Once this decision is made, it should be communicated clearly through the supply chain. There is a regulatory obligation to communicate the intended end uses to the pharmaceutical customer, especially in cases where the communication of the intended use from the manufacturer can be lost as a product moves through the distribution chain. Including USP-NF on the label adds to the ambiguity of the intended market when the product has both excipient and API uses. Although the implications of 21 CFR subpart E and 211.184 are that the user of the ingredient should know if the material it is receiving was manufactured as the active ingredient, FDA regulations state that the manufacturer of a substance to be used as an active ingredient is responsible for registering its facility. Manufacturers of excipients are exempt from registration. The decision not to register may or may not be an indication of the manufacturer's intent to limit the use of its product to excipient applications.

For the excipient manufacturer, how a product is labeled and marketed should be evidence of its intended use apart from how the product is actually used when purchased. Excipients listed in the USP or NF meet the definition of "drug" under both clauses (A) and (D) of Section 201 (g) of the Food, Drug, and Cosmetic Act and their manufacturers are exempt from registration as a drug manufacturing establishment under 21 CFR 207.10 (e). Are the manufacturers of excipients that have an active use excluded from the exemption for registration? If the excipient manufacturer presents the product as an API, then the exemption for inactive ingredients does not apply, and the manufacturing establishment must register. If the product is presented for use as an excipient only, then registration is not required.

Recently, FDA visited member companies of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) that are manufacturing USP or NF excipients that also have applications as active ingredients. The agency intended to inspect the facilities as API manufacturing establishments. However, when the companies showed inspectors copies of their product labels that included the phrase "for excipient use," certificates of analysis stating "for excipient use," and technical data sheets explaining that the product was intended for use as an excipient, agency personnel in each case either continued to inspect the facilities as excipient manufacturing facilities, or simply left and did not conduct an inspection. By having clear documentation indicating intended use for their products, these companies avoided having to defend their decision not to register the plants.

A risk-based argument may be made that excipient GMPs are adequate for the excipients/APIs used in topical or oral applications, especially in cases where they are consumed in much greater quantities (e.g., the food sector) and when the dosage-concentration tolerance for efficacy is large. However, the argument regarding appropriate GMPs does not change the law requiring annual registration of drug manufacturing establishments. A manufacturer could purchase an excipient-grade product and perform further processing at its registered drug establishment following the ICH Q7 guideline. This approach would address the registration issue but, for the most part, the "further processing" would consist of purification steps involving dissolving, filtering, and testing. The excipient product then would no longer technically be the API but rather a raw material used to manufacture the API. As a result, the finished drug-product manufacturer would have to make the risk-based argument that the processing is appropriate and adequate to produce an API for its finished product. Efforts based on science and fact to seek the protection of the consumer goes a long way in helping to show that procurement and processing steps meet the intent of the Q7 guideline. Ideally, if only IPEC or similar-level excipient GMPs are used in the manufacture of USP or NF products, the excipient manufacturer should clearly label the product for excipient use.

Acknowledgments

Sidney A. Goode, PharmD, Dow Chemical Company; Maria Guazzaroni Jacobs, PhD, Pfizer; Alan Mercill, JD, IPEC–Americas; Theodore M. Sullivan, Esq, Buchanan Ingersoll & Rooney PC; David R. Schoneker, Colorcon; Robert G. Pinco, RPh, Esq, Buchanan Ingersoll & Rooney PC; Priscilla Zawislak, Hercules; Brian Matthews, Alcon Laboratories; Philip Merrell, PhD, Jost Chemical Company; R. Christian Moreton, PhD, FinnBritt Conulting; Iain Moore, Croda Europe; Frank Murphy, Dow Chemical Company; Robert Sulouff, Aqualon Division, Hercules; Ann Van Meter, DowWolff Cellulosics; and Phyllis Walsh, Schering-Plough Corporation.

William D. Carter is chair of IPEC–Americas GMP Committee and manager of product quality and management systems at Archer Daniels Midland, 1001 Brush College Road, Decatur, IL 62521, tel. 217.451.8121, dale_carter@admworld.com