Excipient uses and regulation

Excipients are used in food, beverages, nutritional supplements, personal-care products, and industrial products in addition to pharmaceutical applications. The food and beverage industry is the primary market for many excipient manufacturers. Facilities producing food ingredients or food additives that are also sold as excipients are usually dedicated to a single product or product families produced under food good manufacturing practices (GMPs) (1). These products typically ship from the manufacturer in finished-goods packages or in bulk to distribution facilities that may hold and package or transfer the product for regional delivery. This situation presents unique challenges in the excipient supply chain because food GMPs do not contain the appropriate controls for pharmaceutical excipients. The Joint International Pharmaceutical Excipients Council–Pharmaceutical Quality Group's (IPEC–PQG) Good Manufacturing Practices for Pharmaceutical Excipient Guide and the IPEC Good Distribution Practices (GDPs) Guide provide direction on the appropriate controls necessary to ensure pharmaceutical excipient quality.

Food GMPs. The difference between food processors operating under food GMPs and pharmaceutical makers governed by drug GMPs influences the quality systems and operational controls their suppliers adopt. Food GMPs focus on sanitation to prevent the introduction of contaminated or spoiled food. They do not include provisions on quality that ensure the taste, aesthetics, or health benefits of food. GMPs for finished drug products focus on the controls necessary to ensure the identity, strength, quality, and purity of the drug product. The rule of thumb of food regulation is that ingredients should not harm the consumer. The emphasis of drug regulations is that the products also must provide benefit to the health of the patient. Food GMPs do not require specifications for food ingredients. GMP requirements for incoming-goods inspections in the food industry involve inspection to ascertain that the ingredients are clean and suitable for processing into food. Raw materials are often purchased under a supplier's letter of continuing guarantee that assures the ingredient meets food GMP requirements for the absence of pathogens, natural toxins, pests, or extraneous matter. Food-ingredient suppliers provide a letter of continuing guarantee stating that the products shipped will not be adulterated under the Food, Drug and Cosmetic Act in place of certificates of analysis (COAs). Manufacturing personnel release food ingredients for shipment through process-control data monitoring. Their internal audits and controls focus on sanitation inspections, product protection, and cleaning schedules.

Distribution practices. Fungible distribution practices in the food ingredients and industrial chemicals markets, where the same ingredient from multiple manufacturers and manufacturing locations are comingled in a common storage tank, are commonly used to reduce distribution costs. Compatible ingredients may be unloaded into storage with no cleaning, relying on the high dilution factor to maintain product conformance. Samples from these tanks are periodically collected by contract surveyors and tested in local laboratories against multiple specifications to identify suitable customers. When a food ingredient or additive is sold as an excipient, the test results on a COA may list each parameter in a United States Pharmacopoeia–National Formulary (USP–NF) monograph with a statement such as "meets USP–NF specifications." This misleading statement, which indicates conformance to the monograph, implies to the pharmaceutical user that the excipient was manufactured and distributed following appropriate GMPs and GDPs. Conformance to food GMPs is insufficient to assure that the ingredient quality system adequately conforms to excipient GMPs. As such, product testing simply to determine compliance with a USP–NF monograph does not mitigate risk and does not indicate that a food ingredient or additive is suitable for use in drug manufacturing.

Documenting excipient quality

It is paramount for the pharmaceutical manufacturer or user to know where and how the excipients were manufactured and to understand the excipient supply chain thoroughly. The pharmaceutical user is responsible for knowing the excipient pedigree (2). Qualification of the excipient manufacturer begins with the pharmaceutical user's request for information concerning regulatory, quality, and site-security details using the Excipient Information Package (EIP) (3). In the past, an excipient manufacturer would receive questionnaires from each customer, requesting similar information but in different formats and with differing expectations as to the details. IPEC developed the EIP in a standard format, based upon the material safety data sheets that are widely used to convey safety information, to facilitate the communication of this information. This standard document benefits the excipient manufacturer because it provides the essential information that all pharmaceutical users need while assuring the pharmaceutical customer receives detailed information and is notified of changes to the content of the EIP (4).

Many times excipients are not sold directly to the user, but instead go from the excipient manufacturer to a distributor that sells them to the pharmaceutical user. Distributors should maintain the manufacturer's EIP on file to facilitate the delivery of the document from the excipient manufacturer to the pharmaceutical user.