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Clear labels for substances that can be used as excipients, APIs, or both are critical to end-product use.
This article is intended to address the ambiguity of labeling substances with USP–NF monographs that can have dual use as excipients or active pharmaceutical ingredients (APIs). When manufacturers market a substance as an API, current good manufacturing practices (CGMPs) apply and the manufacturing location must be registered with the US Food and Drug Administration as a drug-manufacturing establishment. When marketing a substance as an excipient, manufacturers may apply other appropriate GMPs such as United States Pharmacopeia (USP) General Chapter <1078>, which is aligned with the International Pharmaceuitcal Excipients Council–Pharmaceutical Quality Group's (IPEC–PQG) Good Manufacturing Practices for Pharmaceutical Excipient Guide. Although the USP designation normally is used for APIs and the National Formulary (NF) designation is generally used for excipients, there are exceptions. When a substance is labeled as USP or USP–NF without further clarification, one could assume that the substance may be used either as an API or an excipient, that the substance was manufactured according to CGMPs for APIs, and that the manufacturing facility is registered with FDA.
USP substances commonly used as excipients that also have uses as APIs are typically found in over-the-counter (OTC), topical, ophthalmic products or prescription preparations with a long history of use that may precede pharmaceutical dosage-form regulations. Excipients that also have API uses include inorganic materials such as certain sodium, magnesium, calcium or potassium salts, and zinc oxide; and organic materials such as ethanol, mannitol, citric acid, lactic acid, lanolin, hypromellose, carboxymethyl cellulose sodium, and paraffin and vegetable oils.
Excipients are sold through many supply routes, including distributors that may sell both APIs and excipients. Some distributors may have drug-establishment registration numbers because they repackage bulk APIs. When an excipient that also can be used as an API enters the distributor's supply chain labeled only as a compendial product (USP or NF), opportunities exist for the product to eventually be offered and used for an API function even though the ingredient may not have been manufactured to appropriate GMP requirements (e.g., the International Conference on Harmonization's Q7 Guideline).
When USP or NF is incorporated into the label name of a product having both active and excipient uses, and the product is presented simply as a substance meeting the USP–NF monograph, the implication is that it could be used as both the active and inactive ingredient. When the manufacturer of a USP-NF substance chooses not to offer its product for use as an active ingredient, it should clearly communicate this intent by qualifying the labeling. To avoid confusion and clearly defend the decision not to register its facility, the manufacturer should indicate the product's restricted use as an excipient on its label, certificate of analysis, and marketing materials so that the purchaser is aware of the intended use for the product.
The USP General Notices section states that appropriate GMPs be used in the manufacture of USP Official Articles. The manufacturer of Official Articles labeled USP or NF must follow appropriate GMPs based on its intended market for the product. Manufacturers then may sell the ingredient into the appropriate excipient and/or API markets based upon the GMP selected. In cases where sales volume will not support a separate facility, one set of appropriate GMPs may be applied across the product line or the process may be campaigned to produce a specific grade (e.g., excipient or API) using a level of GMP appropriate for the intended use. Where these options are not practical, an ingredient manufacturer may choose a level of GMP that specifically targets the excipient use of the USP or NF article, rather than the API GMP requirements that allow for either use (API or excipient).
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.
Another issue involving excipients with API uses is that there may not be any manufacturing locations that have registered as a drug manufacturing establishment. Strict enforcement of CGMPs for those excipients used as APIs could result in the withdrawal of products that have been used safely for many years. Historically, some pharmaceutical companies have benefited from the ambiguity of the USP or NF label, and have combined the label statement with their own receipt testing as adequate for APIs with low risk. Even 21 CFR 211.184 (a) states that, "The name and location of the prime manufacturer, if different from the supplier, shall be listed if known." The "if known" clause does not prohibit this practice. OTC products with a long safety record and low inherent risk are less likely to receive FDA scrutiny in the absence of a consumer complaint. This assumption is not well founded or supported by recent FDA emphasis on supply-chain integrity. Assuring that the GMPs used during manufacturing and distribution are appropriate greatly reduces the risk of adulterated product being used, but also may serve to reduce or eliminate the supply of material.
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.
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, firstname.lastname@example.org