• FDA's Proposed Rule for Dietary Supplement cGMPs
  • May 15, 2003 | Author: Todd A. Harrison
  • Law Firm: Buchanan Ingersoll, Professional Corporation - Washington Office
  • A. Introduction

    On March 13, 2003, the Food and Drug Administration (FDA) issued a proposed rule establishing cGMPs in the manufacturing, packing, or holding of dietary ingredients (DIs) and dietary supplements (DSs). The purpose of the proposed rule is to ensure that entities engaged in these activities "do so in a manner that will not adulterate and misbrand" those items.1 Section 402(g)(2) of the Dietary Supplement Health and Education Act (DSHEA), which became law in October 1994, established that any cGMP regulations for dietary supplements promulgated in the future were to be modeled after food cGMPs. In many respects, the requirements set forth in the proposed rule do mirror food cGMPs. FDA notes, however, that "dietary supplements have their own set of unique requirements as a result of the characteristics and hazards due to their 'hybrid' nature, [they] fall somewhere along the continuum between conventional foods on the one hand and drugs on the other."2 Although the proposed rule does not contain discussion regarding any similarities between the proposed dietary supplement cGMPs and drug cGMPs, the proposed regulations do appear to incorporate some of the features of drug cGMPs as well.

    According to FDA, the benefits of the proposed rule include (1) fewer illnesses, resulting in decreased health costs, (2) fewer product recalls, and (3) more consistent, higher quality products. In order to achieve these objectives, the proposed rule covers seven areas:

    (1) personnel, (2) physical plant, (3) equipment and utensils, (4) production and process controls, (5) holding and distribution, (6) consumer complaints, and (7) records and recordkeeping. Following is a brief summary of some of the key requirements of each part of the proposed rule, with emphasis placed on production and process controls.

    FDA has concluded that this proposed rule, if finalized, would be phased-in over a three year period; therefore, only large firms would have to comply within one year. Comments on the proposed rule are requested by June 11, 2003.

    B. Items Addressed in the Proposed Rule

    1. Personnel

      The proposed personnel requirements cover three areas. The first, microbial contamination and hygiene, addresses the exclusion from operations of those people who may be a source of microbial contamination, and lists several required hygienic practices to prevent adulteration, including maintaining personal hygiene and washing hands. The second and third categories cover personnel and supervisor requirements which closely mirror each other, and direct that employees and supervisors must be qualified by training and experience.

    2. Physical Plant

      Physical plant requirements cover two areas: sanitation, and design and construction.

      "Sanitation" is a widely-inclusive term as used in the proposed rule. Here, FDA addresses such areas as plant cleanliness, pest control, water supply, sewage and trash disposal, and plumbing, among others. The design and construction requirements are equally broad, and include operating in a physical plant that is suitable in size, design, and construction for the activities that take place there, that provides adequate lighting, and that is designed and constructed so as to prevent contamination.

    3. Equipment and Utensils

      Proposed regulations covering equipment and utensils, and automatic, mechanical, or electronic equipment, focus strongly on instrument maintenance and calibration, cleanliness, and the function of a quality control (QC) unit. FDA notes that the calibration requirements allow discretion in deciding whether to create and follow a written procedure.

    4. Production and Process Controls

      The proposed regulations for production and process controls are extensive, and in many instances appear to more closely resemble drug cGMPs rather than food cGMPs. The proposed rule covers such areas as QC; master manufacturing and batch production records; laboratory, manufacturing, and packaging/label operations; and rejected items, among others.

      The first key feature of this section is the requirement that a specification (spec) must be established for any point, step, or stage in the manufacturing process where controls are needed to prevent adulteration, including for ensuring the identity, purity, quality, strength, and composition of components, DIs, or DSs that are received (and the DIs and DSs that are manufactured). Each spec must be met, and there must be corrective action plans in place; if a spec is not met, there must be a material review and disposition decision made as to whether the item should be rejected or reprocessed.

      The second key feature involves the testing of finished batches of a DI or DS, and the testing of an incoming shipment of components, DIs or DSs. According to the proposed rule, a finished batch must be tested per the specs established to ensure identity, purity, quality, strength, and composition of the final product, "provided that there are scientifically valid analytical methods available to perform such testing."3 If the QC unit documents that no such method is available, then the incoming shipment lots of components, DIs, and DSs must be tested: "[i]f you do not perform finished product testing under § 111.35(g)(1) for identity, purity, quality, strength, or composition, then you would need to test for that nontested finished product specification upon receipt."4 In such a case, one would also have to "[p]erform testing in-process in accordance with the master manufacturing record where control is necessary to ensure the identity, purity, quality, strength, and composition of dietary ingredients or dietary supplements."5

      A third important aspect of this section is the establishment of master manufacturing records and batch production records. According to FDA, "[a] master manufacturing record is analogous to a recipe that sets forth the ingredients to use, the amounts of ingredients to use, the tests to perform, and the instructions for preparing the amount the recipe calls for¿.[the record] helps ensure that you manufacture each ingredient or dietary supplement in a consistent and uniform manner."6 The master record must both identify the specs discussed above, and establish controls and procedures to ensure that each spec is met. In addition, a batch record must follow the master record, and must be reviewed by the QC unit. If the batch deviates from the master record, the QC unit must make a material review and disposition decision regarding that batch. Representative reserve samples of all batches must be kept for three years from the date of manufacture.

      The fourth and final key area of production and process controls addresses various aspects of operations, including laboratory, manufacturing, and packaging and labeling. The proposed rule states that there must be adequate lab facilities to perform the testing that is necessary to ensure compliance with the specs, and that the QC unit must approve the lab control processes that are utilized. This section of the rule applies equally to any private laboratories that are hired to perform tests; according to FDA, "proposed § 111.60(a) would require that you make sure that the private laboratory's facilities are adequate to perform whatever tests are necessary."7

    5. Holding and Distribution

      The holding and distribution requirements of the proposed rule cover the holding of components, DIs, DSs, packaging, labels, in-process materials, and reserve samples, as well as the handling of the distribution and return of DIs and DSs. In general, components, DIs, DSs, packaging, labels, in-process materials, and reserve samples must be held so as to deter against mixup, contamination, or deterioration, and to control for temperature, humidity, and light.

    6. Consumer Complaints

      The single section in the proposed rule covering consumer complaints specifies, first of all, that a qualified person must review all complaints to determine if compliance with a spec or other requirement may have failed. Next, the QC unit reviews all complaints involving such a failure, and determines if an investigation is warranted. Importantly, the QC unit "must investigate a consumer complaint when there is a reasonable possibility of a relationship between the quality of a dietary supplement and an adverse event."8 Any investigation must include batch records for the batch at issue, as well as other associated batches "that may have been associated with an adverse event."9 Furthermore, FDA suggests in the commentary to the proposed rule that a report be made of the complaint and the results of the investigation to FDA's MedWatch program. FDA also recommends that if a complaint is made to a packager or distributor of a DI or DS, such entity should alert the manufacturer, since the manufacturer may not have received the same complaint and therefore may not be aware of any problems.

    7. Records and Recordkeeping

      Various provisions previously discussed indicate that records should be kept in accordance with § 111.125, the provision addressing records and recordkeeping. Required written records must be kept for three years "beyond the date of manufacture of the last batch of dietary ingredients or dietary supplements associated with those records."10

    C. Conclusion

    The regulations discussed above in the proposed rule cover all major aspects of the manufacturing, packing, and holding of DIs and DSs. The regulations are modeled after FDA's food cGMPs, although FDA indicates that "when Congress used the term 'modeled after' Congress intended that we use the food CGMPs as a 'preliminary pattern' for the dietary supplement CGMPs."11 Therefore, some of the features of the regulations actually appear to more closely resemble drug cGMPs. It is apparent that this rule, if finalized, will have a greater impact on small and very small entities than it will on large entities, although FDA estimates that once all entities are covered by a final rule, the total annual benefits would reach $218 million, with annual costs less than half that much ($86 million).

    _____________________________

    1Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements, 68 Fed. Reg. 12157 (proposed March 13, 2003) (to be codified at 21 C.F.R. pts. 111-112), at 12158.

    2 Id. at 12166.

    3Id. at 12197.

    4Id. at 12202.

    5Id. at § 111.35(g)(2)(ii), p. 12257.

    6Id. at 12203.

    7Id. at 12207.

    8 Id. at § 111.95(c), p. 12263.

    9Id. at § 111.95(d), p. 12263.

    10Id. at § 111.125(a), p. 12263.

    11Id. at 12165.