he 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.
Figure 1: Respondents selling products both in the United States and abroad.
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.
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.
Figure 2: Respondents testing excipient according to USP–NF monograph/general chapter methods
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.
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).
Figure 3: Respondents´ frequency of accepting excipient based on process controls, not on Certificate of Analysis.
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 4: Respondents reporting difficulty finding manufacturer of USP–NF grade excipients.
The PQRI Excipient Working Group developed three surveys to gather responses from each of three respondent groups: excipient manufacturers, excipient distributors, and drug-product manufacturers. The surveys gathered information about excipient-control strategies used by companies that manufacture, distribute, and sell prescription-only and over-the-counter drug products for US-only or US-and-world markets. The anonymous surveys could be completed electronically by individuals belonging to the PQRI member organizations (http://www.pqri.org) and other interested persons. The survey period was from June 13, 2005 to Oct.14, 2005.
Figure 5: Obstacles to labeling excipients as USP–NF.
PQRI received responses from 180 drug-product manufacturers, 26 excipient manufacturers, and 6 distributors of pharmaceutical excipients. It should be recognized that PQRI is a unique US-based organization and that the survey questions were developed in the United States. Some survey responses may, however, have come from companies that manufacture their products for distribution and sale outside, as well as within, the United States.
This report presents findings of the three surveys and an analysis of survey responses. For the purposes of this report, the terms "excipient user" and "drug-product manufacturer" mean the same, and are used interchangeably throughout the document.
Figure 6: Respondents reporting inspections or visits by FDA (for either drug excipient or food use).
The survey clearly indicates that the majority of excipient manufacturers, excipient distributors, and drug-product manufacturers make their products for global distribution (see Figure 1). They test their excipients according to USP–NF monographs and general chapter methods (see Fig. 2). Almost all (97%) drug-product manufacturers perform more than just the identification test when receiving excipients from their vendors along with Certificates of Analysis (C of A). The additional tests include analyses for desired physical and chemical properties.
Less than 20% of drug-product manufacturers accept some or most material based on the excipient manufacturer's process controls and on in-process tests. These controls and tests are not mentioned on C of A, but provide assurance of conformity with USP–NF requirements (see Figure 3). This area offers opportunities for excipient manufacturers and drug-product manufacturers to research and subsequently use information and knowledge that lies in the excipient-maker's "manufacturing process-controls" and "in-process test results" domain. Assessment of such information could also confirm (or otherwise indicate) certain physicochemical quality aspects of an excipient batch, or qualities of an excipient produced under continuous manufacturing conditions.
Figure 7: Respondents reporting familiarity with requirements of Food Drug and Cosmetic Act and 21 CFR Part 211.84.
Drug-product manufacturers qualify new sources of excipients by vendor audits and complete testing according to the compendial monograph. According to the survey, 40% of drug-product manufacturers had difficulty finding a manufacturer of at least one USP–NF grade excipient (see Figure 4). In such a situation, they would use the best grade available, test the excipient according to the compendial monograph, and conduct an audit of the excipient manufacturer. Approximately 75% of drug-product manufacturers indicated they test and perform site audits to confirm compliance (for "a few" to "all" excipients) with compendial-grade standards. In 80% of the cases, respondents used validated test procedures to confirm the compliance of noncompendial grade excipients with compendial grade standards, or confirm that products conforming with one compendial grade also met standards from other compendia.
Figure 8: Respondents testing excipients by Ph.Eur. or JP methods instead of USP–NF.
Only a minority of responding excipient manufacturers and distributors cited specific reasons for not labeling their products as USP–NF compendial grade. Approximately one-third cited low demand for compendial grade products; just under 30% cited restrictive GMP requirements, the prospect of FDA inspection, or the time and resources needed to perform required audits. Only a handful expressed doubts about being able to meet compendial monograph requirements (see Figure 5). Nearly 80% of excipient manufacturers and drug-product manufacturers, and 60% of distributors, have been inspected or visited by FDA for either drug excipient or food use (see Figure 6).
Among drug-product manufacturers, 89% have five or more excipients in reduced-testing programs, and do not perform complete monograph testing after vendor qualification and receipt of C of A.
Figure 9: Respondents applying harmonized monographs and general chapters across all sites.
Excipient manufacturers, distributors, and drug-product manufacturers all responded that they feel adequately familiar with the applicable FDA and compendial requirements and recommendations related to testing of excipients used in a drug product (see Figure 7).
Among manufacturers, distributors, and users of USP–NF excipients, 70% or more perform additional functionality or processability testing that is not part of any USP–NF,European Pharmacopoeia (Ph.Eur.), or Japanese Pharmacopoeia (JP) compendial monograph. Of these, 87% perform the tests because of processing concerns. Most additional testing was performed for solid oral dosage forms (87%), and 24% of drug-product manufacturers have products for which excipient variability is a problem in spite of such extra-compendial testing.
Appendix: Excipient Working Group Recommendations for a PQRI Workshop
At least half of excipient manufacturers, distributors and drug-product manufacturers test some, most, or all of their excipients by alternate international (Ph.Eur., JP) compendial methods instead of USP–NF (see Figure 8).
Nearly 60% of excipient and drug-product manufacturers conduct excipient testing per harmonized monographs, and reduce redundant testing by either demonstrating multiple compendial specification equivalence or using the most stringent method or specification for confirming compliance with more than one compendium. Approximately 50% of both excipient manufacturers and drug-product manufacturers have applied harmonized excipient monographs and harmonized general chapters across all their sites (see Figure 9).
The PQRI and its Excipient Working Group encourage active participation by stakeholders from excipient manufacturers, excipient distributors, drug-product manufacturers, compendia, and regulatory agencies in discussing the current issues and for developing possible solutions to problems faced by pharmaceutical excipient manufacturers, distributors, and drug-product manufacturers (5).
1. European Agency for the Evaluation of Medicinal Product (EMEA), Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product (CPMP/QWP/419/03) (EMEA, London, UK, Feb. 20, 2003).
2. US Food and Drug Administration, Guidance for Industry, Drug Product: Chemistry, Manufacturing, and Controls Information (FDA, Rockville, MD, Jan. 2003), now withdrawn, Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
3. United States Pharmacopeia 29–National Formulary 4, General Notices, section Tests and Assays under Procedures (United States Pharmacopeia Convention, Rockville, MD, 2006).
4. FDA, "Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances," Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
5. Details are posted online at http://www.pqri.org/workshops/Excipient/Excipient06.asp
6. Product Quality Research Institute (PQRI) workshop on Excipient Testing and Control Strategies, Oct. 10–11, 2006, Marriott Bethesda North Conference Center in Maryland.
The authors are members of the Pharmaceutical Quality Research Institute's Excipient Working