Issue link: https://www.e-digitaleditions.com/i/1295512
12 October 2020 Tablets & Capsules and are intentionally included in a drug delivery system. For example, excipients can do the following: • aid in the processing of the drug delivery system during its manufacture; • protect, support, or enhance stability, bioavailabil- ity, or patient acceptability; • assist in product identification; and • enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use" [3]. These two definitions are very similar. The important point in both definitions is that excipients are not APIs. They are intended to bring performance attributes (func- tionality) to the formulation to overcome some of the API's deficiencies. Why we use excipients and what we need from them We use excipients in combination with the API and the product manufacturing process to make the finished dosage form, as shown in Figure 1. Remove any one of these components and we will not have a pharmaceu- tical product. We also must consider the packaging, since many formulations would not be acceptable to the patient without the packaging (liquids, for example). In general terms, we need our excipients to be: • Safe at the level used and via the route of administration; • Made to an acceptable standard of good manufac- turing practice; • Compatible with and able to maintain the chemical and physical stability of the drug product under the specified conditions of storage and use; and • Consistent in performance in the application (for- mulation and product manufacturing process). Above all else, we need to ensure that we can rou- tinely manufacture the drug product at commercial scale. Whatever the cause, drug product shortages can compro- mise patient health and well-being. We rely on excipients to perform a variety of tasks relating to the patient and their treatment, including: • Allowing us to make the API molecule into a form from which it can be absorbed into or distributed through the patient's systemic circulation; • Delivering the API to the site of absorption (in the case of oral medicines) or distribution (in the case of intravenous medicines) in the body; • Releasing the API at a rate that provides optimal therapy for the patient; • Allowing the medicinal product to be manufactured at commercially acceptable speeds and quantities; and • Providing for a sufficiently long shelf-life to allow the medicinal product to pass through the supply chain from the manufacturing site to the patient. Excipients must perform consistently in each formu- lation to ensure the efficacy and quality of the final drug product. It follows that excipient quality must include an evaluation of aspects of performance. However, excipient performance is beyond the scope of the pharmacopeias, as it would be impossible to provide performance tests in a pharmacopeia monograph that would be relevant to all uses of that excipient. So how do we address the quality of our excipients, and how do we assess that quality? Before we attempt to answer these questions, we need to define some key terms. What is quality? Chapter I of Title 21 of the Code of Federal Reg- ulations (21 CFR) applies to the US Food and Drug Administration (FDA) good manufacturing practice, and Parts 210 and 211 detail the current Good Manufactur- ing Practices for pharmaceuticals. Surprisingly, 21 CFR Parts 210 and 211 do not contain a definition of qual- ity. However, 21 CFR 820 Quality System Regulations, which applies to medical devices, defines quality as "the totality of features and characteristics that bear on the ability of a device to satisfy fitness-for-use, including safety and performance" [1]. While clearly related to medical devices rather than pharmaceutical products, this definition does show the FDA's thinking on quality. If we substitute the term "excipient" for "device," we have an applicable definition. What is an excipient? The nearest to an official definition of an excipi- ent can be found in the pharmacopeias. The General Notices of the European Pharmacopoeia defines an excipient as "Any constituent of a medicinal product that is not an active substance. Adjuvants, stabilisers, antimi- crobial preservatives, diluents, antioxidants, for example, are excipients" [2]. General Chapter <1078> Good manufacturing prac- tices for bulk pharmaceutical excipients of the US Phar- macopeia states: "Pharmaceutical excipients are sub- stances other than the active pharmaceutical ingredient (API) that have been appropriately evaluated for safety Excipient performance is beyond the scope of the pharmacopeias, as it would be impossible to provide performance tests in a pharmacopeia monograph that would be relevant to all uses of that excipient.