The Industry’s Potential Excipient Folly
What companies should know about “everything” that goes into the manufacture of a dietary supplement or ingredient.
By Todd Harrison & Debra Goldstein
The proposed dietary supplement current good manufacturing practices (cGMPs) regulations raise an important issue regarding ingredients found in dietary supplements other than dietary ingredients. These other ingredients are often referred to as “excipients” and are generally considered necessary components to the finished dietary supplement product. Moreover, many of the excipients have long and safe histories of use in finished pharmaceuticals. Thus, many manufacturers assume that if an excipient is safe for use in human pharmaceuticals, it is safe for use in dietary supplements. FDA’s proposed cGMPs, however, undermine this assumption.
Specifically, dietary supplement products are considered foods and are subject to an entirely different regulatory structure than finished pharmaceutical products. In this regard, of all the components of a dietary supplement, only dietary ingredients are exempt from the food additive provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). Section 201(s)(6) of the FFDCA states that “an ingredient described in paragraph (ff) [of § 201) in, or intended for use in, a dietary supplement” is exempt from the definition of a food additive. The ingredients that are described in § 201(ff), however, are limited to dietary ingredients and do not include other substances or excipients found in dietary supplements. Because substances other than dietary ingredients are not specifically exempted from the definition of a food additive, these substances must either be FDA-approved food additives for use in dietary supplements or generally recognized as safe (GRAS) for their intended use. Accordingly, just because an excipient may be generally considered safe for use in a pharmaceutical, in FDA’s mind at least, it does not necessarily mean that it is safe for use in dietary supplements.
Neither the preamble to the proposed rule nor the proposed rule itself specifically use the word “excipient,” however, there are requirements for substances, other than dietary ingredients, “the intended use of which results or may reasonably be expected to result, directly, or indirectly, in its becoming a component or otherwise affecting the characteristics of the dietary ingredient or dietary supplement.” (see 68 Fed. Reg. 12195, proposed 21 C.F.R. § 111.35(d)). These substances may “include components that are added to provide certain technical effects to the dietary supplement, such as disintegration, lubrication or binding.” Additionally, proposed 21 C.F.R. § 111.3 defines a “component” as “any substance intended for use in the manufacture of a dietary ingredient or dietary supplement, including those that may not appear in the finished dietary ingredient or dietary supplement. Components include ingredients and dietary ingredients as described in § 201(ff) of the Act.” The preamble cites as examples of components, both cellulose used to make tablets and gelatin used to make capsules. (68 Fed. Reg. at 12176).
Regulatory Status and Documentation
The proposed regulations would require any component of a dietary ingredient or supplement, other than a dietary ingredient be:
•Authorized for use as a food additive under section 409 of the act, or
•Authorized by a prior sanction consistent with 21 CFR 170.3(l), or
•If used as a color additive, subject to a listing that, by the terms of that listing, includes the use in a dietary supplement, or
•Generally recognized as safe (GRAS) for use in a dietary ingredient or dietary supplement. Any claim that a substance is GRAS, other than a dietary ingredient within the meaning of section 201(ff) of the act, must be supported by a citation to the agency’s regulations or by an explanation for why there is a general recognition of safety or the use of the substance in a dietary ingredient or dietary supplement, and
•Must comply with all other applicable statutory and regulatory requirements under the act. (68 Fed. Reg. at 12195, proposed 21 C.F.R. § 11135(d)(1) - (d)(5), emphasis added).
As noted above, while the regulation talks generally about authorized food additives, it specifically provides that color additives be authorized for use in dietary supplements and that GRAS substances be GRAS for use in a dietary ingredient or dietary supplement. For example, the preamble cites the approved food additive sucralose as an additive that may be used in dietary supplements. Sucralose was approved as a food additive for use “as a general purpose sweetener in food, which would include its use in a dietary ingredient or dietary supplement.” However, a color additive used in a dietary supplement or ingredient “must be listed in Title 21 of the … [CFR] for use in food and the listing must, by its terms, include such use in a dietary supplement.”
For those substances that are GRAS, manufacturers would be required to have documentation for the basis for why such a substance is approved for use or is GRAS for use in a dietary supplement or ingredient. The support for the claim of GRAS status may be either a “cite to a FDA regulation [i.e. the substance is either listed as GRAS for such use in 21 C.F.R. Part 182, or affirmed as GRAS for such use in 21 C.F.R. Part 184] or an explanation for why there is general recognition of the safety of the use of the substance in a dietary ingredient or dietary supplement. If such a claim is based on general recognition of safety based on scientific procedure, the explanation would be based on evidence that demonstrates that there is common knowledge about the safety of the substance throughout the scientific community knowledgeable about the safety of such substance.” (68 Fed. Reg. at 12196). FDA also specifically states that agency response to a “GRAS notification” would not qualify as a “basis for asserting compliance with the requirements under proposed § 111.35(d) because an FDA response letter to a GRAS notification is not the same as your explanation, e.g., a response letter does not provide an explanation for why an ingredient is GRAS.” The FDA “encourages” manufacturers to consult with the agency to determine whether the use of a particular ingredient in a dietary supplement or ingredient would be more appropriately submitted for review in a food additive petition, rather than a GRAS notification.
FDA is requesting comment on whether the agency should have specific cGMP requirements for the use of animal-derived substances used in dietary ingredients and supplements, including whether there should be specific requirements designed to prevent the use of animal-derived materials from BSE countries, and whether there are animal-derived materials from BSE countries that do not present a safety concern. (See 68 Fed. Reg. at 12180-81).
Other than the requirements stated above, components used in the manufacture of dietary supplements and dietary ingredients are subject to the GMP requirements for quality, process and controls, handling, testing and holding generally required for all elements of the manufacturing process.
The proposed dietary supplement cGMPs raise some important issues regarding the use of pharmaceutical excipients in dietary supplements that need to be addressed by the industry. In this regard, the industry should start taking steps to develop GRAS positions for those excipients that are neither FDA-approved food additives nor GRAS-affirmed by the agency for use in dietary supplements. Failing to take these initial steps now could have significant consequences to the industry in the near future. Indeed, it should be noted that FDA does not need to finalize the proposed cGMPs to take issue with the excipients that are now present in dietary supplements. Rather, FDA has plenty of authority under the FFDCA to take regulatory action against a dietary supplement that it believes contains an excipient that is an unapproved food additive that is not otherwise GRAS for use in dietary supplements. Thus, the industry must start addressing this issue now rather than later. Otherwise, the industry may very well suffer the consequences for ignoring this issue over the last nine years.NW