International Pharmaceutical Excipients Auditing (IPEA), the conformance services subsidiary of the International Pharmaceutical
Excipients Council of the Americas (IPEC-Americas), sampled excipients available in the United-States market from two US Pharmacopeia
(USP)-verified companies (referred to collectively as established manufacturers) and corresponding ingredients from Nanhang
Industrial Co. (Hangzhou, Zhoupu Xihu, China) and Tianjin Boai NKY International (Caigongzhuang, Jinghai Tianjin, China),
referred to in this article as Manufacturers A and B, respectively, to evaluate their conformance to monographs for Copovidone
NF, Crospovidone NF, and Povidone USP. The goal was to compare the quality of the established manufacturer excipients with
the ingredient quality offered by the two new excipient suppliers. IPEA coordinated the project and was responsible for ensuring
that the excipients were properly sampled from sealed manufacturers' containers and tested in USP-verified laboratories to
develop unbiased data, thus lending credibility to the findings.
Test results support the position of the US Food and Drug Administration as to the importance of having an appropriate supplier-qualification
program (1). Such a program includes laboratory testing to confirm that components from a supplier meet compendial requirements
and a site assessment to ensure that the component was produced under appropriate good manufacturing practices (GMPs). As
described in this article, many of the tested excipient lots failed to conform to USP monograph requirements. However, IPEA
did not conduct an evaluation to ensure conformance of the sites to appropriate GMPs because this was outside the project's
scope. It should be noted that the established manufacturers were in conformance with USP–NF <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients.
Regulatory basis for supplier qualification
Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires that drugs (components and drug products) be manufactured
in conformance with current GMP (CGMP), and 501(b) of the Act further requires that a drug whose name appears in an official
compendium meet the standards set forth in the official compendium. The FDA Compliance Policy Guidance Manual (section 420.100) indicates that a drug, or drug component is considered adulterated if it fails to conform to compendial
requirements. This section further states that "it should be kept in mind that the types of adulteration found under 501(b)
and 501(c) may be indicative of a wider problem involving failure of the manufacturer to adhere to current good manufacturing
practice that should be addressed."
The FDA expectation, under 21 CFR 211.84(d)(2) is implementation of an appropriate supplier-qualification program. Qualification should be completed before
the pharmaceutical manufacturer reviews, and relies on, incoming approval of test results reported on the manufacturers' Certificate
of Analysis (CoA) in addition to satisfactory results from at least one specific identity test. A supplier-qualification program
should include an audit of the supplier's manufacturing facility (2).
Polymeric vinyl pyrrolidinone excipients
Povidone USP, polyvinyl pyrrolidinone, has been used in drug products for more than 50 years. Crospovidone NF, crosslinked
polyvinyl pyrrolidinone, has been marketed as an excipient for more than 25 years and more recently, Copovidone NF, the copolymer
of polyvinyl pyrrolidinone and vinyl acetate, was added to USP–NF. Until recently, these three excipients were marketed by the established manufacturers but are now being offered by new manufacturers
based in Asia. There were reasons to believe the new Asian manufacturers would have difficulties in meeting all monograph
requirements for these excipients because some excipients from the Asian-based manufacturers failed to meet monograph requirements.