due to that reduces search provides measurable Determining the cause of an illness in contaminated supplements that were benefits to consumers. To reduce the small sporadic events is made even not included in our data, the benefits effort devoted to searching, consumers more difficult because only the most from reduced recalls may be of dietary supplements should therefore serious illnesses are likely to be understated. be willing to pay some amount. We lack, reported and because of the difficulty of c. Reduced hypothetical search costs however, a measure of what they would linking the cause of an illness with poor as a measure of the benefit from be willing to pay, partly because some manufacturing practices. Catastrophes increased assurance of quality. consumers may not know that dietary are large but infrequent events that Consumers incur a cost if they purchase supplements may contain more or less create hundreds of illnesses with products but do not get the quality of (or something not even expected) of reporting that is close to complete product they anticipated. Determining what they think they are buying. Indeed, because the public health system the cost they incur is difficult, because if consumers of dietary supplements typically devotes considerable care in we cannot look at the price of poor could determine the quality of these identifying the origin and magnitude of quality products and conclude that products by merely examining the the problem. Adding these two models consumers paid too much, even when product or the label, the market alone should not lead to double counting the they did not get the quality they would be sufficient to ensure that firms health benefits. Double counting would anticipated. We cannot disentangle the responded to consumer preferences for most likely occur if a recalled product price consumers are paying, from the product quality. Consumers would caused both sporadic illnesses and a price they should be paying, because we search for those brands that are more

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likely to have the desired quality, and rule will be the implicit value of the improved mean product quality. We manufacturers would most likely adopt gain in product quality enjoyed by all anticipate little or no change in sufficient quality controls to satisfy consumers. aggregate shopping time for dietary consumer preferences. The market The problem is to measure that gain supplements. response is weak now because only based on hypothetical searches. We We converted the time measure into some consumers know that product needed to use data from searches in a monetary measure by multiplying the quality problems exist, and even these other markets, because we found no time reduction for sophisticated consumers must rely on imperfect information on direct or indirect consumers by the average wage rate. information. If there were uniform searching for minimum dietary The benefits measure reduced search quality control practices throughout the supplement quality standards. For the time associated with improved quality industry that ensured against product sophisticated consumer, we assumed assurance: quality defects, consumers would not that the value of search time should be Quality assurance benefits = reduction have to search for the products that they approximately the same as the in search time (in hours per year) believe are free from contamination or willingness to pay for an attribute of the per sophisticated consumer × have the identity, purity, strength, good. Sophisticated consumers will average wage rate per hour × total quality, and composition they want. hypothetically search until the expected number of consumers. Consumers could more reasonably benefit of continued searching is less The shopping time model is an indirect assume that all products are free from than the expected cost of continued approach to measuring benefits in a contamination and have the identity, searching. The total cost of search time market with asymmetric information; it purity, strength, quality, and will, on average, be no more than the is not a prediction about how shopping composition stated on the label. expected cost of the additional quality behavior will change in that market. We faced the problem of trying to desired. Search time includes the time measure what people would pay for Indeed, we believe that most of the spent: Reading product labels and other beneficiaries of this part of the rule will more uniform products quality if they literature about the product, comparing knew that manufacturing quality never recognize that they are one product with other products, beneficiaries. requirements did not already exist. To examining the product itself (sometimes estimate what people would pay, we Standardization imposes minimum carefully), thinking about the product, requirements on manufacturing, which start with the hypothetical behavior of and second guessing final decisions. It people aware of the lack of uniform in turn should reduce the variance of might also include the time actually product quality. The reduction in product quality; we call these shopping for the product: Finding the hypothetical people the ‘‘sophisticated product quality variation should reduce locations where the product is sold, the amount of information sophisticated consumers.’’ driving there and back, waiting in Sophisticated consumers spend time consumers need to acquire before checkout lines, and walking up and purchasing dietary supplements (Ref. searching for signals about the quality of down the aisles. dietary supplements. The proposed E29). People need not rely as much on We used information on shopping such indicators as brand names, price, CGMP regulations would reduce the times for a range of products to derive amount of search (by some uncertain place of purchase, articles in consumer an estimate for the hypothetical search magazines, or advertising to determine amount) carried out by these consumers. time for dietary supplements. We The benefits of the rule, however, would the likelihood that dietary supplements assumed that some fraction of shopping meet minimum quality standards. not be confined to sophisticated time is pure search time, although we consumers. We also expect ‘‘naive Although no studies deal with dietary also recognize that search time includes supplements directly, the literature on consumers’’ to enjoy the benefits. Naive more than the search for product consumers would incur the costs of consumer search for other commodities quality. Some search time, for example, additional search once the correct or provides insights that increase our is for price, efficacy, and other adverse information about quality is understanding of the search costs for attributes. The reduction in search time available, suffer from worry or an illness supplements (Refs. E30 and E31). for the sophisticated consumer would from taking poor quality products, or Duncan and Olshavsky (Ref. E32) therefore be at most a fraction of total incur the cost of paying for products surveyed buyers of television sets and search time for dietary supplements. that do not meet their needs (Ref. E28). found that 88 percent of respondents The measure of time saved then is: Once good practices are in place they performed some type of search activity would avoid these costs. Naive Reduced search time due to CGMP before purchase. In a study (Ref. E33) of × consumers are those who fail to search regulation = shopping time consumer search for microwave ovens, for quality or search little not because fraction of shopping time spent the average buyer of a new microwave × they do not care but because they do not searching fraction of search time oven was willing to search for four know that quality varies as much as it associated with searches for quality alternative products. Search for × does. In other words, they lack the fraction of search time associated groceries has been characterized as a information that problems exist; if they with searches for quality that would two-stage process (Ref. E34). First, know about the problems, they would be eliminated if CGMP rule people engage in prestore activities, search or be willing to pay more to guaranteed minimum quality. such as reading advertisements, writing ensure that supplements they consume We took the estimated reduction in shopping lists, clipping coupons, and meet minimum quality standards. hypothetical search time for the comparing stores. Second, people Although these naive consumers may sophisticated consumer and applied it engage in search activities at the store, not change their behavior in response to to all consumers to get an estimate of including price and product comparison the proposed CGMP regulation, they the implicit benefits of establishing and search for items with coupons. Most would nonetheless enjoy the benefits. minimum quality standards. This people devote time to search activities The naive consumers, of course, also estimated saving in hypothetical search for all but the most routine purchases. represent real consumers of dietary time is not a forecast of reduced To estimate the reduction in supplements. The total benefits of the shopping time; it is a proxy measure of hypothetical search costs from the quality standards part of the proposed the benefit from reduced variance and proposed rule, we started with estimates

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of the time consumers spend in search • Grocery Store. reveal that adult Americans spent about for groceries and other household We used three models based on 364 minutes per week shopping for purchases (including durable goods). different assumptions because using a personal consumption items, such as We assumed that the search time for range of studies reduced the likelihood groceries and other household products. these products was related to shopping of systematic bias in our analysis. The grocery store model. In the time. Because search costs include the The drug store model. The drug store grocery store study, hidden observers costs of evaluating magazine articles or study recorded the amount of time tracked and recorded shopping time in brochures, the costs of obtaining a people spent looking at an item on the the store (Ref. E38). The study found friend’s advice, and the costs of instore shelf before making a purchase (Ref. that people on average spent about 21 product comparisons, our estimates will E36). Customers, on average, spent 3.75 minutes shopping in the grocery store. not correspond precisely to the actual minutes studying a product before By combining estimated time per trip costs of search for these products (Ref. purchasing it. Although there are with the Food Marketing Institute’s (Ref. E35). We believe, however, that the quality standards in place for over-the- E10) finding that consumers average measure will be a reasonable counter drugs and not for dietary about 2.2 grocery shopping trips per approximation. Although search time supplements, we assumed that this week, we generated an estimate of often takes place outside of measured represented a measure of the amount of search time for all grocery store shopping time, measuring search time time the sophisticated consumer might purchases of 46.2 (= 2.2 × 21) minutes as some proportion of total shopping spend searching for a product with the per week. time should generate a plausible if not desired quality. For each of the models, we needed to a precise estimate. The use of time model. The make assumptions to convert shopping We generated three models of search Americans’ Use of Time Project (Ref. time for other commodities into search time for dietary supplements, based on E37) used time diaries to study how time for dietary supplements. Table 11 three separate studies of shopping time: adults spent all of their time. The study of this document shows the • Drug Store. collected data from over 3,500 adults on assumptions and information used in • Use of Time. use of time. Data from these time diaries each model.

TABLE 11.—THREE MODELS OF SEARCH TIME: ASSUMPTIONS USED IN SIMULATIONS

Variable Value or distribution Source and notes

Drug Store Model

Search time in minutes per item ...... 3.75 ...... Ref. E30. Number of products per person per year ...... 6.57 ...... Ref. E4. Average wage rate ...... $15.65 per hour, or $0.26 per minute ...... Ref. E42. Population ...... 273 million ...... Ref. E19. Fraction of search time devoted to searching 0.2 (based on uniform distribution, 0.1 to 0.3) Based on number of attributes consumers for quality. search for.

Use of Time Model

Weekly shopping time for all items in minutes .. 346 ...... Ref. E37. Fraction percent of budget spent on supple- $15.5 billion/$6,250 billion ...... Ref. E4 and E19. ments. Average wage rate ...... $15.65 per hour, or $0.26 per minute ...... Ref. E42. Adult population ...... 205 million ...... Ref. E19. Ratio of search time to shopping time ...... 0.7 (based on uniform distribution, 0.4 to 1.0) Based on descriptions of shopper behavior. Fraction of search time devoted to searching 0.2 (based on uniform distribution 0.1 to 3.0) Based on number of attributes consumers for quality. search for. Potential reduction in search time attributable to 33% most likely (could be between 15 and Based on likelihood of problem and likelihood CGMP regulations. 50%). that search will decline proportionally, and the expert opinion of pharmacists.

Grocery Store Model

Weekly shopping time for groceries in minutes 46.2 ...... Ref. E38. Ratio of supplement expenditures to grocery $15.5 billion/$710 billion ...... Ref. E38. expenditures. Average wage rate ...... $15.65 per hour, or $0.26 per minute ...... Refs. E4 and E19. Adult population ...... 205 million ...... Ref. E19. Ratio of search time to shopping time ...... 0.7 (based on uniform distribution, 0.4 to 1.0) Based on descriptions of shopper behavior. Fraction of search time devoted to searching 0.2 (based on uniform distribution, 0.1 to 0.3) Based on the number of attributes that con- for quality. sumers search for. Potential reduction in search time attributable to 33% most likely (could be between 1% and Based on likelihood of problem, the likelihood CGMP regulations. 50%). that search will decline proportionally, and the expert opinion of pharmacists.

The drug store data generated a direct could be used to estimate the time total U.S. population to generate an estimate of search time. In the drug store searching for dietary supplements. We estimate of annual search time for model we assumed that the time spent then used data on the number of dietary supplements. standing in front of the drug product products purchased per person and the

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To estimate the time spent searching products, tobacco products, and results for the three models are shown for supplements from the use-of-time smoking supplies. Annual shopping in table 11 of this document. study, we assumed that the share of all time per person for dietary supplements d. Other benefits. The proposed shopping time devoted to supplements would therefore be about 52.5 minutes regulation could also reduce the total would be proportional to the share of a per year (= ($15.5 billion/$710 billion) time and effort that all covered consumer’s budget spent on × 46.2 minutes per week × 52 weeks). establishments expend to monitor supplements. We recognize that it could We again converted shopping time to ingredient suppliers and holders of their well be higher if supplements require search time by assuming that search more search than the average time equaled 40 to 100 percent of products. Because all ingredients and commodity. According to an industry shopping time. Like the estimate from holders would be subject to the same source and FDA projections, consumers the use of time model, this value was uniform minimum requirements, spent about $15.5 billion on dietary then multiplied by 205 million adults. variation in their practices would supplements in 1999 (see table 5 of this We used these three models based on decline, so firm monitoring of upstream document). Consumers spent about different assumptions because we and downstream vendors could decline. $6,250 billion on all personal wanted to explore a range of studies to The provision that requires consumption in 1999, which means that avoid systematic bias in our analysis. establishments to maintain complaints dietary supplements accounted for We recognize that the three estimated files would allow a manufacturer to about 0.24 percent of those annual search times for dietary more readily be able to identify a expenditures. Personal consumption supplements do not represent the search product that causes a significant or expenditures included in this estimate for quality alone. Consumers search for unreasonable risk of illness or injury. are food, alcoholic beverages, a variety of features; only part of every The manufacturer can then take housekeeping supplies (such as laundry search will be devoted to quality. We necessary steps to prevent any and postage), household furnishings and assumed that 10 to 30 percent of pure additional adverse health impact. We equipment (such as furniture and search time involves quality searches. have attempted to quantify this benefit appliances), apparel (includes Estimating the impact of CGMP for preventing catastrophic events, but footwear), personal care products and regulations on consumers’ search time is not for reducing smaller risks. FDA services, reading materials, tobacco difficult, since no previous studies have products, and smoking supplies. Annual analyzed the changes in search time adverse event reports, however, imply shopping time per person for dietary following the adoption of CGMP that many such small events occur, and supplements would therefore be about regulations or from increases in product the proposed rule could prevent some of 44.6 minutes per year (= ($15.5 billion/ quality standardization. However, a them (Ref. E15). $6,250 billion) × 346 minutes per week consistent finding from the literature is In addition, if the same adverse events × 52 weeks). We converted shopping that search time should decline show up in complaints received by time to search time by assuming that following a decrease in the variation in different firms selling products with the search time equaled 40 to 100 percent product quality (Refs. E35 and E40). In same or similar manufacturing of shopping time. Total search time the absence of previous empirical problems, no one firm selling such equaled search time per adult studies, we assumed that the proposed products may recognize the need to multiplied by 205 million adults. We rule would reduce the hypothetical investigate the complaints especially if assumed that all adults would perform search time for quality ‘‘the search time the risk is relatively low. Because we search, although we recognize that not of sophisticated consumers’’ by 1 to 50 would have access to complaint files, all adults consume dietary supplements percent, with 33 percent the most likely our review would be more likely than and not all search is conducted by value. A survey of pharmacists reported any individual firm’s review to identify adults. Children might search for these their belief that 30 percent of their the need to investigate the complaint products also. The opportunity cost for customers place manufacturing quality because of a reasonable possibility of a children, as measured by their wage rate as a top priority in selecting one herbal relationship between the manufacturing is much less than for adults, so we over another (Ref. E41). We also used process of a dietary supplement and the assumed their search time could be evidence from product tests that adverse event. ignored. We used the total adult indicated that up to 33 percent of population rather than just the adult products were missing key ingredients e. Total measured benefits. The total consumers of dietary supplements, or contained unwanted ingredients measured benefits from the proposed because the shopping time studies are (Refs. E25, E26, and E27). If the rule are the sum of the value of health for all adults. proposed rule guarantees that products benefits, the value of the reduced We estimated search time in the will contain what the label claims, then number of product recalls, and the grocery store model with assumptions perhaps search time for quality will reduction in hypothetical search costs. similar to those in the use-of-time decline by that percentage. Table 13 of this document shows the model. We assumed that the ratio of To estimate the value of the possible total benefits. search time for supplements to search reduction in searching for quality, we time for groceries would equal the ratio multiplied our estimated time saving by TABLE 12.—THREE MODELS TO of expenditures on supplements to the average wage rate, which is an ESTIMATED SEARCH COST SAVINGS expenditures on groceries. Estimates estimate of the value of time. The average hourly wage rate for U.S. from the 1998 Consumer Expenditure Baseline model Cost savings Survey (Ref. E39) (adjusted for changes workers was $15.65.7 We ran computer (in millions) in prices between 1998 and 1999) reveal simulations of all three models. The Drug store model ...... $108 that consumers spent approximately Use of time model ...... 101 $710 billion on grocery store purchases 7 Personnel Employment, Hours, and Earnings. Grocery store model ...... 119 in 1999. Grocery store purchases Series ID: EES00510006 Seasonally Adjusted, Industry: Goods-producing Data Type: Average Average of three baseline included food, alcoholic beverages, hourly earnings of production workers, models ...... 109 housekeeping supplies, personal care Employment Cost Index, Bureau of Labor Statistics.

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TABLE 13.—SUMMARY OF ANNUAL the proposed rule requires or microorganisms must be fitted with BENEFITS recommends. We then attached a cost to thermometers to accurately show the each provision that had an activity temperature within the compartments. associated with it. Most provisions did Instruments and devices used in Benefits Mean (in millions) not have costs attached to them, mainly manufacturing must be accurate, because they were either descriptive or adequately maintained, and adequate in Fewer illnesses (from table the costs were included elsewhere. For number. To meet this requirement 8) ...... $39 the rule as a whole, we estimated the establishments might have to purchase Fewer illnesses (from table 10) ...... 66 marginal, or additional costs for over 70 new equipment, replace old equipment, Fewer product recalls (from provisions of the proposed rule. or provide additional maintenance to table 9) ...... 3 We expressed the cost as cost per existing equipment. Reduced consumer search unit, with the unit being either the ii. Production and process controls. (from table 12) ...... 109 establishment, the number of Production and process controls are the employees, or the annual number of main preventive mechanism to ensure Total benefits ...... 218 batches produced. The costs of this the identity, purity, quality, strength, proposed rule included the following and composition in the proposed rule. 7. Costs general activities: Sanitation, Establishments must implement a The same changes in practices that production and process controls, system of production and process produce benefits also have costs, the holding and distributing, and consumer controls that covers all stages of opportunity costs of not doing what complaints. processing, from the receipt and consumers and manufacturers are now b. Costs of general activities. i. acceptance of components, dietary doing. The proposed regulation would Sanitation. Sanitation includes both ingredients, dietary supplements, require dietary supplement one-time capital improvements and packaging, and labels through the establishments to adopt some new ongoing efforts. Some provisions of the release for distribution and holding of practices in order to manufacture, proposed regulation may require the dietary ingredients and dietary package, and hold their products. The establishments to perform one-time supplements. Establishments must costs incurred for those who choose to capital improvements to their physical identify points, steps, or stages in the comply will be for personnel, grounds plant facilities. manufacturing process where control is The proposed regulation would also and physical plant, equipment and necessary to prevent adulteration. require, if not already in place, physical instrumentation controls, quality Establishments must also establish plant owners to install new or specifications for the identity, quality, control and laboratory operations, additional plumbing systems to carry purity, strength, and composition of production and process controls, additional water or sewage, additional components, dietary ingredients, or handling consumer complaints, and toilet or hand washing facilities, dietary supplements. Establishments holding. In some cases, establishments additional facilities for trash disposal, or must monitor the points, steps, or stages would need to make capital new signs to instruct employees. The in the batch production, as specified in improvements to the physical plant, add proposed regulations might also require the master manufacturing record, where or replace equipment or controls, establishments to add space in order to control is necessary to prevent perform additional maintenance, keep keep equipment and materials farther adulteration. Establishments must records, carry out tests, or execute a apart, which will help to prevent establish specifications for packaging to variety of additional tasks that they may contamination or mixups. Other ensure that containers or closures that not have previously performed. We possible capital expenditures (among come into contact with dietary estimated the additional costs of many other possible requirements) ingredients or dietary supplements are production associated with the include: not reactive or absorptive and are proposed rule and the leading • Replacing floors, walls, or ceilings composed of substances that are safe for regulatory options, using the survey with smooth, hard surfaces; use in or on food. (Ref. E2) to estimate baseline • Changing fixtures, ducts, or pipes Establishments that have not already manufacturing practices. that might be a source of contamination done so must establish a quality control a. Description of the costs. To estimate by dripping or condensation; unit with one or more individuals that costs for the dietary supplement • Adopting ventilation control have with the authority and industry, we initially divided the systems including filters, fans, or other responsibility to review the results of industry into four product categories air-blowing equipment to prevent odors monitoring, make decisions on the and three size categories. Because the or vapors; disposition of materials, and identify survey showed that there were only a • Additional lighting to ensure that whether actions taken to correct any few establishments in some categories, equipment, contact surfaces, or other deviations are appropriate. The quality we consolidated the size and product areas where supplements are examined, control operation must ensure that into three size categories. The size processed, or held can be adequately components, dietary ingredients, and categories were: seen. dietary supplements conform to • Very small (fewer than 20 Sanitation also requires that specifications. employees). equipment utensils must be of suitable iii. Holding and distributing. • Small (20 to 499 employees). design, construction, and workmanship Establishments must hold and distribute • Large (500 or more). to enable them to be adequately cleaned dietary ingredients and dietary Although this consolidation glosses and maintained. To meet this supplements under appropriate over the important differences across requirement, some establishments may conditions of temperature, humidity, products, the purpose is to estimate the need to provide additional maintenance and light so that the identity, quality, broad average costs of the rule. or additional cleaning and sanitation for purity, strength, and composition of the For each category, we constructed a their equipment and utensils. Also, dietary ingredients and dietary cost model that included every freezers and cold storage compartments supplements are not affected. provision of the CGMP regulations that used to slow or arrest the growth of Establishments must also identify and

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hold components, in-process materials, are measured by the workers’ wage rate, costs to develop tests, for the number of and dietary supplements under which we assumed is $15.65 per hour tests and the costs for performing each conditions that will protect them against based on the average manufacturing test to comply with this requirement. mixups and physical, chemical, and wage, multiplied by the expected labor • Number of tests: Model. To estimate microbial contamination. Packaging hours necessary to perform a written or the costs of testing, we first estimated materials must also be protected against electronic record and the time necessary the number and costs of individual deterioration. Establishments that do for management to review the records to tests, without adjusting for the amount not now perform these requirements see the actions are documented of testing already being done. In this and the other provisions associated with accurately. For electronic records, the section we show how we estimated the holding will incur a compliance cost. recurring time is the time necessary to likely number of required tests, iv. Consumer complaints. The quality ensure that the equipment is serviced unadjusted for current voluntary testing. control unit must review all consumer and maintained properly. For a representative manufacturer, the complaints involving the failure of a ii. Capital costs for physical plant and annual number of tests would be the dietary supplement to meet any of its equipment. We estimated capital costs number of new tests per batch specifications, or the failure to meet any for physical plant redesign at $50 per multiplied by the number of batches other requirements under proposed part square foot (Ref. E45). For produced in a year. 111, including those specifications and establishments with inadequate The proposed rule requires only tests facilities, we assumed that between 0 other requirements that, if not met, may for identity, purity, quality, strength, and 20 percent of the physical plant result in possible illness or injury. In and composition of the final product. would have to be renovated, with 10 addition, the quality control unit must The option for stricter CGMP percent the most likely. For equipment investigate such a consumer complaint regulations would also require tests of costs, we assumed that very small where there is a reasonable possibility components. Estimating the number of establishments would on average spend of a relationship between the component tests per batch is 0 to $1,000, with $100 the most likely consumption of a dietary supplement complicated, because component tests amount. Small establishments would and an adverse event. The complaint are made on the shipment lots, rather bear costs 3 times that of very small and report of the investigation results than on the parts of the lots that actually establishments, which is the ratio of the should be reported to FDA when there go into the final product. For example, size of the physical plants of small is a possibility of a serious adverse if a lot of some ingredient is used in 6 establishments to the size of the event. batches of final products, it would physical plants of very small c. Major costs by type of activity. probably be tested only once. Within these four categories (sanitation, establishments. We assumed that large The establishment itself may test the production and process controls, establishments would bear (if necessary) shipment lots, and during inprocess holding and distributing, consumer costs 20 times that of very small stages for identity, purity, quality, complaints), the major costs of the establishments, which is the ratio of the strength, and composition, unless final proposed rule are recordkeeping (except size of the physical plants of large product testing is done. for sanitation), capital costs for physical establishments to the size of the plant and equipment, finished product physical plants of very small The number of component tests per quality testing (part of production and establishments. In other words, we batch of final product would equal the process controls only), labor costs for assumed capital costs for physical plant number of tests per component, certain required tasks, and some other and equipment would be proportional multiplied by the number of costs that were not easily classified. to facility size, as measured in square components per batch, divided by the i. Recordkeeping. We used a study of feet. batches per shipment lot (to account for a medical device CGMP regulation to iii. Testing. Establishments that do the production of multiple batches of estimate the costs of recordkeeping (Ref. not already conduct the required dietary supplements from single lots of E44). We request comments on the product quality tests of each batch of components). applicability of a study of the medical dietary ingredients or dietary The option for stricter CGMP device CGMP’s to dietary supplements. supplement produced would incur the regulations options would also require The compliance cost of recordkeeping cost for those tests. Under the option for some inprocess tests upon receipt. The is the sum of both the initial design and more restrictive CGMP rules, each lot of number of inprocess tests per batch is printing of the recordkeeping components would also be tested. The the same as the number of potential documents and the recurring costs of costs per establishment depend on both inprocess product defects. The maintaining the records. The cost of the number of tests and the costs per estimated number of inprocess tests training personnel to use mandatory test. We did not estimate the cost of counts only tests for defects that can records is a recurring cost that depends developing new, validated tests occur during production, not tests for on how frequently records are modified, methods because we lacked information the defects of dietary ingredients and the frequency of personnel turnover, about the costs for this requirement and components supplied to the producer. and how complicated the tasks are that the number of such tests that need to be We used the following formulas to are being recorded. The recurring costs developed. We ask for comments on the estimate the number of tests:

  Component test per batch =∑ m ()IR× +×∑ n () U R× (/) SB  j jkj kk o × Inprocess quality tests per batch = ∑ 1 ()HR11

Quality tests per batch of final product Where: m = number of ingredients per batch; = max [m × (1/z), 1] Ij = jth listed ingredient; Rj = required tests for ingredient j;

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Uk = kth unlisted component (an tests per listed dietary ingredient would establishments produce an average of inactive substance); be between one and six: One identity 309 batches per year. n = number of unlisted components per test for identity, purity, strength, • Inprocess potential defects. batch; quality, and composition and zero to Inprocess defects involve many of the Rk = required tests for unlisted five tests for defects. same potential defects that can occur in component k; • Number of unlisted components. components. The more restrictive CGMP S = number of shipments (or lots) of Dietary supplements are manufactured option requires inprocess tests at all ingredients and unlisted using solvents, binders, and lubricants points where contamination or other components; that may not show up in the final defects can occur. Filth, chemicals, B = number of batches produced; product. An industry source (Ref. E47) microbial pathogens, physical objects, H1 = 1th inprocess potential defects; says that four to six unlisted and insects can be introduced into the R1 = required inprocess tests per batch components are typical per product, product during manufacturing. In for potential defect H1; although fewer are certainly possible. addition, purity, quality, strength, and o = number of potential inprocess The minimum number is zero. We composition can be compromised. • defects per batch; assumed that the number of unlisted Number of potential inprocess z = number of ingredients identified per components would be zero to six, with defects. Some processes may have no quality test. four the most likely. control points, steps, or stages that • Number of tests per unlisted involve the potential for defects. If • Number of tests: Evidence and components. The unlisted components certain manufacturing processes in the distributions. The quantity and quality tend to be manufactured products, such production of a dietary supplement can of evidence on the variables used to as solvents. Therefore, one identity test be carried out without being subject to estimate the number of required tests would likely be sufficient. potential defects, no inprocess tests varies greatly. In this section, we • Number of shipments (or lots) of would be required for those processes. explain the evidence and assumptions ingredients and unlisted components. We therefore assumed that zero we used to construct the formulas for We have no direct evidence on the inprocess tests would be the lower the number of tests. • number of shipment lots of dietary bound requirement. For the upper Number of ingredients. We based ingredients and components. We also bound, we assumed that no products our measure of the number of dietary have no evidence on the number of would have more than five potential ingredients per product on a sample of shipments per lot or on the number of control points or steps that could lead almost 3,000 dietary supplement labels shipments per batch. The increasing use to defects. We believe that most (Ref. E46). Although some dietary of just-in-time inventory practices production processes will have fewer ingredients may be missing from the indicates that one shipment lot of than 5 control points, so we assumed an labels and some listed dietary components per batch may be the rule average of 2.5 control points requiring ingredients may be missing from the for some products and some producers. inprocess tests for defects. products, the ingredient list represents It is costly and difficult to store • Number of required inprocess tests the best evidence we are likely to have ingredients for an extended time, so per control point. We assumed one test on what dietary ingredients are used in establishments tend to buy more and per defect per control point. dietary supplements. smaller lots of components rather than • Number of ingredients identified • Number of ingredients per batch. a few large lots and storing them in bulk per quality test. We had no direct According to the sample of listed over an extended period (Ref. E48). evidence on the number of identity tests ingredients (Ref. E46). Vitamin and Crude botanical and other ingredients per final dietary supplement. For the mineral products contain about 13 listed are inherently unstable and may lose maximum, we assumed that the number ingredients. Other dietary supplements, their quality in even a short time unless of tests would equal the number of mainly herbals, contain about four. costly temperature, humidity, and light ingredients. The number of ingredients • Number of tests per ingredient lot. controls are in place (Ref. E49). We also identified per test varies from less than The option for more restrictive CGMP know, however, that some dietary one to a very large number. We assumed regulations would require that virtually ingredient suppliers produce large that for vitamins and minerals, the all dietary ingredients be tested for amounts and then ship out smaller minimum number of identity tests identity and defects at some stage packages. For dietary supplements would be one and the maximum would between harvesting the raw product and produced using part of a large be 30, with 2 the most likely. Botanical the beginning of the production of the production run of a dietary ingredient, and herbals are less easily characterized final product. We assumed one identity the number of batches per lot could be than vitamins; so identifying large test per ingredient lot. The number of large. Also, some producers buy a single numbers of ingredients with a single test tests for defects depends on the number shipment lot of a raw material and use would be highly unlikely. We assumed of possible defects, which can include: it in many batches. We assume that as that one to two ingredients would be Filth; Microbial pathogens; Chemical many as 12 batches per shipment lot of identified per test for herbal products. hazards, including pesticides; Insects; dietary ingredient is a plausible • Number of final product tests per Physical hazards, such as metals; maximum. In the cost calculation, we batch. We had no direct evidence on the Natural toxins, such as aflatoxin; and assumed that 1 was minimum and 12 number of quality tests per final dietary Inadequate purity, quality, strength, or the maximum number of batches supplement. After adjusting for the composition. produced per lot, with 6.5 the average. possibility of multiple results from a The number of potential defects is • Number of batches produced. We single test, multiple ingredients in potentially unlimited. As a practical have survey results (Ref. E2) on the single products, and the differing maximum, however, few products number of batches produced per number of ingredients in herbal and would have more than five potential establishment. According to the survey, vitamin products, we estimated that the defects. In the calculation of ingredient very small establishments produce an proposed rule would require about three testing costs (part of the option for more average of 223 batches per year, small tests for identity, purity, quality, restrictive CGMP regulations), we establishments produce an average of strength, and composition for each assumed that the average number of 554 batches per year, and large batch of final product. These are the

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only required tests in the proposed rule, prices fell into the $20 to $80 range, so We estimate that the adjusted total but establishments may choose to we selected $50 (the midpoint) as most cost for testing for the proposed perform inprocess tests and tests on likely. The average cost per test was regulation will be: ingredients in order to prevent waiting 8 about $60. $11,230 for very small establishments; until final product testing to discover Changing our assumption about the defects. midpoint of testing costs would change $19,907 for small establishments; iv. Costs per test. We estimated the our estimate of the cost of the rule. If the $7,626 for large establishments. costs per test partly with published cost of testing each batch is actually We found some corroboration for prices of independent laboratories as significantly higher, then the impact to these estimates in a comment on the posted on the Internet (Refs. E50 and those firms that incur the cost and to Advance Notice of Proposed E51), and partly from our conversations society will have been understated. Rulemaking entitled ‘‘Current Good with FDA and industry experts on v. The number and cost of tests: Manufacturing Practice in testing. We found that testing costs vary summary. We estimated the number of Manufacturing, Packing, or Holding according to frequency and complexity. tests required of the representative Dietary Supplements’’ published in the The more frequently technicians manufacturer as a weighted average of Federal Register of February 6, 1997 (62 perform tests, the lower are the costs per the number of tests required for FR 5699 to 5709). According to the test. Many tests require sophisticated vitamins and minerals and the number comment, the cost of testing equipment, such as gas chromatography, of tests required for all other components and final products inhouse high pressure liquid chromatography, supplements (which were mainly herbal would be at least $650 per batch plus distillation, extraction, various products). We used survey responses to microbiological tests. Testing costs spectrophotometers, and other types of a question about the establishment’s could be more if establishments sent equipment. Using sophisticated primary line of business for the weights samples to independent laboratories for equipment requires trained personnel. used to compute the average number of testing or if they conducted extensive Even simple physical or organoleptic tests. We dealt with multiple responses identity tests of herbal and botanical testing requires training or experienced by treating all nonvitamin and products. If we apply the $650 to the personnel. The type of ingredient, nonmineral responses as other dietary annual number of batches per compound, or product can also affect supplements. The following weights, as establishment, the comment implies the cost because some are easily shown below, differed by size of identified using routine or single step that very small establishments would manufacturer: × techniques and others require multiple • 24 percent of very small perform $145,000 (223 $650) worth of steps or complex techniques, especially tests, small establishments would manufacturers produce vitamins and × if there are similar products that can be minerals; 76 percent produce other perform $360,000 (554 $650) worth of mistaken for the products being tests, and large establishments would dietary supplements. × identified. The type of defect tested for • 42 percent of small manufacturers perform $200,000 (309 $650) worth of affects the cost; some defects can be produce vitamins and minerals; 58 tests. These estimates are reasonably found visually if they are found on the percent produce other dietary close to our simulation estimate. surface, but others are latent. Some tests supplements. The unadjusted testing costs represent require multiple samples or multiple • 69 percent of large manufacturers the total requirements and steps. In addition, tests require the produce vitamins and minerals; 31 recommendations, not the additional taking and of samples, whose cost can percent produce other dietary costs that would be incurred in response vary. supplements. to the proposed rule. Tests on incoming We assumed that $20 per test The annual cost of testing differed by components and inprocess tests would represented a plausible lower bound. the size of the firm, because the average not be required by the proposed rule. This cost represents the full cost of number of batches produced differed. Most establishments already conduct carrying out a test, including collecting For the option calling for more strict some tests, or send samples out for and storing the sample, the time for regulation, the total costs of testing testing. We, therefore, adjusted the training the personnel who carry out the would be much higher than in the estimated testing costs of the proposed test, and any associated records. proposed rule. The unadjusted total cost rule to include only required tests and Although some Internet testing prices of testing under the more restrictive to account for the testing costs currently for tests were as high as $300, we CGMP option would be: borne voluntarily by manufacturers. The assumed that with frequent testing $150 $148,000 for very small establishments; survey results showed how many would be a more plausible upper bound $415,000 for small establishments; respondents were conducting various average cost. The majority of listed $263,000 for large establishments. types of tests.

TABLE 14.—VALUES USED IN TESTING COST CALCULATIONS

Name Value or distribution used Source

Number of dietary ingredients per product batch Vitamins and minerals—13; All other Sample from 3,000 dietary supplement labels categories—4. (Ref. E46).

8 The average cost is higher than the most likely is p. The Beta shows the distribution of the value 6. We used the Beta-Pert distribution because we cost because we modeled costs with a Beta-Pert of p when s successes occur in n trials. The Beta- did not have a representative sample to derive the distribution that was skewed rightward (toward Pert distribution is a Beta distribution that has been distribution, but we did have enough information higher costs). The Beta distribution is part of the rescaled to run between values other than 0 and 1. to identify a plausible maximum, minimum, and Bernoulli family of distributions and is closely The Beta-Pert uses a minimum, maximum, and most likely value. The use of the Beta-Pert, then, related to the Binomial. The Binomial gives the most likely value to generate a distribution running indicates that we do not know the shape of the distribution of the number of successes (s) in n from the minimum to the maximum, with a mean probability distribution of possible testing costs, but trials if the probability of the success in each trial equal to (minimum + (4 × most likely) + maximum)/ we do have limited data.

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TABLE 14.—VALUES USED IN TESTING COST CALCULATIONS—Continued

Name Value or distribution used Source

Number of identify tests per ingredient lot ...... 1 Identity test per ingredient lot ...... Assumption based on discussions with industry—FDA requests comments. Number of tests for defects per ingredient lot ... 0 to 5 tests for defects ...... Assumption based on discussions with industry—FDA request comments. Number of unlisted components ...... 0 to 6 components; 4 most likely ...... Ref. E47. Number of tests per unlisted components ...... 1 identity test per component ...... Assumption based on discusssions with industry—FDA requests comments. Number of shipments (Lots) of ingredients and 1 to 12 batches per shipment lot of dietary in- Assumption based on discussions with unlisted components. gredients. industry—FDA requests comments (Ref. E48). Number of batches produced ...... Very small establishments—223; Small Ref. E2. establishments—554; Large—309. Number of inprocess potential defects ...... 0 to 5 potential control points; 2.5 average ..... Assumption based on discussions with industry—FDA requests comments. Number of inprocess tests per control point ...... 1 test per defect per control point ...... Assumption based on discussions with industry—FDA requests comments. Number of ingredients identified per identity test Vitamins and minerals—1 to 30; 2 most likely; Assumption based on discussions with All other categories—1 to 2. industry—FDA requests comments. Number of final product tests per batch ...... 3 tests batch ...... Assumption based on discussions with industry—FDA requests comments. Costs per test ...... Beta per distribution skewed rightward be- Refs. E50 and E51. tween $20 to $150; $50 most likely; $60 av- erage.

vi. Labor costs. We used the average assumptions about the full cost of a establishments in each size category manufacturing wage of $15.65 per hour provision. We then adjusted these (from the survey) by the average costs to estimate the cost of labor. We estimates to account for the many per establishment in that category. We assumed that various tasks required by activities already being carried out, as then adjusted for the establishments that the proposed rule would take some well other activities that would not have did not respond to the survey but are number of hours per year, per batch of to be carried out by all establishments. believed to be in the industry. Two product, or per square foot of physical We used the survey to estimate the hundred thirty eight establishments plant. For example, we assumed that likelihood that an establishment would responded to the survey; we estimated time spent on the sanitation of physical incur a cost. To get an estimate of the that 1,566 firms are in the industry. We plants is a function of the square average cost of provision (adjusted for estimated costs with the following footage. We assumed 1 hour per week baseline activities) for each category, we calculation: for very small establishments, 3 hours multiplied the average cost per [Number of very small establishments × per week for small establishments, and establishment by the probability that the costs per very small establishment) 20 hours per week for large establishment would need to undertake + (Number of small establishments establishments. We request comment or the expense (one minus the probability × costs per small establishment) + data about costs, hours, and the other that the establishment was already (number of large establishments × requirements for these proposed doing it). For each provision of the costs per large establishment)] × required procedures. proposed rule, the simulation carried vii. Other costs. The main costs in this out the following calculation: adjustment for establishments not category are for pest and rodent control. Cost per unit of analysis for each in survey We consulted a commercial supplier of provision = number of units of analysis The rule is complex and the industry is these services for the estimated monthly per establishment × probability that made up of very different kinds of firms, costs, which were $400 to $600 a month establishment incurs cost × adjustment so cost estimates are averages with, in for very small establishments, $480 to for requirement (yes or no) = cost per some cases, large variances. The cost per $720 for small establishments, and $700 provision per establishment unit, number of batches and employees, to $1,000 for large establishments (Ref. We estimated both a setup cost (a one- and probability that the establishment E52). For each size of establishment, we time fixed cost) of the provision and an would incur the cost all contain selected the midpoint of the range as the annual recurring cost. The first-year uncertainty. The values in table 15 of most likely value. costs would be the setup costs plus the this document are used in the cost d. Estimating costs. We initially annual costs. To get the total costs of the estimates, and are generated from gathered information and made rule, we multiplied the number of multiple sources.

TABLE 15.—VALUES USED IN COST CALCULATIONS

Name Value or distribution used Source

Average wage per hour ...... $15.65 ...... Employment Index, Bureau of Labor Statis- tics. Average size of establishments in square feet .. Very small = 24,674; small = 71,354; large = Ref. E2. 596,000. Average number of employees ...... Very small = 7.6; small = 95; large = 1,005 .... Ref. E2. Average annual number of batches ...... Very small = 223; small = 554; large = 309 .... Ref. E44.

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TABLE 15.—VALUES USED IN COST CALCULATIONS—Continued

Name Value or distribution used Source

Annual time recordkeeping ...... 1/10 of setup time per provision ...... Ref. E44. Personnel sanitation ...... 1 hour per week per worker ...... Assumption, based on requirements of pro- posed rule. Sanitation time for physical plant ...... 1 hour per week for very small establish- Assumption, based on difference in average ments; 3 hours per week for small estab- physical plant size. lishments; 20 hours for physical plant per week for large establishments. Sanitation supervisor ...... Very small and small establishments = 1 hour Assumption, based on number of workers. per week; large establishments = 1 hour per week. Pest control setup costs ...... $1,500 to $2,000 for very small establish- Ref. E52. ments; $1,800 to $2,400 for small establish- ments; $2,600 to $3,400 for large establish- ments. Average for each size establishment was midpoint ($1,750, $2,100, $3,000). Pest control annual costs ...... $400 to $600 per month for very small estab- Ref. E52. lishments; $480 to $720 for small establish- ments; $700 to $1,000 for large establish- ments. Average for each size establishment was the midpoint ($500, $600, $850). Renovation cost ...... $50 per square foot; with 0 to 20 percent of Based on construction costs and square feet. physical plant to be renovated, with 10 per- cent most likely. Minimum quality control unit ...... 1 person or 1 percent of establishment work Assumption based on requirements of pro- force. posed rule. Equipment replacement ...... For very small establishments, 0 to $1,000, Assumption, based on size of establishments. with $100 most likely; small, 0 to $10,000, with $1,000 most likely; large, 0 to $100,000 with $1,000 most likely. Setup costs for automatic equipment ...... $500 for hardware, 16 hours ...... Software costs and assumptions about labor hours. Annual costs for automatic equipment ...... 1 to 2 hours per month for very small and Assumption based on average size of estab- small establishments; 2 to 4 hours per lishments. month for large establishments. Sanitation of equipment and surfaces...... 5 hours per week for very small establish- Assumption based on average sizes of estab- ments, 15 hours per week for small estab- lishments. lishments, 100 hours per week for large es- tablishments. Number of dietary ingredients per batch, sup- 12.8; standard deviation = 15.6 ...... Ref. E46. plements other than vitamins. Number of dietary ingredients per batch, sup- 3.6; standard deviation = 4.8 ...... Ref. E46. plements other than vitamins. Cost per test ...... $20 to $150, with $50 most likely ...... See text discussion. Holding products and dietary ingredients: cap- Setup cost for very small 0 to $1,000, with Based on average sizes of establishments. ital requirements. $100 most likely. Multiply by 3 for small es- tablishments and by 20 for large establish- ments. Default probabilities that establishments are not For very small establishments, 0.2; for small Based on results of survey for other practices. currently acting in accordance with a provi- establishments, 0.1, for large establish- sion. ments, 0.01.

We combined the costs per rule. Table 16 of this document first year and annually after the first establishment with the number of summarizes the estimated total costs for year, assuming that the proposed rule is establishments and probabilities from very small establishments, small phased in over 3 years. Table 18 of this the survey, and adjusted for establishments, large establishments, document shows the total costs of the establishments not in the survey to and warehouses. Table 17 of this proposed rule compared to the total estimate the total costs of the proposed document shows the total costs for the costs of other options.

TABLE 16.—SUMMARY OF COSTS BY SIZE OF ESTABLISHMENT

1st Year costs Annual costs Total 1st Total annual Number of per per year costs costs establishments establishments establishments (in millions) (in millions)

Very small establishments ...... 740 $62,000 $38,000 $46 $28 Small establishments ...... 766 99,000 61,000 76 47 Large establishments ...... 60 83,000 47,000 5 3 Warehouses and other holders ...... 26,617 436 342 12 9

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TABLE 17.—ESTIMATED TOTAL COSTS [In millions]

4th Year 1st Year 2nd Year 3rd Year and after

Very small establishments ...... 0 0 $46 $28 Small establishments ...... 0 $76 47 47 Large establishments ...... 5 3 3 3 Warehouses ...... 12 9 9 9

Total ...... 17 88 105 87

8. Summary of Benefits and Costs recall benefit, which is based directly on is in turn based on: (1) The value of a We estimated that, once it is fully FDA recall records, each component of statistical life of $5 million; (2) the implemented, the measured annual the estimated benefits involves expected remaining life of consumers of benefits from the proposed rule would assumptions that reflect our uncertainty. 21.84 years (average), discounted from Our basic assumption is that be $218 million; measured annual costs 36 years; and, (3) the social rate of time manufacturers lack market-based preference of 3 percent. The estimate is would be about $86 million. Additional incentives to prevent hidden product derived from workers in somewhat risky but unmeasured benefits should also be quality defects. Our survey (Ref. E2) occupations who demand a wage recognized when comparing the total indicated that many firms do not have premium for their additional risk of costs and benefits. Table 18 of this reliable quality control mechanisms in fatality. If our estimate of the value of document compares the benefits and place. The survey was a one-time look a statistical life of workers does not costs of the proposed rule to the benefits at the manufacturing practices during represent the value of a statistical life of and costs of the leading regulatory the time of the survey. If the trend in the consumers of dietary supplements, then options. Because the phase in period, market is toward the adoption of the our benefits estimate will be different complicates the comparison for the controls that we are proposing here in from the true health benefits of the rule. early years, we limit the comparison to the absence of regulation, then both the If consumers value their life differently annual benefits once all establishments cost and benefits of the rule will be less than workers or if consumers place are covered. than we estimate. If the market-based different values for different kinds of trend is toward fewer controls, then hazard-related deaths than do workers TABLE 18.—ANNUAL BENFITS AND both the cost and benefits of the for job-related safety hazards, then we COSTS OF REGULATORY OPTIONS regulation will be greater. Other key will have incorrect estimates for the true [In millions] assumptions are listed below: health benefits. If we discount life The assumptions for the health expectancy by 7 percent instead of 3 Regulatory Annual Annual benefits from reducing the number of percent, the benefits would be much option benefits costs sporadic illnesses model are: higher. Proposed rule ... $218 $86 1. The baseline health of consumers is 3. There is one illness for each recall. Fewer require- normal, not perfect. To estimate the We assumed that for each class 1 and 2 ments for vita- change in health status from consuming recalled product there was only one mins and min- defective products, we assumed that the illness that was reported to the public erals ...... 109 69 baseline health of consumers is normal, health authority. For instance, if a Stricter CGMP .. 218 178 which does not mean that we assumed product was recalled because the HACCP only ..... 42 38 that consumers have perfect health. We defective product contained lead, we Testing only (un- recognize that consumers will already assume that a person was made ill from able to esti- mate) ...... 32 have ‘‘background’’ health problems, by lead poisoning and that was how the High risk prod- which we mean that many will have recalled product was discovered. If ucts only (un- health problems unrelated to the there were more illnesses per recall than able to esti- consumption of defective products. Our one, then our estimates of benefits will mate) ...... (1) assumption is that only the change in be low. If fewer than one illness per health status is relevant for our analysis. recall occurred (or is likely to occur in 1 Less than $86 million. If an immune-compromised consumer is the future), then our estimate of health Uncertainties in the analysis. In this made ill by a defective product, e.g., benefits will be more than the actual section, we list all of the significant gets lead poisoning, the consumer might health benefits. assumptions in the analysis, which if in fact have more difficulty recovering 4. The assumed frequency of actual varied, could significantly change the than an otherwise healthy person. illnesses is 100 times the frequency of estimates of costs and benefits. Such However, we assume that the change in reported illnesses. This assumption is changes could have importance for the productivity, functional state, pain and based on Ref. E16. We recognize that the construction of any potential final rule. suffering, and medical costs will be the factor of 100, although it has empirical Therefore, we ask that comments same, regardless of prior health status. support, might be wrong and that there address these aspects of the analysis Accounting for confounding factors is likely to be considerable uncertainty and, where possible, provide FDA with would have the effect of making health about this point estimate. It is widely better data to reduce the uncertainty. problems worse than we estimate, not believed in the public health We estimated the benefits using indirect better, so our estimate may be community that most illnesses are methods, which required several key understating the true health benefits. underreported to public health assumptions that are critical for our 2. The average value of a QALY is authorities, particularly in passive estimates. With the exception of the $630 per day. That value, $630 per day, reporting systems, such as the case with

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dietary supplements. Mild cases are the there would be no benefit from adopting preferences for dietary supplement most underreported. For instance, a rule to avoid it. If a rare event would quality. With the adoption of the victims rarely notify public health have happened more frequently than proposed rule, the standardization of authorities when they have minor our estimate of once every 30 years, manufacturing practices will reduce gastrointestinal tract related illnesses. It then our estimate of the benefits would product differentiation. In a perfect is even more rare to report the likely underestimate the true health benefits. information market, the change in source of a mild illness. It is also widely 2. Number of illnesses per rare event. product differentiation would be believed that severe illnesses and death We based our estimate of the health reflected in the change in the price are reported much more frequently than impact from contaminated L- differences between low and high milder illnesses, even when the cause of Tryptophan. If the number of illnesses quality products. In the existing market, illness or death is not included in the from a future rare event differed—either price differences alone are an report. Although the number of deaths more or less—then the health benefits inadequate signal because the that are reported probably approach 100 would differ from our estimated differences in product quality are percent, the cause of death from a benefits. If a future event would have typically hidden from the view of both contaminated dietary supplement had 10,000 cases, not 1,500 cases, then consumers and (though less so) product might not be reported. We our estimate would understate the true manufacturers. In this hypothetical believe that using a single composite health benefits of avoiding such a large model, we assumed that if there were factor—100—to represent the total catastrophe. actually indicators of product quality in number of all unreported cases, The assumptions for fewer products the market now, consumers would including mild, severe, and death, does recalled are: spend a certain amount of time not invalidate our assumption. The 1. The reported class 1 and 2 recalls attempting to find a reasonably high factor of 100 represents an estimate of that have occurred over the last 10 years quality product. Time spent searching is the composite probability of the full represent the number and type of recalls an economic cost. In fact, in markets range of probabilities for each severity that would have occurred in the future where quality is discernible prior to level of an illness being reported. but for the implementation of this purchase, such search does take place Increasing the factor multiplier from 100 regulation. If the number or types of and it is from those markets that our to some number higher would increase recalls are not representative, then we estimates were derived. In such a world the health benefits, while lowering the over or under estimated the benefit of of easily available product quality multiplier would decrease the health avoiding recalls. Avoiding one very signals, this regulation, by standardizing benefits. If we assume that all illnesses large recall could result in significantly product quality at the high end, would are reported—there are no unreported higher benefits. Conversely, merely reduce that search time. Our assumption illnesses and no factor of 100, then the avoiding fewer or smaller recalls would is that this is a reasonable indicator of health benefits from fewer sporadic result in smaller benefits. consumers’ value for high quality illnesses will be less than $1 million. 2. A product recall causes sellers to products. Further, we assume that in 5. Introducing CGMP’s will reduce the lose both goodwill and the value of the fact consumers of dietary supplements probability of a recall to zero. We recalled product and lost goodwill do wish to purchase high quality believe that the proposed CGMP’s equals the value of the recalled product. products, as the absence of quality creates the most reliable means for These two embedded assumptions have could mean either an ineffective discovering product adulteration. empirical support from Ref. E24. A product or worse, illness or death. We Indeed, we believe that it will, if strictly product recall adversely affects the used various assumptions at each step used, cause the discovery of all wealth of sellers—a recall leads to lost in our model, and the benefits change adulteration. Therefore, we assume that goodwill—by signaling to consumers when the assumptions change. The once an establishment fully adopts the that products are defective. From assumptions that we used for the search requirements, there should be no more evaluating the declines in public share model are: health risk from adulterated dietary prices after product recalls in various 1. Consumers will search until the supplements and consequently, no more industries, the authors in Ref. E24 expected benefits of the search equal the class 1 and 2 recalls. This conclusion determined that the loss in share price expected cost of additional search. The rests on the assumption that there will is twice the value of the loss of the expected cost is the value of their time, be 100 percent compliance with this actual value of the product recalled. which we estimated is the average wage regulation. We recognize that human They attribute the difference to lost firm rate for manufacturing workers—$15.65/ error is inescapable. If recalls—or a goodwill. hour. If the true wage rate is different, health risk from adulteration—would 3. Full compliance with the proposed the benefits of the rule will be different. still exist, then we overstated the true CGMP’s will reduce the probability of a 2. The three models—drug store, use health benefits of the regulation. recall to zero. As in our earlier of time and grocery store models— The assumptions for the health assumption about the probability of represent consumers of dietary benefits from lowering the likelihood of recalls after the rule is adopted, supplements. If not, then we will not rare catastrophic event model are: consistency requires that if we believe have estimated the true preferences of 1. We assume that a rare catastrophic that the rule will reliably cause the consumers. If consumers value dietary event would occur every 30 years. We discovery of adulterated products before supplements more highly than either recognize that the occurrence of a single they are commercially available, there drugs, groceries or other uses of time, event provides little evidence about should be no more health risk from and they search more for better quality, what will happen in the future. If the adulterated dietary supplements. then we understated the benefits of event reported in this analysis was in Consequently, there should be no more product standardization. If consumers fact a one-time occurrence, then our recalls. value dietary supplements less highly estimate of the benefits from the We developed the hypothetical search than either drugs, they search more for prevention of the catastrophic health model to estimate the implicit value to better quality, then we overstated the event would overstate the true benefits, consumers of better product quality benefits. which in fact should be zero. There although we lacked a model that could 3. The quality controls will reduce would have been no future event, and enable us to directly estimate consumer consumer search time by approximately

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33 percent. If our estimate is not practices that create defective products. percent, then the benefits of representative of the true average Recordkeeping ensures that preventative recordkeeping would be $25 million. reduction, then our estimate will be controls are carried out for each batch We were not able to quantify the wrong. of dietary supplements produced. marginal benefits of this requirement 4. The type and number of consumers Records serve as a checklist that quality with numbers like this. Comments are represent the true value. If children, the control personnel can consult to requested for how well records are elderly or other consumers search for monitor that necessary controls are likely to perform this function. We these products in significantly greater implemented or corrective actions estimate that the additional cost to amounts than average workers or the taken. Further, mandatory society for the proposed new estimated population, then we may have recordkeeping provides an incentive for recordkeeping requirement will be overstated the benefits, because their manufacturers to comply more fully foregone wages would be less than that approximately 10 percent of the total with the provisions of the rule where annual cost of the proposed regulation, of average workers. recordkeeping is required. Knowing that In an ideal analysis, the benefits and or a little less than $9 million per year. FDA inspectors will examine records costs of each provision would be Further, we request comments on all and that falsifying them is a criminal evaluated. We were not able to quantify of the provisions that would be of a offense provides strong incentives to the benefits for each of the provisions in similar nature to this example. our analysis although we do have fairly keep thorough and accurate records that The costs of the rule depend on our detailed estimates of the cost. We the required safety functions have been request comments on marginal costs and performed adequately and in a timely assumptions about the amount and cost benefits of specific provisions in the manner. Thus, the benefits of of testing. The amount of testing is rule. Comments can be directed either at recordkeeping are to permit detection of highly uncertain; we have tried to how well a specific provision might defective products and increase model the number of tests based on work to make dietary supplements compliance with the provisions for number of ingredients and types of tests. either safer or of higher quality, or be which recordkeeping is required. If, for We first characterized the uncertainty directed at the cost of the provision. An example: (1) The total benefits of the as a probability distribution. We ran example of this type of provision requirements that have recordkeeping 1,000 computer simulations to estimate follows for recordkeeping: attached to them were $50 million (not both benefits and costs. The simulations the real value); (2) only half of the used distributions and assumptions Benefits of Recordkeeping requirements would be met without from tables 8 through 13 of this Mandatory recordkeeping is intended recordkeeping; and, (3) recordkeeping document in place of single estimates. to help the discovery of manufacturing raised the compliance rate to 100

TABLE 19.—DISTRIBUTION OF SIMULATION RESULTS FOR ANNUAL BENEFITS AND COSTS [In millions]

5th 95th Percentile Median Mean Percentile

Annual benefits ...... $89 $198 $218 $405 Annual costs ...... 62 80 86 128

The computer simulation gives the then the results in table 19 of this results are to plausible changes in distribution of estimated benefits and document give a clear picture of the individual variables. We start with costs. If the underlying distributions uncertainty. Another way to show the benefits. capture the uncertainty of the estimates, uncertainty is to see how sensitive the

TABLE 20.—SENSITIVITY OF BENEFITS [In millions]

Estimated an- Description nual benefits

The proposed rule ...... $218 If reporting rate of illness is 0.1 (baseline is 0.01) ...... 182 If reporting rate of illness is 0.005 (baseline is 0.01) ...... 257 If the value of a statistical life is $3 million (baseline is $5 million) ...... 175 If the value of a statistical life is $7 million (baseline is $5 million) ...... 259 If consumer search time per item is 1 minute (baseline is 3.75 minutes) ...... 137 If consumer search time per item is 5 minutes (baseline is 3.75 minutes) ...... 250 If consumer search time equals 40 percent of shopping time (baseline is 70 percent) ...... 166 If consumer search time is equal to shopping time (baseline is 70 percent) ...... 254 If consumer search for quality accounts for 30 percent of search time (baseline is 20 percent) ...... 278 If consumer search time for quality accounts for 10 percent of search time (baseline is 20 percent) ...... 158 If catastrophic events are not prevented (baseline is $66 million annual benefit from prevention) ...... 152

We mainly looked at the cost effects of changing assumptions about testing and consumer complaints. As table 21 of this document shows, annual costs are quite sensitive to the assumptions about the average cost and number of tests.

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TABLE 21.—SENSITIVITY OF COSTS [In millions]

Estimated An- Description nual Costs

The proposed rule ...... $86 6 tests per batch (baseline is 3) ...... 119 1 test per batch (baseline is 3) ...... 66 $100 per test (baseline is $60) ...... 101 1 consumer complaint per 20 batches (baseline is 1 per 10) ...... 77 1 consumer complaint per 5 batches (baseline is 1 per 10) ...... 104

C. Initial Regulatory Flexibility Analysis a large decline in profitability from the questions, including how many proposed CGMP regulations. We lack employees they had and what their 1. Introduction precise information about those existing practices were. From the FDA has examined the economic establishments. Based on the survey, we survey, we determined that small implications of this proposed rule as estimated that 830 establishments, 53 establishments do not now follow all of required by the Regulatory Flexibility percent of the total establishments, the provisions of the proposed CGMP Act (5 U.S.C. 601–612). If a rule has a could be classified as very small (under regulations now. Those that do not significant economic impact on a 20 employees) and 564 as small (20 to follow the proposed requirements will substantial number of small entities, the 499 employees), which is 36 percent of incur a cost to do so. Regulatory Flexibility Act requires the total establishments. agencies to analyze regulatory options We estimated that 95 percent of all b. Costs to small entities. that would lessen the economic effect of holders (warehouses and wholesalers) Implementation costs vary across the rule on small entities. We find that covered by this regulation are small establishments based on current this proposed rule would have a using the Small Business practices and the types of products significant economic impact on a Administration definition. The total manufactured, packaged, or held. We substantial number of small entities. number of holders likely to be affected estimated the range of current practices by this regulation is 26,617 (see table 4 using the survey of the industry. The 2. Economic Effects on Small Entities of this document), so the total number cost model divided establishments by a. Number of small entities affected. of holders that are small would be size, which allowed us to estimate the The proposed regulations would affect 25,286 (= 0.95 × 26,617). distribution of costs per establishment many small entities. Our classification The small establishments that would for each size and product class. Table 22 of establishment size is based on the be affected by the proposed regulations of this document shows the cost per Small Business Administration’s are those establishments that would establishment for very small and small definition for small, as discussed have to perform the various required establishments. For comparison, we previously in this document. A small activities, and that would not have done include the estimated average cost per business by this definition is any so without the regulations. As in the large establishment and the median establishment with fewer than 500 preliminary regulatory impact analysis revenues for each size category. As the employees. For this analysis, we defined (section VII.B of this document), we table shows, costs per establishment are very small establishments as determined our estimate of baseline proportionally higher for very small establishments with fewer than 20 (pre-CGMP) manufacturing practices than for large establishments. The employees. Some small and very small with the survey of the industry (Ref. E2). table’s most striking result is that costs establishments produce very large The survey asked representative are highest for small (20 to 499 revenues and would probably not incur respondents to answer a series of employees) establishments.

TABLE 22.—COST PER ESTABLISHMENT

1st year Annual

Very small—fewer than 20 employees; median revenue under $1 million ...... $62,000 $38,000 Small—20 to 499 employees; median revenue $5 to 10 million ...... 99,000 61,000 Large—500 or more employees; median revenue $20 to $50 million ...... 83,000 47,000

Small establishments that do not In addition, the average annual largely be determined by changes made perform a substantial number of the compliance cost for a small by large establishments) would be much actions required by the proposed CGMP establishment is around $61,000. As the smaller than the increase in the average regulations would bear relatively high survey indicated, about 14 percent of costs of very small producers. The costs for compliance with the provisions establishments with 20 to 499 average burden to very small low of this proposed rule. As shown in table employees or about 200 firms have revenue firms, then, would be at least 8 22 of this document, we estimated the annual sales revenues under $500,000. percent of their annual revenue. The average annual compliance costs for a For purposes of our analysis, we regard average burden to small low revenue very small establishment to be around firms with revenues of $500,000 or less firms would be at least 12 percent of $38,000. About one-third of those to be low revenue firms. Although the annual revenue. Establishments with establishments or about 500 firms have proposed rule would raise product above average costs, and even annual sales revenues under $500,000. prices, the price increase (which would establishments with average costs,

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would be hard pressed to continue to 4. Description of Recordkeeping and Mandates Act of 1995 include assessing operate. Therefore, some of these Reporting the rule’s effects on future costs; establishments, for example, such as The Regulatory Flexibility Act productivity; particular regions, those that produce other products (foods requires a description of the communities, or industrial sectors; or pharmaceuticals) or are part of firms recordkeeping and recording required economic growth; full employment; job with more than one establishment, may for compliance with this proposed rule. creation; and exports. decide it is too costly and either change This proposed rule would require the Future Costs product lines or go out of business. If we preparation of records. As described in assume that one half of these firms have the Preliminary Regulatory Impact The future costs from the rule include sales revenues from other products and Analysis, records must be written or the recurring costs, which reach their locations and remove them from the at- electronic documents must be kept that long-term value in the third year after risk group, we are left with demonstrate that specific action or the proposed rule would become final. approximately 350 very small and small actions occurred in the manufacturing These costs would be incurred by the establishments with less than $500,000 process in compliance with the establishments that manufacture, process, pack, transport, distribute, in revenue. It is possible that a large proposed regulations. Records that receive, hold, or import dietary number of these 350 very small and would be required in this proposed rule ingredients or dietary products. small establishments would be unable would demonstrate, that corrective actions were taken, that equipment, Recurring costs from the regulatory to absorb the compliance costs and will requirements would be incurred in each close. instruments, and controls used in laboratory operations and quality future year. Table 18 of this document 3. Regulatory Options control were installed properly, and summarizes the annual future recurring calibrated; that maintenance programs costs. a. Exemptions for small entities. The were followed; and that the results of Particular Regions, Communities, or burden on small establishments would any testing meet the necessary Industrial Sectors be reduced if they were exempt from specifications. some provisions of the proposed rule. The compliance cost of recordkeeping The costs of the rule will be shared Most entities affected by this proposed is the sum of both the initial design and among manufacturers, processors, rule, however, are small. Exempting printing of the recordkeeping packagers, transporters, receivers, small establishments from some or all of documents and the recurring costs of holders, and importers of dietary its provisions would be likely to reduce maintaining the records. The cost of ingredients or dietary products as well benefits. training personnel to use the new as domestic consumers. The higher costs incurred by domestic suppliers of b. Longer compliance periods. documents is a recurring cost depending on how frequently documents are dietary supplement products as a result Lengthening the compliance period of these regulations will mostly be would provide regulatory relief for modified, how often personnel turn over, and how complicated the tasks are passed on to consumers in the form of small entities. A longer compliance higher prices. Since consumer demand period for small entities would allow that are being recorded. The recurring costs are measured by the workers’ wage for dietary supplements is price elastic, additional time for setting up rate multiplied by the expected labor most of the higher costs incurred by recordkeeping, making capital hours necessary to perform a written or suppliers will be passed on to improvements to the physical plant, electronic record and the time necessary consumers. Consequently, higher purchasing new or replacement for management to review the records to dietary supplement prices will reduce equipment, and other one-time see that actions are documented real incomes for many consumers. expenditures. It would also delay the accurately. In addition, electronic However, the reduction in real incomes impact of the annual costs of records necessitate recurring time spent is thought to be more than offset by the compliance. We have given very small ensuring that the equipment is serviced benefits from these regulations. These and small firms an additional 2 years for and maintained properly. benefits are measured as an improved compliance. The proposed rule, then, ability by the FDA to respond to and would be phased-in over 3 years, with 5. Summary contain threats of serious adverse health large firms complying after 1 year, and The proposed CGMP regulations consequences from accidental both very small and small firms after 3 would have a significant economic contamination of dietary supplements. years. After 3 years, the annual costs impact on a substantial number of small National Productivity, Economic would be incurred. The cost savings of entities. Growth, Job Creation, and Full delay may well be larger than simply D. Unfunded Mandates Employment the present value of the delay because very small and small firms may also be The Unfunded Mandates Reform Act Although this proposed regulation is able to reduce their compliance costs by of 1995 (Pub. L. 104–4) requires cost- significant, we do not expect it to taking advantage of increases in benefit and other analyses for rules that substantially affect national industry knowledge and experience in would cost more than $100 million in productivity, growth, jobs, or full a single year. The current inflation- employment. The total costs will be implementing CGMP regulations. A adjusted statutory threshold is $112 small relative to the economy, and will summary of the compliance costs is million. The proposed rule qualifies as be offset by benefits. The improved shown in table 22 of this document. a significant rule under the statute ability to respond to, and contain, Although lengthening the compliance because there is a significant possibility serious adverse health consequences period would provide some regulatory that the cost of the rule will be above means less illness and fewer sick days relief to small entities, relief for these the threshold. Most of the requirements taken by employees, and lower provisions would also delay the full of the Unfunded Mandates are fulfilled adjustment costs by firms that would realization of the benefits of the in the Executive Order 12866 analysis. otherwise need to hire replacement proposed rule. The requirements under the Unfunded employees.

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Exports comments regarding this document. Basis of Therapeutics, 5th ed., New This proposed rule would require Submit a single copy of electronic York. Macmillan Publishing, pp. 653– additional controls to be kept comments to http://www.fda.gov/ 682, 1975. 11. ‘‘Survey on Botanical throughout the production and dockets/ecomments or two hard copies Adulteration,’’ American Herbal distribution chain for the manufacture of any written comments, except that Products Association, 8484 Georgia of dietary ingredients and dietary individuals may submit one hard copy. Ave., suite 370, Silver Spring, MD supplements. The additional control Comments are to be identified with the 20910, March 4, 1998. costs would increase the total costs of docket number found in brackets in the 12. Roy, A. K. and H. K. Chourasia, production and distribution for all of heading of this document. Received ‘‘Mycotoxin Incidence in Root Drugs,’’ the regulated products, including comments may be seen in the Dockets International Journal of Crude Drug products sold within the U.S. and across Management Branch between 9 a.m. and 4 p.m., Monday through Friday. Residues, 28:2, pp. 157–160, 1990. national borders. These increased costs 13. Kumar, S. and A. K. Roy, will be largely passed on to consumers X. References ‘‘Occurrence of Aflatoxin in Some Liver in the form of higher prices, which will We have placed the following Curative Herbal Medicines,’’ Letters in tend to reduce the quantity demanded references on display in the Dockets Applied Microbiology, 17, pp. 112–114, of the regulated products. The increased Management Branch (see ADDRESSES). 1993. prices of U.S. exports could reduce the You may see them between 9 a.m. and 14. Kumar, S. and G. Prasad, ‘‘Efficacy quantity of U.S. exports demanded, 4 p.m., Monday through Friday. of Medicinal Plant (Andrographis particularly in comparison with exports 1. Section 2, ‘‘Findings,’’ Dietary peniculata) Extract on Aflatoxin from countries that do not implement Supplement Health and Education Act, Production and Growth of Aspergillus similar regulations. We expect this Pub. L. 103–417, pp. 4325–4326, flavus,’’ Letters in Microbiology 15, pp. effect to be insignificant, because under October 25, 1994. 131–132, 1992. the proposed rule the increases in the 2. ‘‘Manufacturing Practices for 15. ‘‘Adverse Events Associated with price of United States exports (and Nutritional Supplements,’’ United Ingestion of Gamma-Butyrolactone: resulting decreases in quantity States Pharmacopeia, 12601 Twinbrook Minnesota, New Mexico, and Texas, demanded) would be quite small. Pkwy., Rockville, MD 20852, General 1998–1999,’’ MMWR Weekly, 48:07, pp. VIII. Federalism Chapter 2750, 2186–2192, and 2834, 137–140, February 26, 1999. 1993. 16. FDA Establishment Inspection FDA has analyzed this proposed rule 3. ‘‘NNFA Good Manufacturing Report, Ducoa Co., CFN #1944182, in accordance with the principles set Practice in Manufacturing, Packing, or August 31, 1998 and September 1, 1998. forth in Executive Order 13132. We Holding Dietary Supplements,’’ 17. FDA Health Hazard Evaluation, consulted with seven State officials to National Nutritional Foods Association, Classification, and FDA Enforcement make a tentative determination about 3931 MacArthur Blvd., suite 101, Report for Firm-Initiated Recall—Lead, whether this proposed rule would have Newport Beach, CA 92660, 1999. U.S. FDA Recall #F–006–5 and #F–137/ federalism implications. Based on this 4. ‘‘Draft Report of the Food Advisory 145–5, 1994. consultation, it does not appear that this Committee Dietary Supplement 18. FDA Health Hazard Evaluation, proposed rule has federalism Working Group on Ingredient Identity Classification, and FDA Enforcement implications. In addition, we sent a Testing and Records and Retention,’’ Report for Firm-Initiated Recall letter on March 7, 2000, to elected State FDA Food Advisory Committee Dietary Salmonella, U.S. FDA Recall #F–164/ officials and their representative Supplement Working Group, Center for 171–8, 1988. organization to notify them that our Food Safety and Applied Nutrition, 19. FDA Health Hazard Evaluation, unified agenda was published on FDA, June 25, 1999. Classification, and FDA Enforcement November 22, 1999, and identified this 5. ‘‘Consumer Use of Dietary Report for Firm-Initiated Recall— proposed CGMP rule as a rule that Supplements,’’ Rodale Press, 733 Third Klebsiella Pneumonia, U.S. FDA Recall would publish in the year 2000. In that Ave., New York, NY 10017, 2000. #F–522–0, 1990. letter, we solicited comments on any 6. Slifman, N. R., W. R. Obermeyer, B. 20. FDA Health Hazard Evaluation, federalism implications that this K. Aloi, S. M. Musser, W. A. Correll, S. Classification, and FDA Enforcement proposed rule may have. To date, no M. Cichowicz, J. M. Betz, and L. A. Report for Firm-Initiated Recall— responses have been received to our Love, ‘‘Contamination of Botanical Botulism, U.S. FDA Recall #F–563/564– solicitation. After publishing this Dietary Supplements by Digitalis 9, 1989. proposed rule, FDA will send a letter to Lanata,’’ New England Journal of 21. FDA Health Hazard Evaluation, elected State officials and their Medicine, 339:12, pp. 806–811, 1998. Classification, and FDA Enforcement representative organization requesting 7. ‘‘Cardiac Glycoside Drugs,’’ In: Report for Firm-Initiated Recall—Glass consultation about any federalism Wagner, H., and S. Bladt, Plant Drug Fragments, U.S. FDA Recall #F–540–3, implications. We invite comment on our Analysis: A Thin Layer Chromatography 1993. tentative determination that this Atlas, 2d ed., Berlin, Germany: 22. FDA Health Hazard Evaluation, proposed rule does not have federalism Springer-Verlag, pp. 99–123, 1996. Classification, and FDA Enforcement implications, and therefore, does not 8. Bruneton, J., Pharmacognosy, Report for Firm-Initiated Recall Super- contain policies that have substantial Phytochemistry, Medicinal Plants, Paris, Potent Vitamin A, U.S. FDA Recall #F– direct effects on the States, or on the Lavoisier Publishing, pp. 572–598, 157/158–5, 1994. distribution of power and 1995. 23. FDA Health Hazard Evaluation, responsibilities among the various 9. Evans, W. C., Trease and Evans’ Classification, and FDA Enforcement levels of government. Pharmacognosy. 14th ed., Philadelphia, Report for Firm-Initiated Recall—Super- W. B. Saunders, pp. 309–318, 1996. Potent Vitamin D, U.S. FDA Recall IX. Request for Comments 10. Moe, G. K. and A. E. Farah, #F0610–3, 1993. Interested persons may submit to the ‘‘Digitalis and Allied Cardiac 24. FDA Health Hazard Evaluation, Dockets Management Branch (see Glycosides,’’ In L. S. Goodman and A. Classification, and FDA Enforcement ADDRESSES) written or electronic Gilman, eds., The Pharmacological Report for Firm-Initiated Recall—Super-

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Food Intakes by Individuals; Food President, Washington, DC, United Wee, ‘‘Heavy Metals in Some Chinese Surveys Research Group, Beltsville States Government Printing Office, Herbal Plants,’’ Biological Trace Human Nutrition Research Center, 2000. Element Research, 36, pp. 135–142, Agricultural Research Service, U.S. E20. Kaplan, M., J. A. Anderson, and 1993. Department of Agriculture, Riverdale, T. G. Ganiats, ‘‘The Quality of Well- 76. ‘‘Reviewer Guidance, Validation MD; February 1999; accessed at http:// being Scale: Rationale for a Single of Chromatographic Methods Center for www.barc.usda.gov/bhnrc/foodsurvey/ Quality of Life Index,’’ edited by S. R. Drug Evaluation and Research, FDA, home.htm. Walker and R. M. Rosser, In Quality of November 1994. E7. Prevention Research Associates, Life Assessment: Key Issues in the 77. FDA Health Hazard Evaluation, Special Nutritionals Survey, Report for 1990’s, The Netherlands: Kluwer Classification, and FDA Enforcement Prevention Magazine, June 8, 1999. Academic Publishers, 65–94, 1993. Report for Firm-Initiated Recall #F–321– E8. Roe, B. E., B. M. Derby, A. L. Levy, E21. Kaufman, L. D. ‘‘Chronicity of 0, 1989. ‘‘Demographic, Lifestyle and the Eosinophilia-Myalgia Syndrome. A

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Reassessment After Three Years,’’ Americans Use Their Time, University 21 CFR Part 112 Arthritis and Rheumatism, 37:884–887, Park, PA: The Pennsylvania State Drugs, Packaging and containers, 1994 Abstract. University Press, 1997. Labeling. E22. Hedberg, C., et al., E38. ‘‘How Consumers Shop,’’ ‘‘Eosinophilia-Myalgia Syndrome, Progressive Grocer, December, 62–64, Therefore, under the Federal Food, Natural History in a Population Based 1992. Drug, and Cosmetic Act and under Cohort,’’ Archives of Internal Medicine, E39. United States Department of authority delegated to the Commissioner 152:1189–1892, 1992 Abstract. Labor, Bureau of Labor Statistics (BLS), of Food and Drugs, FDA proposes to E23. Vanherweghem, J. L., ‘‘Misuse of Consumer Reports, March, 44– E42. Bureau of Labor Statistics (BLS), Authority: 21 U.S.C. 321, 342, 343, 348, 48, 1999. ‘‘Consumer Price Index-All Urban 371, 374, 381, 393; 42 U.S.C. 264. E26. ConsumerLab, Independent tests Consumers,’’ Accessed at http:// 2. The part heading for part 111 is of herbal, vitamin, and mineral 146.142.4.24/cgi-bin/surveymost?cu on revised as set forth above. supplements, accessed at http:// July 13, 1999. 3. Add new subpart A to part 111 to www.consumerlab.com/results on E43. Gurley, B. J. , S. F. Gardner, and read as follows: March 16, 2000. M. A. Hubbard, ‘‘Content Versus Label E27. Rothman, G., ‘‘Herbal Remedy Claims in Ephedra-Containing Dietary Subpart A—General Provisions Ripoffs,’’ D Magazine, April, 39–44, Supplements,’’ American Journal Sec. 2000. Health Systems Pharmacy, 57:963–969, 111.1 Who is subject to these regulations? E28. Foster, W. and R. E. Just, May 15, 2000. 111.2 What are these regulations intended to accomplish? ‘‘Measuring Welfare Effects of Product E44. Eastern Research Group (ERG), Contamination with Consumer 111.3 What definitions apply to this part? ‘‘Economic Analysis of Proposed 111.5 Do other statutory provisions and Uncertainty,’’ Journal of Environmental Revisions to the Good Manufacturing regulations apply? Economics and Management, 17, pp. Practices Regulation for Medical 111.6 Exclusions. 266–283, 1989. Devices,’’ Contract No. 223–91–8100: E29. Jones, P. and J. Hudson, Task Order 1, pp. 4–23 to 4–25, Subpart A—General Provisions ‘‘Standardization and the Costs of November, 1993. Assessing Quality,’’ European Journal of § 111.1 Who is subject to these E45. R. S. Means, Building regulations? Political Economy, 12:355–361, 1996. Construction Cost Data, 2000. E30. Newman, J. W. and B. D. You are subject to the regulations in E46. RTI, 1999b, ‘‘Dietary Supplement Lockeman, ‘‘Measuring Prepurchase this part if you manufacture, package, or Sales Information,’’ Contract No. 223– Information Seeking,’’ Journal of hold a dietary ingredient or dietary 96–2290: Task Order 4, October, 1999. Consumer Research, 2:216–222, 1975. supplement. E31. Punj, G. N. and R. Staelin, ‘‘A E47. Vardon, P., Memorandum: Model of Consumer Information Search Conversation with industry expert § 111.2 What are these regulations intended to accomplish? Behavior for New Automobiles,’’ regarding inventory practices, April 4, Journal of Consumer Research, 9:366– 2000. The regulations in this part establish 380, 1983. E48. Ramey, V. A. and K. West, the minimum current good E32. Duncan C. and R. Olshavsky, ‘‘Inventories,’’ National Bureau of manufacturing practices that you must ‘‘External Search: The Role of Consumer Economic Research, working paper use to the extent that you manufacture, Beliefs,’’ Journal of Marketing Research, 6315, Abstract, 1997. package, or hold a dietary ingredient or 19:32–43, 1982. E49. Madis, V. H. and V. Madis, ‘‘The dietary supplement. E33. Andrews, R. L., ‘‘Economics of Sampling of Crude Botanicals,’’ Drug § 111.3 What definitions apply to this part? Information and Heterogeneous and Cosmetic Industry, pp. 38–79, 1986. Products,’’ Journal of Economic E50. Plant Bioactives Research The definitions and interpretations of Psychology, 13:399–420, 1992. Institute, ‘‘Costs for Analysis,’’ accessed terms in section 201 of the Federal E34. Avery, R. J., ‘‘Determinants of at http://www.plant-bioactives.com on Food, Drug, and Cosmetic Act (the act) Search for Nondurable Goods: An April 10, 2000. apply to such terms when used in these Empirical Assessment of the Economics E51. ‘‘Fees, Methods, and Analytical regulations. For the purpose of these of Consumer Theory,’’ The Journal of Capabilities of Laboratories-Summary,’’ regulations, the following definitions Consumer Affairs, 30(2):390–420, 1996. unpublished summary of prices listed also apply: E35. Hawkins, D. I., R. J. Best, and K. on the Internet, 1999. Actual yield means the quantity that is actually produced at any appropriate A. Coney, Consumer Behavior: 52. McLaughlin, C., Memorandum: step of manufacture or packaging of a Implications for Marketing Strategy, 6th Costs of pest control, 2000. ed., Chicago: Irwin, 1995. particular dietary ingredient or dietary E36. ‘‘The Power of Persuasion at the List of Subjects supplement. Moment of Truth,’’ Drug Store News, Batch means a specific quantity of a 21 CFR Part 111 19(20):3–8, 22, 24, 1997. dietary ingredient or dietary supplement E37. Robinson, J. P. and G. Godbey, Dietary foods, Drugs, Foods, that is intended to meet specifications Time for Life: The Surprising Ways Packaging and containers. for identity, purity, quality, strength,

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and composition, and is produced is not necessarily limited to, a dietary ingredients, or dietary supplements that during a specified time period according ingredient as described in section have been previously removed from to a single manufacturing record during 201(ff) of the Act. manufacturing for reasons other than the same cycle of manufacture. Inprocess material means any insanitary conditions and that have Batch number, lot number, or control material that is fabricated, compounded, been made suitable for use in the number means any distinctive group of blended, ground, extracted, sifted, manufacture of a dietary ingredient or letters, numbers, or symbols, or any sterilized, derived by chemical reaction, dietary supplement. combination of them, from which the or processed in any other way for use Sanitize means to adequately treat complete history of the manufacturing, in the manufacture of a dietary equipment, containers, utensils, or any packaging, or holding of a batch or lot ingredient or dietary supplement. other dietary product contact surface by of dietary ingredients or dietary Lot means a batch, or a specific applying cumulative heat or chemicals supplements can be determined. identified portion of a batch intended to on cleaned food contact surfaces that Component means any substance have uniform identity, purity, quality, when evaluated for efficacy, yield a intended for use in the manufacture of strength, and composition; or, in the reduction of 5 logs, which is equal to a dietary ingredient or dietary case of a dietary ingredient or dietary 99.999 percent reduction, of supplement including those that may supplement produced by continuous representative disease microorganisms not appear in the finished dietary process, a specific identified amount of public health significance and ingredient or dietary supplement. produced in a specified unit of time or substantially reduce the numbers of Component includes ingredients and quantity in a manner that is intended to other undesirable microorganisms, but dietary ingredients as described in have uniform identity, purity, quality, without adversely affecting the product section 201(ff) of the Act. strength, and composition. or its safety for the consumer. Consumer complaint means Microorganisms means yeasts, molds, Theoretical yield means the quantity communication that contains any bacteria, viruses, and other similar that would be produced at any allegation, written or oral, expressing microscopic organisms having public appropriate step of manufacture or dissatisfaction with the quality of a health or sanitary concern. This packaging of a particular dietary dietary ingredient or a dietary definition includes, but is not limited ingredient or dietary supplement, based supplement related to good to, species that: upon the quantity of components or manufacturing practices. Examples of (1) Have public health significance; packaging to be used, in the absence of product quality related to good (2) Could cause a component, dietary any loss or error in actual production. manufacturing practices are: Foul odor, ingredient, or dietary supplement to Water activity (aw) is a measure of the off taste, superpotent, subpotent, wrong decompose; free moisture in a component, dietary ingredient, drug contaminant, other (3) Indicate that the component, ingredient, or dietary supplement and is contaminant (e.g., bacteria, pesticide, dietary ingredient, or dietary the quotient of the water vapor pressure mycotoxin, glass, lead), disintegration supplement is contaminated with filth; of the substance divided by the vapor time, color variation, tablet size or size or pressure of pure water at the same variation, under-filled container, foreign (4) Otherwise may cause the temperature. material in a dietary supplement component, dietary ingredient, or We means the United States Food and container, improper packaging, or dietary supplement to be adulterated. Drug Administration (FDA). mislabeling. For the purposes of the Must is used to state mandatory You means a person who regulations in this part, a consumer requirements. manufactures, packages, or holds complaint about product quality may or Pest means any objectionable insects dietary ingredients or dietary may not include concerns about a or other animals including, but not supplements. possible hazard to health. However, a limited to, birds, rodents, flies, mites, consumer complaint does not include and larvae. § 111.5 Do other statutory provisions and an adverse event, illness, or injury Physical plant means all or parts of a regulations apply? related to the safety of a particular building or facility used for or in In addition to the regulations in this dietary ingredient independent of connection with manufacturing, part, you must comply with other whether the product is produced under packaging, or holding a dietary applicable statutory provisions and good manufacturing practices. ingredient or dietary supplement. regulations under the Act related to the Contact surface means any surface Quality control means a planned and manufacturing, packaging, or holding of that contacts a component, dietary systematic operation or procedure for dietary ingredients or dietary ingredient, dietary supplement, and preventing a dietary ingredient or supplements. those surfaces from which drainage onto dietary supplement from being the component, dietary ingredient, adulterated. § 111.6 Exclusions. dietary supplement, or onto surfaces Quality control unit means any person The regulations in this part do not that contact the component, dietary or group that you designate to be apply to a person engaged solely in ingredient, or dietary supplement responsible for quality control activities related to the harvesting, ordinarily occurs during the normal operations. storage, or distribution of raw course of operations. Examples of Representative sample means a agricultural commodities that will be contact surfaces include, but are not sample that consists of a number of incorporated into a dietary ingredient or limited to, containers, utensils, tables, units that are drawn based on rational dietary supplement by other persons. contact surfaces of equipment, and criteria, such as random sampling, and 4. Add new subpart B to part 111 to packaging. intended to ensure that the sample read as follows: Ingredient means any substance that accurately portrays the material being Subpart B—Personnel is used in the manufacture of a dietary sampled. Sec. ingredient or dietary supplement that is Reprocessing means using, in the 111.10 What microbial contamination and intended to be present in the finished manufacture of a dietary ingredient or a hygiene requirements apply? dietary ingredient or dietary dietary supplement, clean, 111.12 What personnel qualification supplement. An ingredient includes, but unadulterated components, dietary requirements apply?

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111.13 What supervisor requirements be adequately sanitized during periods 111.15 What sanitation requirements apply apply? in which components, dietary to your physical plant? ingredients, or dietary supplements are 111.20 What design and construction Subpart B—Personnel manipulated by hand. If hand jewelry requirements apply to your physical plant? § 111.10 What microbial contamination cannot be removed, it must be covered and hygiene requirements apply? by material that is maintained in an Subpart C—Physical Plant (a) Microbial contamination. You intact, clean, and sanitary condition and must take measures to exclude from any that effectively protects against § 111.15 What sanitation requirements apply to your physical plant? operations any person who might be a contamination of components, dietary source of microbial contamination of ingredients, dietary supplements, or (a) Physical plant facilities. (1) You any material including components, contact surfaces; must maintain your physical plant in a dietary ingredients, dietary (5) Maintaining gloves used in clean and sanitary condition; and supplements, and contact surfaces used handling components, dietary (2) You must keep your physical plant in the manufacture, packaging, or ingredients, or dietary supplements in in repair sufficient to prevent holding of a dietary ingredient or a an intact, clean, and sanitary condition. components, dietary ingredients, dietary dietary supplement. Such measures The gloves must be of an impermeable supplements, or contact surfaces from include, but are not limited to, the material; becoming contaminated. (6) Wearing, where appropriate, in an following: (b) Cleaning compounds, sanitizing (1) Excluding any person who, by effective manner, hair nets, caps, beard agents, and pesticides. (1) You must use medical examination or supervisory covers, or other effective hair restraints; cleaning compounds and sanitizing (7) Not storing clothing or other observation, is shown to have, or agents that are free from microorganisms personal belongings in areas where appears to have an illness, open lesion, of public health significance and safe components, dietary ingredients, or or any other abnormal source of and adequate under the conditions of dietary supplements or any contact microbial contamination, which may be use. surfaces are exposed or where contact expected to result in microbial (2) You must not use or hold toxic surfaces are washed; contamination of components, dietary materials in a physical plant in which (8) Not eating food, chewing gum, contact surfaces, components, dietary ingredients, dietary supplements, or drinking beverages and using tobacco contact surfaces, from working in any ingredients, or dietary supplements are products in areas where components, manufactured or exposed, unless those operations until the condition is dietary ingredients, dietary corrected; and materials are necessary: supplements, or any contact surfaces are (i) To maintain clean and sanitary (2) Instructing your employees to exposed, or where contact surfaces are notify their supervisor(s) if they have or conditions; washed; and (ii) For use in laboratory testing if there is a reasonable possibility that (9) Taking any other precautions procedures; they have a health condition described necessary to protect against the (iii) For maintaining or operating the in paragraph (a)(1) of this section that contamination of components, dietary physical plant or equipment; or could contaminate any components, ingredients, dietary supplements, or dietary ingredients, dietary contact surfaces with microorganisms, (iv) For use in the plant’s operations. supplements, or any contact surface. filth, or any other extraneous materials, (3) You must identify and hold toxic (b) Hygienic practices. If you work in including, but not limited to, cleaning compounds, sanitizing agents, operations during which adulteration of perspiration, hair, cosmetics, tobacco, pesticides, and pesticide chemicals in a the component, dietary ingredients, chemicals, and medicines applied to the manner that protects against dietary supplement, or contact surface skin. contamination of components, dietary may occur, you must use hygienic ingredients, dietary supplements, or practices to the extent necessary to § 111.12 What personnel qualification contact surfaces. protect against contamination of requirements apply? (c) Pest control. (1) You must not components, dietary ingredients, dietary (a) You must have qualified allow animals or pests in any area of supplements, or contact surfaces. These employees to manufacture, package, or your physical plant. Guard or guide hygienic practices include, but are not hold dietary ingredients or dietary dogs are allowed in some areas of your limited to: supplements; and physical plant if the presence of the (1) Wearing outer garments in a (b) Each person engaged in dogs will not result in contamination of manner that protects against the manufacturing, packaging, or holding components, dietary ingredients, dietary contamination of components, dietary must have the training and experience supplements, or contact surfaces; ingredients, dietary supplements, or any to perform the person’s duties. (2) You must take effective measures contact surface; to exclude pests from the physical plant § 111.13 What supervisor requirements (2) Maintaining adequate personal apply? and to protect against contamination of cleanliness; components, dietary ingredients, dietary (a) You must assign qualified (3) Washing hands thoroughly (and supplements, and contact surfaces on personnel to supervise the sanitizing if necessary to protect against the premises by pests; and manufacturing, packaging, or holding of contamination with microorganisms) in (3) You must not use insecticides, dietary ingredients and dietary an adequate hand-washing facility: fumigants, fungicides, or rodenticides, supplements. (i) Before starting work; and unless you take precautions to protect (b) You and the supervisors you use (ii) At any time when the hands may against the contamination of must be qualified by training and have become soiled or contaminated; components, dietary ingredients, dietary experience to supervise. (4) Removing all unsecured jewelry 5. Add new subpart C to part 111 to supplements, or contact surfaces. and other objects that might fall into read as follows: (d) Water supply. (1) You must components, dietary ingredients, dietary provide water that is safe and of supplements, equipment, or packaging, Subpart C—Physical Plant adequate sanitary quality, at suitable and removing hand jewelry that cannot Sec. temperatures, and under pressure as

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needed, in all areas where water is (3) Provide doors that do not open § 111.20 What design and construction necessary for: into areas where components, dietary requirements apply to your physical plant? (i) Manufacturing dietary ingredients ingredients, dietary supplements, or Any physical plant you use in the or dietary supplements; contact surfaces are exposed to airborne manufacture, packaging, or holding of (ii) Making ice that comes in contact contamination except where alternate dietary ingredients or dietary with components, dietary ingredients, means have been taken to protect supplements must: dietary supplements, or contact against contamination (such as double (a) Be suitable in size, construction, surfaces; doors or positive airflow systems). and design to facilitate maintenance, (iii) Cleaning any surface; and (h) Hand-washing facilities. You must cleaning, and sanitizing operations; (iv) Employee bathrooms and hand- provide hand-washing facilities that are (b) Have adequate space for the washing facilities. adequate, convenient, and furnish orderly placement of equipment and (2) Water that contacts components, running water at a suitable temperature. holding materials as is necessary for dietary ingredients, dietary You must do this by providing: maintenance, cleaning, and sanitizing supplements, or any contact surface (1) Hand-washing and, where operations and to prevent must at a minimum comply with the appropriate, hand-sanitizing facilities at contamination and mixups of National Primary Drinking Water each location in your physical plant components, dietary ingredients, and regulations prescribed by the where good hygienic practices require dietary supplements during Environmental Protection Agency under employees to wash or to sanitize or both manufacturing, packaging, or holding; (c) Permit the use of proper 40 CFR part 141 and any state and local wash and sanitize their hands; government requirements; precautions to reduce the potential for (3) You must have documentation or (2) Effective hand-cleaning and mixups or contamination of otherwise be able to show that water sanitizing preparations; components, dietary ingredients, dietary that contacts components, dietary (3) Air driers, sanitary towel service, supplements, or contact surfaces, with ingredients, dietary supplements, or any such as disposable paper towels, or microorganisms, chemicals, filth, or contact surface meets the requirements other suitable drying devices; other extraneous material. Your in paragraph (d)(2) of this section. (4) Devices or fixtures, such as water physical plant must have and you must (e) Plumbing. The plumbing in your control valves, designed and use separate or defined areas of physical plant must be of an adequate constructed to protect against adequate size or other control systems, size and design and be adequately recontamination of clean, sanitized such as computerized inventory installed and maintained to: hands; controls or automated systems of (1) Carry sufficient amounts of water (5) Signs that are easy to understand separation, to prevent contamination to required locations throughout the and are posted throughout the physical and mixups of components, dietary physical plant; plant that direct employees handling ingredients, and dietary supplements (2) Properly convey sewage and liquid components, dietary ingredients, dietary during the following operations: disposable waste from your physical supplements, or contact surfaces to (1) Receiving, identifying, holding, plant; wash and, where appropriate, to sanitize and withholding from use, components, (3) Avoid being a source of their hands before they start work, after dietary ingredients, dietary contamination to components, dietary each absence from their duty station, supplements, packaging, and labels that ingredients, dietary supplements, water and when their hands may have become will be used in or during the supplies, or any contact surface, or soiled or contaminated; and manufacturing, packaging, or holding of creating an unsanitary condition; (6) Trash bins that are constructed dietary ingredients and dietary (4) Provide adequate floor drainage in and maintained in a manner to protect supplements; all areas where floors are subject to against recontamination of hands and (2) Separating, as necessary, flooding-type cleaning or where normal contamination of components, dietary components, dietary ingredients, dietary operations release or discharge water or ingredients, dietary supplements, or any supplements, packaging, and labels that other liquid waste on the floor; and contact surface. are to be used from components, dietary (5) Not allow backflow from, or cross (i) Trash disposal. You must convey, ingredients, dietary supplements, connection between, piping systems store, and dispose of trash to: packaging, or labels that are awaiting that discharge waste water or sewage (1) Minimize the development of material review and disposition and piping systems that carry water odor; decision, reprocessing, or are awaiting used for manufacturing dietary (2) Minimize the potential for the disposal after rejection; ingredients or dietary supplements, for trash to attract, harbor, or become a (3) Separating the manufacturing, cleaning contact surfaces, or for use in breeding place for pests; packaging, and holding of different bathrooms or hand-washing facilities. product types including, but not limited (3) Protect against contamination of (f) Sewage disposal. You must dispose to, different types of dietary ingredients, components, dietary ingredients, dietary of sewage into an adequate sewage dietary supplements and other foods, supplements, any contact surface, water system or through other adequate cosmetics, and pharmaceutical supplies, and grounds surrounding your means. products; (g) Bathrooms. You must provide your physical plant; and (4) Performing laboratory analyses employees with adequate, readily (4) Control hazardous waste to and holding laboratory supplies and accessible bathrooms. The bathrooms prevent contamination of components, samples; must be kept clean and must not dietary ingredients, dietary (5) Cleaning and sanitizing contact become a potential source of supplements, and contact surfaces. surfaces; contamination to components, dietary (j) Sanitation supervisors. You must (6) Packaging and label operations; ingredients, dietary supplements, or assign one or more employees to and contact surfaces. You must: supervise overall sanitation. These (7) Holding dietary ingredients or (1) Keep the bathrooms in good repair supervisors must be qualified by dietary supplements. at all times; training and experience to develop and (d) Be designed and constructed in a (2) Provide self-closing doors; and supervise sanitation procedures. manner that prevents contamination of

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components, dietary ingredients, dietary (3) Placement in areas where you can (v) Maintained to protect components, supplements, or contact surfaces. The check regularly for pests, pest dietary ingredients, and dietary design and construction must include, infestation, filth or any other extraneous supplements from being contaminated but not be limited to: materials; and by any source. (1) Floors, walls, and ceilings that are (4) Use of skimming equipment. (4) Equipment and utensils you use of smooth and hard surfaces that can be (h) Use adequate screening or other must have seams that are smoothly adequately cleaned and kept clean and protection against pests, where bonded or maintained to minimize in good repair; necessary. accumulation of component, dietary (2) Fixtures, ducts, and pipes that do 6. Add new subpart D to part 111 to ingredient, or dietary supplement not contaminate components, dietary read as follows: particles, dirt, filth, organic material, or ingredients, dietary supplements, or Subpart D—Equipment and Utensils any other extraneous materials or contact surfaces by dripping or contaminants to minimize the Sec. condensate; 111.25 What requirements apply to the opportunity for growth of (3) Adequate ventilation or equipment and utensils you use? microorganisms. environmental control equipment such 111.30 What requirements apply to (5) Each freezer and cold storage as air flow systems, including filters, automatic, mechanical, or electronic compartment you use to hold fans, and other air-blowing equipment, equipment? components, dietary ingredients, or that minimize odors and vapors dietary supplements: (including steam and noxious fumes) in Subpart D—Equipment and Utensils (i) Must be fitted with an indicating areas where they may contaminate thermometer, temperature-measuring § 111.25 What requirements apply to the components, dietary ingredients, dietary equipment and utensils you use? device, or temperature-recording device supplements, or contact surfaces; that shows the temperature accurately (a)(1) You must use equipment and (4) Fans and other air-blowing within the compartment; and equipment located and operated in a utensils that are of appropriate design, (ii) Must have an automatic device for manner that minimizes the potential for construction, and workmanship to regulating temperature or an automatic microorganisms and particulate matter enable them to be suitable for their alarm system to indicate a significant to contaminate components, dietary intended use and to be adequately temperature change in a manual ingredients, dietary supplements, or cleaned and properly maintained. operation. contact surfaces; Equipment and utensils include, but are (6) Instruments or controls used in the (5) Equipment that controls not limited to, the following: manufacturing, packaging, or holding of temperature and humidity; and (i) Equipment used to hold or convey; a dietary ingredient or dietary (ii) Equipment used to measure; (6) Aisles or working spaces between (iii) Equipment using compressed air supplement, including but not limited equipment and walls that are adequately or gas; to, instruments or controls you use to unobstructed and of adequate width to (iv) Equipment used to carry out measure, regulate, or record permit all persons to perform their processes in closed pipes and vessels; temperatures, hydrogen ion duties and to protect against and concentration (pH), water activity, or contamination of components, dietary (v) Equipment used in automatic, other conditions that control or prevent ingredients, dietary supplements, or mechanical, or electronic systems. the growth of microorganisms or other contact surfaces with clothing or (2) You must use equipment and contamination must be: personal contact. utensils of appropriate design and (i) Accurate and precise; (e) Provide adequate light in: construction so that use will not result (ii) Adequately maintained; and (1) All areas where components, in the contamination of components, (iii) Adequate in number for their dietary ingredients, or dietary dietary ingredients, or dietary designated uses. supplements are examined, processed, supplements with: (7) Compressed air or other gases you or held; (i) Lubricants; introduce mechanically into or onto a (2) All areas where contact surfaces (ii) Fuel; component, dietary ingredient, dietary are cleaned; and (iii) Coolants; supplement, or contact surface or that (3) Hand-washing areas, dressing and (iv) Metal or glass fragments; you use to clean any contact surface locker rooms, and bathrooms. (v) Filth or any other extraneous must be treated in such a way that the (f) Use safety-type light bulbs, material; component, dietary ingredient, dietary fixtures, skylights, or other glass that is (vi) Contaminated water; or supplement, or contact surface is not suspended over exposed components, (vii) Any other contaminants. contaminated. dietary ingredients, or dietary (3) All equipment and utensils you (b)(1) You must calibrate instruments supplements in any step of preparation, use must be: and controls you use in manufacturing unless otherwise constructed in a (i) Installed and maintained to or testing a component, dietary manner that will protect against facilitate cleaning the equipment, ingredient, or dietary supplement. contamination of components, dietary utensils, and all adjacent spaces; (2) You must calibrate before first use; ingredients, or dietary supplements in (ii) Corrosion-resistant if the and case of glass breakage. equipment or utensils contact (i) As specified in writing by the (g) Provide protection by any effective components, dietary ingredients, or manufacturer of the instrument and means against contamination of dietary supplements; control, or components, dietary ingredients, and (iii) Made of nontoxic materials; (ii) At routine intervals or as dietary supplements in bulk (iv) Designed and constructed to otherwise necessary to ensure the fermentation vessels, including withstand the environment of their accuracy and precision of the consideration of: intended use, the action of components, instrument and control. (1) Use of protective coverings; dietary ingredients, or dietary (c) You must: (2) Placement in areas where you can supplements, and, if applicable, (1) Establish a written procedure for eliminate harborages for pests over and cleaning compounds and sanitizing calibrating instruments and controls you around the vessels; agents; and use in manufacturing or testing a

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component, dietary ingredient, or the same dietary ingredient or dietary you use and that only authorized dietary supplement and document that supplement, you must clean and personnel institute the changes; the written procedure was followed sanitize the contact surfaces as (4) Establish and use appropriate each time a calibration is performed, or necessary. controls to ensure that the equipment (2) Document at the time of (4) You must clean surfaces that do functions in accordance with its performance that the instrument and not touch components, dietary intended use. These controls must be control calibration established in ingredients, or dietary supplements as approved by your quality control unit; accordance with this section was frequently as necessary to protect and performed. against contaminating components, (5) Make and keep backup file(s) of (d) You must identify the following dietary ingredients, or dietary software programs and of data entered for calibrating instruments and controls supplements. into your computer system. Your in any written procedure or at the time (5) Single-service articles (such as backup file (e.g., a hard copy of data you of performance: utensils intended for one-time use, have entered, diskettes, tapes, (1) The instrument or control paper cups, and paper towels) must be: microfilm, or compact disks) must be an calibrated; (i) Stored in appropriate containers; exact and complete record of the data (2) The date of calibration; and you entered. You must keep your (3) The reference standard used (ii) Handled, dispensed, used, and backup software programs and data including the certification of accuracy of disposed of in a manner that protects secure from alterations, inadvertent the known reference standard and a against contamination of components, erasures, or loss. history of recertification of accuracy; dietary ingredients, dietary (c) You must keep automatic, (4) The calibration method used supplements, or any contact surface. mechanical, or electronic equipment including appropriate limits for (6) Cleaning compounds and records required by this section in accuracy and precision of instruments sanitizing agents must be adequate for accordance with § 111.125. and controls when calibrating; intended use and safe under condition (5) The calibration reading or readings of use; § 111.50 [Redesignated as § 111.72 and found; and (7) You must store cleaned and Amended] (6) The recalibration method used if sanitized portable equipment and 7. Redesignate § 111.50 as § 111.72 accuracy or precision or both accuracy utensils that have contact surfaces in a and transfer it to a new subpart E, and precision limits for instruments and location and manner that protects them Production and Process Controls, and controls were not met; and from contamination. revise the section heading to read as (7) The initials of the person who (f) You must keep calibration records follows: performed the calibration. as required by this section in (d) You must repair or replace accordance with § 111.125. § 111.72 What requirements apply to instruments or controls that cannot be packaging of iron-containing dietary adjusted to agree with the reference § 111.30 What requirements apply to supplements? standard. automatic, mechanical, or electronic * * * * * (e)(1) You must maintain, clean, and equipment? 8. Add §§ 111.35 through 111.70 and sanitize as necessary, all equipment, (a) When you use automatic, § 111.74 to newly added subpart E to utensils, and any other contact surfaces mechanical, or electronic equipment to read as follows: that are used to manufacture, package, manufacture, package, label, and hold a or hold components, dietary dietary ingredient or dietary § 111.35 What production and process ingredients, or dietary supplements. supplement, you must: controls must you use? Equipment and utensils must be taken (1) Design or select equipment to (a) You must implement a system of apart as necessary for thorough ensure that dietary ingredient or dietary production and process controls that maintenance, cleaning, and sanitizing. supplement specifications are covers all stages of manufacturing, (2) You must ensure that all contact consistently achieved and packaging, labeling, and holding of the surfaces used for manufacturing or (2) Determine the suitability of your dietary ingredients and dietary holding of low-moisture components, equipment by ensuring that your supplements. dietary ingredients, or dietary equipment is capable of operating (b) Your production and in-process supplements are in a dry and sanitary satisfactorily within the operating limits control system must be designed to condition at the time of use. When the required by the process. ensure that the dietary ingredient or surfaces are wet-cleaned, they must be (b) For any automatic, mechanical, or dietary supplement is manufactured, sanitized, when necessary, and electronic equipment you use, you packaged, and held in a manner that thoroughly dried before subsequent use. must: will prevent adulteration of the dietary (3) If you use wet processing during (1) Routinely calibrate, inspect, or ingredient or dietary supplement. The manufacturing, you must clean and check to ensure proper performance. production and in-process control sanitize all contact surfaces, as Your quality control unit must approve system must include all requirements of necessary, to protect against the these calibrations, inspections, or this subpart and must be reviewed and introduction of microorganisms into checks; approved by the quality control unit. components, dietary ingredients, or (2) Make and keep written records of (c) You must use a quality control dietary supplements. When cleaning equipment calibrations, inspections, or unit in your manufacturing, packaging, and sanitizing is necessary, you must checks; and label operations for producing the clean and sanitize all contact surfaces (3) Establish and use appropriate dietary ingredient or dietary supplement before use and after any interruption controls, to ensure that your quality to ensure that these operations are during which the contact surface may control unit approves changes in the performed in a manner that prevents have become contaminated. If you use master manufacturing record, batch adulteration and ensures that the dietary contact surfaces in a continuous control records, packaging operations ingredient or dietary supplement meets production operation or in back-to-back and label operations, or changes to other specifications for identity, purity, operations involving different batches of operations related to the equipment that quality, strength, and composition.

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(d) Any substance, other than a (g) You must ensure, through testing (ii) If any step established in the ‘‘dietary ingredient’’ within the meaning or examination, that each specification master manufacturing record is not of section 201(ff) of the Federal Food, that you established under paragraph (e) completed; Drug, and Cosmetic Act (the Act), the of this section is met. Specific testing (iii) If there is any unanticipated intended use of which results or may requirements are as follows: occurrence during the manufacturing reasonably be expected to result, (1) You must test each finished batch operations that adulterates or may lead directly or indirectly, in its becoming a of the dietary ingredient or dietary to adulteration of the component, component or otherwise affecting the supplement produced before releasing dietary ingredient, dietary supplement, characteristics of the dietary ingredient for distribution to determine whether packaging, or label; or dietary supplement must be: established specifications for identity, (iv) If calibration of an instrument or (1) Authorized for use as a food purity, quality, strength, and control suggests a problem that may additive under section 409 of the Act; or composition are met, provided that have caused batches of a dietary (2) Authorized by a prior sanction there are scientifically valid analytical ingredient or dietary supplement to consistent with § 170.3(l) of this methods available to conduct such become adulterated; or chapter; or testing. (v) If a dietary ingredient or dietary (3) If used as a color additive, subject (2) For any specification for identity, supplement is returned. to a listing that, by the terms of that purity, quality, strength, or composition (4) For any deviation or unanticipated listing, includes the use in a dietary for which you document cannot be occurrence which resulted in or could supplement; or tested on the finished batch of a dietary lead to adulteration of the component, (4) Generally recognized as safe ingredient or dietary supplement, dietary ingredient, dietary supplement, (GRAS) for use in a dietary ingredient or because there is no scientifically valid packaging, or label: dietary supplement. Any claim that a analytical method available for such (i) You must reject the component, substance is GRAS, other than a dietary testing, then you must: dietary ingredient, dietary supplement, ingredient within the meaning of (i) Perform testing on each shipment packaging, or label, unless the quality section 201(ff) of the Act, must be lot of components, dietary ingredients control unit determines that in-process supported by a citation to the agency’s or dietary supplements received to adjustments are possible to correct the regulations or by an explanation for why determine whether such specification is deviation or occurrence; there is general recognition of safety of met; and (ii) You must not reprocess a rejected the use of the substance in a dietary (ii) Perform testing in-process in component, dietary ingredient, or ingredient or dietary supplement; and accordance with the master dietary supplement unless approved by (5) Must comply with all other manufacturing record where control is the quality control unit; and applicable statutory and regulatory necessary to ensure the identity, purity, (iii) You must not reprocess any requirements under the Act. quality, strength, and composition of component, dietary ingredient or dietary (e) You must establish a specification dietary ingredients or dietary supplement if it is rejected because of for any point, step, or stage in the supplements; and contamination with microorganisms or manufacturing process where control is (3) Your quality control unit must other contaminants, such as heavy necessary to prevent adulteration. determine when finished batch testing metals; Specifications must be established for: cannot be completed for any (5) Have your quality control unit (1) The identity, purity, quality, specification on the identity, purity, review and approve any material review strength, and composition of quality, strength, and composition of and disposition decision described in components, dietary ingredients, or dietary ingredients or dietary paragraphs (i)(2) and (i)(3) of this dietary supplements that you receive; supplements. section. (2) The in-process controls in the (h) You must use an appropriate test (j) The person who conducts the master manufacturing record where or examination to determine whether material review and makes the control is necessary to ensure the your specifications are met. An disposition decision must, at the time of identity, purity, quality, strength, and appropriate test is one that is a performance, document every material composition of dietary ingredients or scientifically valid analytical method. review and disposition decision in dietary supplements; (i) You must: paragraph (i) of this section. The (3) The identity, purity, quality, (1) Establish corrective action plans documentation must be included in the strength, and composition of the dietary for use when an established appropriate batch production record ingredient or dietary supplement that specification is not met; and must: you manufacture; and (2) Review the results of the (1) Identify the specific deviation (4) The dietary ingredient or dietary monitoring required by this section and from the specification or the supplement labels and the packaging conduct a material review of any unanticipated occurrence; that may come in contact with dietary component, dietary ingredient, dietary (2) Describe your investigation into ingredients and dietary supplements. supplement, packaging or label for the cause of the deviation from the The packaging must be safe and suitable which you establish a specification that specification or the unanticipated for its intended use and comply with all is not met, or any unanticipated occurrence; other applicable statutory and occurrence that adulterates or could (3) Evaluate whether or not the regulatory requirements under the Act result in adulteration of the component, deviation from the specification or and must not be reactive or absorptive dietary ingredient, dietary supplement, unanticipated occurrence has resulted so as to affect the safety of the dietary packaging, or label; and in or could lead to adulteration; ingredient and dietary supplement. (3) Make a material disposition (4) Identify the action(s) taken to (f) You must monitor the in-process decision for any component, dietary correct and prevent a recurrence of the control points, steps, or stages to ensure ingredient, dietary supplement, deviation or the unanticipated that specifications established under packaging, or label: occurrence; and paragraph (e) of this section are met and (i) If a component, dietary ingredient, (5) Discuss what you did with the to detect any unanticipated occurrence dietary supplement, packaging, or label component, dietary ingredient, dietary that may result in adulteration; fails to meet specifications; supplement, packaging, or label.

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(k) You must test or examine (b) Your quality control unit must do supplements to determine that you used components, dietary ingredients, and the following: the packaging specified in the master dietary supplements for those types of (1) Approve or reject all processes, manufacturing record and applied the contamination that may adulterate or specifications, controls, tests, and label specified in the master may lead to adulteration. You must use examinations, and deviations from or manufacturing record. an appropriate scientifically valid modifications to them, that may affect (12) Keep the reserve samples for 3 method for the test or examination. The the identity, purity, quality, strength, years from the date of manufacture for types of contamination include, but are and composition of a dietary ingredient use in appropriate investigations not limited to, the following: or dietary supplement; including, but not limited to, consumer (1) Filth, insects, or other extraneous (2) Determine whether all complaint investigations to determine, material; components, dietary ingredients, dietary for example, whether the dietary (2) Microorganisms; and supplements, packaging, and labels ingredient or dietary supplement (3) Toxic substances. conform to specifications; associated with a consumer complaint (l) Tests in accordance with this (3) Approve or reject all components, failed to meet any of its specifications section must include at least one of the dietary ingredients, dietary for identity, purity, quality, strength, following: supplements, packaging, and labels; and composition. The reserve samples (1) Gross organoleptic analysis; (4) Review and approve all master must: (2) Microscopic analysis; manufacturing records and all (i) Be identified with the batch or lot (3) Chemical analysis; or modifications to the master number; and (4) Other appropriate test. manufacturing records; (ii) Consist of at least twice the (m) You must record results of all (5) Review and approve all batch quantity necessary for tests. testing and examinations performed in production-related records which (13) Perform appropriate tests and accordance with this section. If a test or include, but are not limited to, cross examinations of: examination is performed on a batch referencing receiving and batch (i) Components, dietary ingredients, production you must record the test or production records, approval of a dietary supplements, packaging, and examination result in the batch material review and disposition labels received to ensure that they meet production record in accordance with decision, approval for reprocessing, and specifications; § 111.50(c)(10). Your records must approval for releasing for distribution; (ii) Dietary ingredient and dietary document whether the testing and (6) Review and approve all processes supplement batch production at points, examination demonstrates that for calibrating instruments or controls; steps, or stages identified in the master specifications are met. (7) Review all records for calibration manufacturing record where control is (n) For any specification that is not of instruments, apparatus, gauges, and necessary to prevent adulteration; met, you must conduct a material recording devices; (iii) Dietary ingredients and dietary review and disposition decision under (8) Review all records for equipment supplements that you manufacture to paragraph (i) of this section. calibrations, inspections, and checks; ensure that they meet specifications; (o) You must make and retain records, (9) Review and approve all laboratory and in accordance with § 111.125, to ensure control processes, and testing results; (iv) Packaged and labeled dietary that you follow the requirements of this (10) Review and approve all ingredients and dietary supplements to section. The records must include, but packaging and label records which ensure that you used the packaging are not limited to: include, but are not limited to, cross- specified in the master manufacturing (1) The specifications established; referencing receiving and batch record and you applied the label (2) The actual results obtained during production records, approval for specified in the master manufacturing the monitoring operation; record. (3) Any deviation from specifications repackaging and relabeling, and approval for releasing for distribution; (14) Review and approve all material and any unanticipated occurrences; review and disposition decisions; and (4) Any corrective actions taken; (11) Collect representative samples of: (i) Each shipment lot of components, (15) Approve the reprocessing or (5) The disposition decisions and distribution of returned dietary followup; and dietary ingredients, dietary supplements, packaging, and labels ingredients or dietary supplements. (6) The identity of the individual (c) Your quality control unit must qualified by training and experience received to determine whether the component, dietary ingredient, dietary establish and maintain written who investigated any deviation from documentation at the time of specifications or unanticipated supplement, packaging, or labels meet specifications; performance that it performed the occurrence and the identity of the review, approval, or rejection individual from the quality control unit (ii) Inprocess materials at points, steps, or stages, in the manufacturing requirements of this section by who reviewed the results of that recording the following: investigation. process as specified in the master manufacturing record where control is (1) Date the required review, § 111.37 What requirements apply to necessary to ensure the identity, purity, approval, or rejection was performed; quality control? quality, strength, and composition of and (a) You must use a quality control dietary ingredients or dietary (2) Signature of the person performing unit to ensure that your manufacturing, supplements; the requirement. (d) You must keep quality control packaging, label, and holding operations (iii) Each batch of dietary ingredient records in accordance with § 111.125. in the production of dietary ingredients or dietary supplement manufactured to and dietary supplements are performed determine, before releasing for § 111.40 What requirements apply to in a manner that prevents adulteration distribution, whether the dietary components, dietary ingredients, dietary and misbranding, including ensuring ingredient or dietary supplement meets supplements, packaging, and labels you that dietary ingredients and dietary its specifications for identity, purity, receive? supplements meet specifications for quality, strength, and composition; and (a) For components, dietary identity, purity, quality, strength, and (iv) Each batch of packaged and ingredients, or dietary supplements you composition. labeled dietary ingredients or dietary receive, you must:

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(1) Visually examine each container release packaging and labels from each dietary ingredient for each batch or grouping of containers in a shipment quarantine before you use them; size; for appropriate content label, container (3) Identify each shipment lot of (2) A complete list of components to damage, or broken seals to determine packaging and labels in a manner that be used; whether the container condition has allows you to trace the shipment lot to (3) An accurate statement of the resulted in contamination or the supplier, the date received, the weight or measure of each component to deterioration of the components, dietary name of the packaging and label and the be used; ingredients, or dietary supplement; status (e.g., quarantined, approved, or (4) The identity and weight or (2) Visually examine the suppliers rejected) and to trace the shipment lot measure of each dietary ingredient that invoice, guarantee, or certification to to the dietary ingredient or dietary will be declared on the Supplement ensure that the components, dietary supplement manufactured and Facts label and the identity of each ingredients, or dietary supplements are distributed. You must use this unique ingredient that will be declared on the consistent with your purchase order and identifier whenever you record the ingredients list of the dietary perform testing, as needed, to determine disposition of each shipment lot supplement in compliance with section whether specifications are met. received; and 403(s) of the Federal Food, Drug, and (3) Quarantine components, dietary (4) Hold packaging and labels under Cosmetic Act; (5) A statement that explains any ingredients, or dietary supplements conditions that will protect against intentional excess amount of a dietary until your quality control unit reviews contamination, deterioration, and avoid mixups. ingredient; the suppliers invoice, guarantee, or (6) A statement of theoretical yield of certification and performs testing, as (c)(1) The person who performs the component, dietary ingredient, dietary a manufactured dietary ingredient or needed, of a representative sample to dietary supplement expected at each supplement, packaging, or label determine that specifications are met. If point, step, or stage of the requirements of this section must specifications are not met, you must manufacturing process where control is document, at the time of performance, conduct a material review and make a needed to prevent adulteration, and the that the requirements were followed. disposition decision. Your quality expected yield when you finish The documentation must include, but control unit must approve and release manufacturing the dietary ingredient or not be limited to: the components, dietary ingredients, dietary supplement, including the (i) The date that the components, and dietary supplements from maximum and minimum percentages of dietary ingredients, dietary quarantine before you use them; theoretical yield beyond which a supplements, packaging, or labels were (4) Identify each lot of components, deviation investigation of a batch is received; dietary ingredients, or dietary performed and material review is (ii) The signature of the person supplements in a shipment in a manner conducted and disposition decision is performing the requirement; that allows you to trace the shipment to made; the supplier, the date received, the (iii) Any test results; and (7) A description of packaging and a (iv) Any material review and name of the component or dietary copy of the label to be used; and supplement, and the status (e.g., disposition decision you conducted in (8) Written instructions including, but quarantined, approved, or rejected) and accordance with § 111.35(i) and not limited to, the following: to trace the shipment lot to the dietary disposition of any rejected material (i) Specifications for each point, step, ingredient or dietary supplement under § 111.74. or stage in manufacturing the dietary manufactured and distributed. You (2) You must keep component, dietary ingredient or dietary supplement must use this unique identifier supplement, packaging, and label necessary to prevent adulteration; whenever you record the disposition of receiving records in accordance with (ii) Sampling and testing procedures; each shipment lot received; and § 111.125. (iii) Specific actions necessary to (5) Hold components, dietary § 111.45 What requirements apply to perform and verify points, steps, or ingredients, or dietary supplements establishing a master manufacturing stages, necessary to meet specifications under conditions that will protect record? and otherwise prevent adulteration, against contamination, deterioration, (a) You must prepare and follow a including, but not limited to, one person and avoid mixups. written master manufacturing record for weighing or measuring a component (b) For packaging and labels you each type of dietary ingredient or and another person verifying the weight receive, you must: dietary supplement that you or measure and one person adding the (1) Visually examine each container manufacture and for each batch size to component and another person or grouping of containers in a shipment ensure uniformity from batch to batch. verifying the addition; (iv) Special notations and precautions for appropriate content label, container The master manufacturing record must: to be followed; and damage, or broken seals to determine (1) Identify specifications for the (v) Corrective action plans for use whether the container condition has points, steps, or stages in the resulted in contamination or when a specification is not met. manufacturing process where control is (c) You must have the quality control deterioration of the packaging and necessary to prevent adulteration; and unit review and approve each master labels; (2) Establish controls and procedures manufacturing record and any (2) Quarantine packaging and labels to ensure that each batch of dietary modifications to a master manufacturing until your quality control unit tests or ingredient or dietary supplement record. examines a representative sample to manufactured meets those (d) You must keep master determine that specifications are met. specifications. manufacturing records in accordance You must conduct at least a visual (b) The master manufacturing record with § 111.125. identification on the containers and must include the following information: closures. If specifications are not met, (1) The name of the dietary ingredient § 111.50 What requirements apply to you must conduct a material review and or dietary supplement to be establishing a batch production record? make a disposition decision. Your manufactured and the strength, (a) You must prepare a batch quality control unit must approve and concentration, weight, or measure of production record every time you

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manufacture a batch of a dietary record review and any approval for from the date of manufacture for use in ingredient or dietary supplement and reprocessing or repackaging. appropriate investigations including, the batch production record must (d) The quality control unit must but not limited to, consumer complaint include complete information relating to review in accordance with § 111.37(b)(5) investigations to determine whether, for the production and control of each the batch production record established example, the dietary ingredient or batch. in paragraph (c) of this section. dietary supplement associated with a (b) Your batch production record (1) If a batch deviates from the master consumer complaint failed to meet any must accurately follow the appropriate manufacturing record, including any of its specifications for identity, purity, master manufacturing record and you deviation from specifications, the quality, strength, and composition; and must perform each step in producing quality control unit must conduct a (i) You must keep batch production the batch. material review and make a disposition records in accordance with § 111.125. (c) The batch production record must decision and record any decision in the include, but is not limited to, the batch production record. § 111.60 What requirements apply to following information: (2) The quality control unit must not laboratory operations? (1) The batch, lot, or control number; approve and release for distribution any (a) You must use adequate laboratory (2) Documentation at the time of batch of dietary ingredient or dietary facilities to perform whatever testing performance, showing the date on supplement that does not meet all and examinations are necessary to which each step of the master specifications. determine that components, dietary manufacturing record was performed, (e) The quality control unit must ingredients, and dietary supplements and the initials of the persons document in accordance with received meet specifications; that performing each step, including but not § 111.37(c) the review performed in specifications are met during in-process, limited to: accordance with paragraph (d) of this as specified in the master manufacturing (i) The person responsible for section and it must be documented at record; and that dietary ingredients and weighing or measuring each component the time of performance. The review dietary supplements manufactured meet used in the batch; and and documentation must include, but is specifications. (ii) The person responsible for adding not limited to, the following: (b)(1) You must establish and follow the component to the batch. (1) Review of component, dietary laboratory control processes that are (3) The identity of equipment and ingredient, and dietary supplement approved by the quality control unit. processing lines used in producing the receiving records including review of Laboratory control processes must batch; testing and examination results; include, but are not limited to, the (4) The date and time of the (2) Identification of any deviation following: maintenance, cleaning, and sanitizing of from the master manufacturing record (i) Use of criteria for selecting the equipment and processing lines that may have caused a batch or any of appropriate examination and testing used in producing the batch; its components to fail to meet methods; (5) The shipment lot unique identifier specifications identified in the master (ii) Use of criteria for establishing of each component, dietary ingredient, production record; appropriate specifications; and dietary supplement, packaging, and (3) Records of investigations, (iii) Use of sampling plans for label used; (6) The identity and weight or conclusions, and corrective actions obtaining representative samples of: (A) Components, dietary ingredients, measure of each component used; performed in accordance with (7) The initials at the time of paragraph (d) of this section; and and dietary supplements received to performance or at the completion of the (4) The identity of the person determine whether specifications are batch of the person responsible for qualified by training and experience met; verifying the weight or measure of each who performed the investigation in (B) In-process materials during the component used in the batch; accordance with paragraph (d) of this batch manufacturing when testing or (8) The initials at the time of section. examination is required in the master performance or at the completion of the (f) You must not reprocess a batch manufacturing record; batch of the person responsible for that deviates from the master (C) Each batch of dietary ingredient or verifying the addition of components to manufacturing record unless approved dietary supplement manufactured to the batch; by the quality control unit. You must determine that the dietary ingredient or (9) A statement of the actual yield and not reprocess a dietary ingredient or dietary supplement meets a statement of the percentage of dietary supplement if it is rejected specifications; theoretical yield at appropriate phases because of contamination with (D) Packaging and labels received to of processing; microorganisms of public health determine that the materials meet (10) The actual test results for any significance or other contaminants, such specifications; and testing performed during the batch as heavy metals; (E) Each batch of packaged and production; (g) Any batch of dietary ingredient or labeled dietary ingredients or dietary (11) Documentation that the dietary dietary supplement that is reprocessed supplements to ensure that the label ingredient and dietary supplement must meet all specifications for the specified in the master manufacturing meets specifications; batch of dietary ingredient or dietary record has been applied. (12) Copies of all container labels supplement and be evaluated and (iv) Use of criteria for selecting used and the results of examinations approved by the quality control unit standard reference materials used in conducted during the label operation to before releasing for distribution. The performing tests and examinations; ensure that the containers have the results of the reevaluation by the quality (v) Use of appropriate test method correct label; control unit must be documented in the validations; and (13) Any documented material review batch production record; (vi) Use of test methods and and disposition decision in accordance (h) You must collect representative examinations in accordance with with § 111.35(j); and reserve samples of each batch of dietary established criteria. (14) Signature of the quality control ingredient or dietary supplement and (2) The person who conducts the unit to document batch production keep the reserve samples for 3 years testing and examination at the time of

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performance, must document that that can support the rapid growth of holding dietary ingredients or dietary laboratory methodology established in microorganisms of public health supplements meets specifications so accordance with this section is significance in a manner that prevents that the condition of the packaging followed. The documentation must the components, dietary ingredients, container will not contaminate your include the testing and examination and dietary supplements from becoming dietary ingredients or dietary results. adulterated; supplements nor cause them to (3) You must keep laboratory (7) Identifying and holding any deteriorate; examination and testing records in components, dietary ingredients, or (b) You must fill, assemble, package, accordance with § 111.125. dietary supplements, for which a and perform other related operations in (c) You must verify that the laboratory material review and disposition a way that protects your dietary examination and testing methodologies decision is required, in a manner that ingredients or dietary supplements are appropriate for their intended use. protects the components, dietary against adulteration and misbranding. (d) You must identify and use the ingredients, or dietary supplements You must do this using any effective appropriate validated testing method for against contamination and mixups; means, including but not limited to, the each established specification for which (8) Performing mechanical following: testing is required to determine whether manufacturing steps (such as cutting, (1) Cleaning and sanitizing all filling the specification is met. sorting, inspecting, shredding, drying, and packaging equipment, utensils, and grinding, blending, and sifting) by any dietary ingredient or dietary supplement § 111.65 What requirements apply to effective means to protect the dietary containers, as appropriate; manufacturing operations? ingredients or dietary supplements (2) Protecting manufactured dietary (a) You must design or select against contamination. Such steps must ingredients and dietary supplements manufacturing processes to ensure that include consideration of: from contamination, particularly dietary ingredient or dietary supplement (i) Cleaning and sanitizing contact airborne contamination; specifications are consistently achieved. surfaces; (3) Using sanitary handling (b) You must conduct all (ii) Using temperature controls; and procedures; manufacturing operations in accordance (iii) Using time controls. (4) Establishing physical or spatial with adequate sanitation principles. (9) Using effective measures to protect separation of packaging and labels from (c) You must take all the necessary against the inclusion of metal or other operations on other dietary ingredients precautions during the manufacture of a foreign material in components, dietary and dietary supplements to prevent dietary ingredient or dietary supplement ingredients, or dietary supplements. mixups; to prevent contamination of Compliance with this requirement must (5) Identifying, by any effective components, dietary ingredients, or include consideration of the use of: means, filled dietary ingredient or dietary supplements. These precautions (i) Filters or strainers; dietary supplement containers that are (ii) Traps; include, but are not limited to: set aside and held in unlabeled (1) Performing manufacturing (iii) Magnets; or (iv) Electronic metal detectors. condition for future label operations, to operations under conditions and (10) Segregating and identifying all prevent mixups; controls that protect against the containers for a specific batch of dietary (6) Identifying the dietary ingredient potential for growth of microorganisms ingredients or dietary supplements to or dietary supplement with a batch, lot, and the potential for contamination; identify their contents and, where or control number that can be used to (2) Washing or cleaning components necessary, the phase of manufacturing; determine the manufacturing history that contain soil or other contaminants; and and control of the batch; (3) Using water that meets the (11) Identifying all processing lines (7) Examining a representative sample National Primary Drinking Water and major equipment used during of each batch of the packaged and regulations or, where necessary, higher manufacturing to indicate their contents labeled dietary ingredient or dietary sanitary quality and that complies with including the name of the dietary supplement to ensure that the dietary all applicable Federal, State, and local ingredient or dietary supplement and ingredient or dietary supplement meets regulations for water that is used in the the specific batch or lot number and, specifications and that the label manufacturing operation. If you reuse when necessary, the phase of specified in the master manufacturing water that was used to wash manufacturing. record has been applied; and components to remove soil or (d) You must conduct a material (8) Suitably disposing of labels and contaminants, the reused water must be review and make a disposition decision other packaging for dietary ingredients safe and of adequate sanitary quality so in accordance with § 111.35(i) for any or dietary supplements that are obsolete that it does not become a source of component, dietary ingredient, or or incorrect to ensure that they are not contamination; dietary supplement that fails to meet used in any future packaging and label (4) Performing chemical, specifications or that is or may be operations. microbiological, or other testing, as adulterated. If the material review and (c) You must conduct a material necessary to prevent the use of disposition decision allows you to review and make a disposition decision contaminated components, dietary reprocess the component, dietary of any packaged and labeled dietary ingredients, and dietary supplements; ingredient, or dietary supplement, you ingredients or dietary supplements that (5) Sterilizing, pasteurizing, freezing, must retest or reexamine the do not meet specifications. refrigerating, controlling hydrogen-ion component, dietary ingredient, or (d) You must only repackage or concentration (pH), controlling dietary supplement to ensure that it relabel dietary ingredients or dietary humidity, controlling water activity meets specifications and is approved by supplements after the quality control (aw), or using any other effective means the quality control unit. unit has approved and documented to remove, destroy, or prevent the such repackaging or relabeling. growth of microorganisms and prevent § 111.70 What requirements apply to (e) You must retest or reexamine any decomposition; packaging and label operations? repackaged or relabeled dietary (6) Holding components, dietary (a) You must take necessary actions to ingredients or dietary supplements. ingredients, and dietary supplements ensure that each packaging container for They must meet all specifications and

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the quality control unit must approve or Subpart F—Holding and Distributing supplements until the quality control reject their release for distribution. unit conducts a material review and § 111.80 What requirements apply to makes a disposition decision. (f)(1) You must control the issuance holding components, dietary ingredients, and use of packaging and labels and (b) You must not salvage returned dietary supplements, packaging, and dietary ingredients and dietary reconciliation of any issuance and use labels? discrepancies; and supplements, unless: (a) You must hold components, (1) Evidence from their packaging (or, (2) You must examine, before dietary ingredients, and dietary if possible, an inspection of the packaging operations, packaging and supplements under appropriate premises where the dietary ingredients labels for each batch of dietary conditions of temperature, humidity, and dietary supplements were held) ingredient or dietary supplement to and light so that the identity, purity, indicates that the dietary ingredients ensure that the label and packaging quality, strength, and composition of the and dietary supplements were not conform to the master manufacturing components, dietary ingredients, and subjected to improper storage record. dietary supplements are not affected. conditions; and (g) The person that performs the (b) You must hold packaging and (2) Tests demonstrate that the dietary requirements of this section must labels under appropriate conditions of ingredients or dietary supplements meet document at the time of performance temperature, humidity, and light so that all specifications for identity, purity, that the requirements are performed the quality of the packaging and labels quality, strength, and composition. including, but not limited to, are not affected. (c) You must destroy or suitably documentation in the batch production (c) You must hold components, dispose of the returned dietary record of: dietary ingredients, dietary ingredients or dietary supplements if supplements, packaging, and labels (1) The identity and quantity of the such dietary ingredients or dietary under conditions that do not lead to the packaging and labels used and supplements do not meet specifications mixup, contamination, or deterioration reconciliation of any discrepancies for identity, purity, quality, strength, of components, dietary ingredients, between issuance and use; and composition, unless the quality dietary supplements, packaging, and control unit conducts a material review (2) The examination conducted in labels. and makes a disposition decision to accordance with paragraph (b)(7) of this allow reprocessing. section; § 111.82 What requirements apply to (d) If the reason for a dietary holding in-process material? (3) The conclusions you reached from ingredient or a dietary supplement retests conducted in accordance with (a) You must identify and hold in- being returned implicates associated paragraph (e) of this section; and process material under conditions that batches, you must conduct an will protect them against mixup, (4) Any material reviews and investigation of your manufacturing contamination, and deterioration. disposition decisions for packaging and processes and those other batches to (b) You must hold in-process material labels. determine compliance with under appropriate conditions of (h) You must keep packaging and specifications. temperature, humidity, and light. (e) You must establish and keep label operations records required under records for this section on the material this section in accordance with § 111.83 What requirements apply to review and disposition decision and any § 111.125. holding reserve samples of components, dietary ingredients, and dietary testing conducted to determine § 111.74 What requirements apply to supplements? compliance with established rejected components, dietary ingredients, (a) For any reserve samples of specifications in the master dietary supplements, packaging, and components or dietary ingredients you manufacturing record for the type of labels? collect, you must hold such reserve dietary ingredient or dietary supplement You must clearly identify, hold, and samples in a manner that protects that was returned. control under a quarantine system any against contamination and deterioration. (f) You must keep returned dietary component, dietary ingredient, dietary (b) You must hold reserve samples of ingredient and dietary supplement supplement, packaging, and label that is dietary supplements in a manner that records in accordance with § 111.125. rejected and unsuitable for use in protects against contamination and § 111.90 What requirements apply to manufacturing, packaging, or label deterioration. This includes, but is not distributing dietary ingredients or dietary operations. limited to: supplements? 9. Add subpart F to part 111 to read (1) Holding the reserve samples under Distribution of dietary ingredients and as follows: conditions of use recommended or dietary supplements must be under suggested in the label of the dietary conditions that will protect the dietary Subpart F—Holding and Distributing supplement and, if no conditions of use ingredients and dietary supplements Sec. are recommended or suggested in the against contamination and deterioration. 111.80 What requirements apply to holding label, then under ordinary conditions of 10. Add subpart G to part 111 to read components, dietary ingredients, dietary use; and as follows: supplements, packaging, and labels? (2) Using the same container-closure 111.82 What requirements apply to holding system in which the dietary supplement Subpart G—Consumer Complaints in-process material? is marketed or in one that provides the 111.83 What requirements apply to holding § 111.95 What requirements apply to reserve samples of components, dietary same level of protection against consumer complaints? contamination or deterioration. ingredients, and dietary supplements? (a) A qualified person must review all 111.85 What requirements apply to § 111.85 What requirements apply to returned dietary ingredients or dietary consumer complaints to determine returned dietary ingredients or dietary supplements? whether the consumer complaint supplements? 111.90 What requirements apply to involves a possible failure of a dietary distributing dietary ingredients or (a) You must identify and quarantine ingredient or dietary supplement to dietary supplements? returned dietary ingredients or dietary meet any of its specifications, or any

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other requirements of this part, dietary ingredient independent of (b) Records required under this part including those specifications and other whether the product is produced under must be kept as original records, as true requirements that, if not met, may result good manufacturing practices. The copies (such as photocopies, microfilm, in a possible risk of illness or injury. consumer complaint written record microfiche, or other accurate (b) Your quality control unit must must include, but is not limited to, the reproductions of the original records), or review all consumer complaints following: as electronic records. If you use involving the possible failure of a (1) The name and description of the reduction techniques, such as dietary ingredient or dietary supplement dietary ingredient or dietary microfilming, you must make suitable to meet any of its specifications, or any supplement; reader and photocopying equipment other requirements of this part, (2) The batch or lot number of the readily available to FDA. All electronic including those specifications and other dietary supplement, if available; records must comply with part 11 of requirements that, if not met, may result (3) The name of the complainant, if this chapter. in a possible risk of illness or injury, to available; (c) You must have all records required determine whether there is a need to (4) The nature of the complaint under this part, or copies of such investigate the consumer complaint. including how the consumer used the records, readily available during the (c) Your quality control unit must product; retention period for authorized investigate a consumer complaint when (5) The reply to the complainant, if there is a reasonable possibility of a any; and inspection and copying by FDA when relationship between the quality of a (6) Findings of the investigation and requested. dietary supplement and an adverse followup action taken when an 12. Part 112 is added to read as event. investigation is performed. follows: (d) Your quality control unit’s (f)(1) The person who performs the investigation of a consumer complaint requirements in accordance with this PART 112—RESTRICTIONS FOR must include the batch records section must document at the time of SUBSTANCES USED IN DIETARY associated with the dietary ingredient or performance that the requirement was SUPPLEMENTS dietary supplement involved in the performed. Subpart A—General Provisions [Reserved] consumer complaint. Your quality (2) You must keep consumer control unit must extend the complaint records in accordance with Subpart B—New Dietary Ingredients investigation to other batches of dietary § 111.125. [Reserved] ingredients or dietary supplements that 11. Add subpart H to part 111 to read Subpart C—Restricted Dietary Ingredients may have been associated with an as follows: adverse event. [Reserved] (e) You must make and keep a written Subpart H—Records and Authority: 21 U.S.C. 321, 342, 343, 371. record of every consumer complaint that Recordkeeping is related to good manufacturing Dated: January 29, 2003. practices. For the purposes of the § 111.125 What requirements apply to Mark B. McClellan, recordkeeping? regulations in this part, a consumer Commissioner of Food and Drugs. complaint about product quality may or (a) You must keep written records Dated: January 29, 2003. may not include concerns about a required by this part for 3 years beyond possible hazard to health. However, a the date of manufacture of the last batch Tommy G. Thompson, consumer complaint does not include of dietary ingredients or dietary Secretary of Health and Human Services. an adverse event, illness, or injury supplements associated with those [FR Doc. 03–5401 Filed 3–12–03; 11:30 am] related to the safety of a particular records. BILLING CODE 4160–01–P

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