Source: https://www.khlaw.com/1482
Timestamp: 2019-10-17 10:14:27
Document Index: 348818429

Matched Legal Cases: ['art 110', 'art 110', 'art 106', 'art 113', 'art 114', 'art 129', '§ 402', '§ 201', '§ 111', '§ 111', '§ 111']

Keller Heckman | FDA Publishes Final Rule on Current Good Manufacturing Practices (cGMPs) for Dietary Supplements
FDA Publishes Final Rule on Current Good Manufacturing Practices (cGMPs) for Dietary Supplements
The Food and Drug Administration (FDA) has now published its long-awaited final regulation describing the current good manufacturing practice (cGMP) requirements for the manufacture, packaging, labeling, or holding of dietary supplements. 72 Fed. Reg. 34752 (June 25, 2007). The final rule largely tracks the proposal FDA issued in 2003 (68 Fed. Reg. 12158 (March 13, 2003)), although the requirements have been modified in several respects. Once implemented, the cGMP requirements are intended to address product quality issues such as subpotency; superpotency; contamination with filth, bacteria, microorganisms, or drug ingredients; variation in tablet size or color; mis-filled containers; use of incorrect labeling; and use of improper packaging.
The most important change is that the final cGMP regulations apply only to domestic and foreign parties that manufacture, package, label, or hold finished dietary supplements. Producers of dietary ingredients are not subject to these requirements (unlike in FDA's 2003 proposal), although FDA states that they are subject to general "food" GMP requirements. However, as discussed in more detail in Section IV of this article, all suppliers of components to finished dietary supplement manufacturers may face additional demands from their customers, since supplement manufacturers will be required to maintain more detailed information establishing the quality of the component materials they use. As a result, dietary supplement manufacturers may impose more stringent quality and information requirements on their component suppliers than has been the case in the past.
The final regulation takes effect on August 24, 2007. However, FDA has established the following schedule for compliance with the new provisions, based on the size of the dietary supplement company involved:
Number of Full-Time Employees: Compliance Date:
500 or more June 25, 2007
20 - 499 June 25, 2009
fewer than 20 June 25, 2010
Although some provisions of the final rule may be controversial (such as FDA's claim to records access authority), the major dietary supplement trade associations have long encouraged FDA's development of dietary supplement cGMP regulations and have expressed support for the final rule. Thus, it is not expected that there will be any major challenges to the new provisions.
The remainder of this article (1) provides background on the development of the cGMP regulations, (2) highlights the final rule's basic provisions, (3) summarizes the changes from the 2003 proposal, and (4) evaluates the potential impact on component/ingredient suppliers. Please let us know if you have any questions or would like more detailed information about any of these points.
The final rule establishes industry-wide standards that specify requirements for the following areas: (1) personnel; (2) physical plants and grounds; (3) equipment and utensils; (4) production and process controls; (5) quality control; (6) components; (7) manufacturing; (8) laboratory operations; (9) packaging and labeling; (10) holding and distribution; (11) returned dietary supplements; (12) handling product complaints; and (13) record-keeping. The new regulations are the result of a process that began with the passage of the Dietary Supplement Health and Education Act (DSHEA), 1 which amended the Federal Food, Drug, and Cosmetic Act (FDC Act) to establish a framework for regulating dietary supplements. Among other provisions, the Secretary of Health and Human Services (through delegation to FDA) was given the authority to promulgate regulations establishing cGMPs for dietary supplements. These requirements were to be "modeled after" CGMPs for food2 and could not impose requirements for which there were no generally available analytical methods.3FDA published an Advanced Notice of Proposed Rulemaking (ANPR) in 1997,4 followed by numerous public meetings to gather input from affected parties. This process led to the publication of the 2003 proposal. After reviewing nearly 400 comments on the proposal, the Agency reorganized and modified numerous provisions as reflected in the final rule.
FDA goes to great lengths to describe how the final rule has been "modeled" after the food GMPs. Nevertheless, it is likely that there will continue to be controversy over the scope of certain of the final rule's requirements (and especially FDA's assertion of its authority to access the records required to be compiled and maintained).
II.Highlights of the Final Rule
In summary, the final rule does the following:
Establishes minimum requirements for (1) personnel, (2) physical plant and grounds, and (3) equipment and utensils;
Requires the establishment and use of written procedures for operations related to (1) equipment, (2) physical plant sanitation, (3) certain manufacturing operations, (4) quality control, (5) laboratory testing, (6) packaging and labeling, and (7) product complaints;
Requires the establishment of specifications in the production and process control system that will ensure dietary supplements meet the identity, purity, strength, and composition established in specifications and are properly packaged and labeled as specified in the master manufacturing record;
Provides for the option to use a certificate of analysis (for specifications other than the identity of a dietary ingredient) from a component supplier instead of having manufacturers conduct tests or examinations on the components they receive;
Requires testing of all finished batches of a dietary supplement or testing of a subset of finished batches of dietary supplements based on a sound statistical sampling plan;
Requires implementation of quality control operations to ensure the quality of a dietary supplement;
Requires the preparation and use of a written master manufacturing record (MMR) for each unique formulation of a manufactured dietary supplement, and for each batch size, to ensure that the manufacturing process is performed consistently and to ensure uniformity in the finished product from batch to batch;
Requires the preparation of a batch production record (BPR) every time a dietary supplement batch is made. The BPR must accurately follow the appropriate MMR;
Requires the establishment and use of laboratory control processes related to establishing specifications and to the selection and use of testing and examination methods;
Requires reserve samples of dietary supplements to be held in a manner that protects against contamination and deterioration;
Requires identification and quarantine of returned dietary supplements until quality control personnel conduct a material review and make a disposition decision;
Requires quality control personnel to conduct a material review and make a disposition decision under numerous circumstances;
Requires a qualified person to investigate any "product complaint" that involves a possible failure of a dietary supplement to meet any cGMP requirement, with oversight by quality control personnel; and
Requires records associated with the manufacture, packaging, labeling, or holding of a dietary supplement to be kept for 1 year beyond the shelf life dating (when such dating is used, such as expiration dating, shelf life dating, or "best if used by" dating), or if shelf life dating is not used, for 2 years beyond the date of distribution of the last batch.
Interestingly, although DSHEA specifically authorized FDA to establish expiration dating requirements for dietary supplements, the Agency did not include such provisions in the 2003 proposal and has not incorporated them into the final rule.5
III.Significant Changes from 2003 Proposal
Based on the comments received on the 2003 proposal, FDA modified the final rule in several respects. As noted above, the most significant change is that the final rule applies only to producers of finished dietary supplements; producers of "dietary ingredients"6 are not subject to the final rule. Other changes from the 2003 proposal include the following points:
Written procedures are now required for several aspects of dietary supplement production.
The final rule now refers to "product complaints," rather than "consumer complaints," to make clear that complaints covered by the final rule are ones related to product quality. As you know, a separate, new requirement for the mandatory reporting of serious adverse health effects associated with dietary supplements takes effect on December 22, 2007.7
FDA has clarified that it did not intend for dietary supplement producers to have to establish a separate quality control (QC) division to oversee QC responsibilities. The Agency specifically notes that the person with QC responsibility for a particular manufacturing operation can be the same person who performs that operation.8
The Agency has expanded the scope of permitted "reprocessing" operations, so long as there is "appropriate oversight" by QC personnel to ensure that the dietary supplement will still meet required specifications.9
The final rule provides additional flexibility in the testing of finished dietary supplements and incoming component materials. Producers can either test every batch of finished dietary supplements or use a "statistically sound sampling program" to justify testing only a subset of finished batches.10
Dietary supplement producers must confirm the identity of each component used. However, FDA has reconsidered its position in the 2003 proposal and now allows dietary supplement producers to rely on a certificate of analysis (CofA) from their component suppliers to demonstrate compliance with required specifications, except for the identity of a dietary ingredient.11 Each dietary ingredient must be tested to confirm its identity. Recognizing that 100% identity testing may not always be necessary, FDA has published a separate "interim final rule" that will allow dietary supplement producers to submit a petition to the Agency requesting a reduced identity testing frequency for dietary ingredients, based on appropriate data showing that the reduced frequency will still provide adequate assurance of the identity of the dietary ingredient.12 Dietary supplement producers are expected to qualify their suppliers and periodically repeat that qualification process to ensure that the CofA continues to be reliable.13
QC personnel are required to review and approve the results of all appropriate tests and examinations conducted during the dietary supplement production, but the QC personnel do not need to be the ones who actually conduct the tests.14
FDA dropped language from the 2003 proposal that repeated existing statutory or regulatory requirements for the non-dietary ingredients in a dietary supplement (principally that these components must be the subject of a food additive regulation authorizing their particular use or be generally recognized as safe (GRAS) for that use). In the 2003 proposal, FDA had stated that the Agency's response to a GRAS Notification would not be an adequate basis for taking a GRAS position for a particular component. In the final rule, however, FDA noted that it had received "comments related to the documentation that . . . would have been required" to support a GRAS position, but concluded that it "is unnecessary to respond" to them because the documentation requirement is not included in the final rule.1It is not clear whether FDA has abandoned its position in the 2003 proposal about the ability to rely on a response to a GRAS Notification. At this point, however, any challenge to such reliance would have to be made on a case-by-case basis. We expect that FDA is unlikely to raise such questions in the absence of information that clearly suggests a potential health concern.
IV.Impact on Suppliers of Components
As noted above, manufacturers of dietary ingredients and other components16 used in the manufacture of dietary supplements (e.g., binders, fillers, flow aids, solvents, etc.) are not subject to the requirements of the new rule. However, FDA states that dietary ingredient manufacturers are still subject to the existing "general" food GMP regulations found in 21 C.F.R. Part 110. 17 In addition, the Agency appears to endorse the idea that dietary supplement manufacturers may wish to impose certain of the final rule's provisions on their suppliers:
Because the final rule gives manufacturers an incentive to qualify suppliers of dietary ingredients, persons who manufacture, package, label, or hold dietary ingredients may wish to familiarize themselves with these dietary supplement CGMP requirements and use them in manufacturing, packing, labeling, or holding operations for dietary ingredients.18
Apart from this potential "upstream push" of the cGMP requirements, there are provisions of the final rule that will affect suppliers. For example, while a dietary supplement producer can rely on a CofA from a supplier (except to establish the identity of a dietary ingredient), the CofA must include the following information:19
(1) a description of the test or examination method(s) used by the supplier; (2) limits of the test or examinations; and
(3) actual results of the tests or examinations.
As a result, suppliers of all components used in dietary supplements (not just dietary ingredients) may need to provide more detailed information to their dietary supplement customers than they have in the past. In addition, for component ingredients that are the subject of a compendial monograph (such as the U.S. Pharmacopeia (USP) or National Formulary (NF)), it will no longer be sufficient to simply note that the ingredient "meets" or "passes" the compendial specification; the actual test results will need to be provided.
Along with the use of the CofA, component suppliers may be subject to greater quality scrutiny by their customers. Dietary supplement manufacturers are also required to initially qualify their suppliers by establishing the reliability of the supplier's CofA through confirming the supplier's reported analytical results. Subsequently, the customer is required to periodically re-confirm the reliability of the CofA and maintain documentation of how this process was carried out.20 Thus, ingredient suppliers may be subject to greater quality scrutiny by their customers (possibly including conducting quality audits of supplier's manufacturing operations).
Overall, the dietary supplement cGMPs are expected to be viewed as a positive development for the industry, leading to greater consumer confidence in the quality of the products available in the marketplace.
For further information about this issue or FDA's regulation of dietary supplements generally, please contact Frederick A. Stearns at 202-434-4288 or via e-mail at stearns@khlaw.com.
1Pub. L. No. 103-417 (1994).
2FDA's "umbrella" food GMPs are found in 21 C.F.R. Part 110. More specific quality requirements have been established for infant formula (21 C.F.R. Part 106); thermally processed low-acid foods (21 C.F.R. Part 113); acidified foods (21 C.F.R. Part 114); and bottled drinking water (21 C.F.R. Part 129).
3FDC Act § 402(g)(2).
4 62 Fed. Reg. 5700 (February 6, 1997).
572 Fed. Reg. at 34852 (col. 3) ("[W]e decline to require expiration dating because there may not be adequate methods available for assessing the strength of a dietary ingredient.").
6Dietary ingredients include: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by humans to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any these ingredients. FDC Act § 201(ff).
7The "Dietary Supplement and Nonprescription Drug Consumer Protection Act" (Pub. L. No. 109-462) (signed into law on December 22, 2006).
872 Fed. Reg. at 34800 (FDA response to Comment 51) (col. 2).
9Id. at 34801 (FDA response to Comment 53) (col. 1-2).
1072 Fed. Reg. at 34835 (FDA response to Comment 145) (col. 1).
11Id. (col. 1-3).
12The interim final rule can be found at 72 Fed. Reg. 34959 (June 25, 2007).
1372 Fed. Reg. at 34835 (FDA response to Comment 145) (col. 3).
14Id. at 34862 (FDA response to Comment 214) (col. 2-3).
15Id. at 34875 (FDA response to Comment 237) (col. 3).
16For purposes of the final rule, a "component" means "any substance intended for use in the manufacture of a dietary supplement, including those that may not appear in the finished batch of the dietary supplement." New 21 C.F.R. § 111.3; 72 Fed. Reg. at 34944. This term includes dietary ingredients and other ingredients intended to be present in the finished dietary supplement. FDA did not intend for the term "component" to include things like packaging materials, although the Agency recognized that the term may be confusing, noting that "[t]here may be differences in how components are referred to by certain manufacturers and how we refer to it in this final rule." 72 Fed. Reg. at 34795 (FDA response to Comment 39) (col. 3).
1772 Fed. Reg. at 34792 (FDA response to Comment 29) (col. 2).
19New 21 C.F.R. § 111.75(a)(2)(ii)(B); 72 Fed. Reg. at 34949.
20New 21 C.F.R. § 111.75(a)(2); 72 Fed. Reg. at 34949.