The Product Quality Research Institute (PQRI) conducted an open, publicly available, electronic survey of current excipient-control strategies among pharmaceutical excipient manufacturers, excipient distributors, and drug-product manufacturers (excipient users). Among the major findings are:
- the majority of respondents supply their products for global markets, and thus must meet substantially different test requirements for different regions;
- the majority of respondents use reduced-testing strategies employing equivalent methods;
- a large majority of respondents perform tests on the excipients beyond those given in pharmacopeias to determine physical and chemical properties necessary for their intended use;
- drug-product manufacturers typically follow their own company procedures to qualify excipient manufacturers and suppliers.
The survey results provide insights about the decisions of excipient manufacturers and drug-product manufacturers regarding testing excipient quality and using excipients in pharmaceutical manufacturing.
Figure 1: Respondents selling products both in the United States and abroad.
When the European Agency for the Evaluation of Medicinal Products (1) and US Food and Drug Administration (2) issued excipients guidances in 2003, industry predicted that they would have the unintended result of causing additional paperwork and excessive testing for excipient control strategies, without adding benefits. In addition, industry believed the guidances effectively eliminated generally accepted and common excipient control strategies.
FDA's interpretation of International Conference on Harmonization (ICH) common technical document (CTD) language used in section P.4, "Control of Excipients" required that manufacturers specify each method used for routine excipients testing, unless the method is exactly that of the pharmacopeia and full monograph testing is performed.
Figure 2: Respondents testing excipient according to USP–NF monograph/general chapter methods
Often, a drug-product manufacturer has methods used internally that are shown to produce equivalent results to those in a pharmacopeia. In addition, many manufacturers with global markets seek to eliminate redundant testing of the same property by selecting a single method shown to be capable of ensuring compliance with requirements of many pharmacopeias. The United States Pharmacopeia (USP) has been clear that alternate methods are acceptable to demonstrate compliance with USP–National Formulary (NF) requirements (3).
FDA recently announced its Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances (4). By focusing on the Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative) and ICH Guidelines, FDA has strategically reduced industry's regulatory and paperwork concerns, and changed the regulatory focus to concentrate on those aspects of manufacturing that pose the greatest risk to product quality. Although excipients constitute a large portion of most drug products, they have been viewed as a low-risk aspect of drug-product safety. They are, however, a key aspect of product Quality by Design (QbD).
Figure 3: Respondents´ frequency of accepting excipient based on process controls, not on Certificate of Analysis.