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Irwin Silverstein, PhD, is vice-president and chief operating officer at International Pharmaceutical Excipients Auditing, 1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.351.5266.
This article demonstrates that test results support the position of FDA on the importance of an appropriate supplier-qualification program.
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.
Excipient sampling program
IPEA developed scientific data to demonstrate the quality of these excipients in the marketplace. The IPEA sampling protocol for excipients from commercial packages was intended to obtain unbiased test results for these excipients in the USP-verified laboratories for comparison against USP–NF requirements. Several excipients from the established manufacturers and the two Asian manufacturers were shipped to the sample preparation site. The excipient packages provided were single samples; there were no excipients from multiple lots of the same product.
IPEA supervised the preparation of test samples from the commercial packages. Before opening, each package was carefully examined to confirm the tamper-evident seal was in-place and the appearance of each package was documented, both through written observation and photography. Each package appeared to have been labeled and sealed by the manufacturer.
Table I: Copovidone NF from Asian manufacturer A.
Each package was opened in an environmentally controlled room (temperature ~70 °F, relative humidity ~35%) and the excipient was scooped into plastic 1-L bottles. The excipient was surface sampled with a scoop and the first bottle from each package was kept as retains. The sample bottles were labeled to indicate the excipient compendial name and coded so that their manufacturer was not disclosed. They were then sealed and sent to the established manufacturers' USP-verified laboratories for compendial testing.
Table II: Povidone USP K-17 from Asian manufacturer A.
On occasion, multiple samples of the same excipient from the same manufacturer were sent to the laboratories to reduce the likelihood of the analyst identifying the manufacturer of the sample and thus potentially adding bias to the results. Assessment of the reproducibility of laboratory test results was an added benefit arising from multiple samples. Matching excipient samples were tested at both established manufacturers' laboratories assessed under the USP-verified program.
Table III: Povidone USP K-17 from Asian manufacturer B.
Results and discussion
The test results confirmed that all excipient produced at the established manufacturers met compendial requirements. Excipients from the Asian-based manufacturers failed to meet monograph requirements. Specifically, Copovidone NF from Asian manufacturer A failed to conform to the limit of monomers, content of polymerized vinyl acetate, and nitrogen. This is an indication that the polymer is deficient in vinyl acetate (see Table I). Povidone USP K-17 from Asian manufacturer A exceeded the limit for hydrazine and K-value (see Table II). Povidone USP K-17 from Asian manufacturer B exceeded the specified K-value and was high in ash (residue on ignition) and aldehydes (see Table III). Povidone USP K-12 from Asian manufacturer B exceeded the allowable limit for aldehydes (see Table IV). Povidone USP K-90 from Asian manufacturer B exceeded the allowable limit for vinyl pyrrolidinone (see Table V).
Table IV: Povidone USP K-12 from Asian manufacturer B.
Several common excipients from the two Asian manufacturers, Nanhang Industrial and Tianjin Boai NKY International, and the established producers were evaluated for conformance to the current USP–NF. For the Asian-based manufacturers, the data demonstrated that four of six Povidone lots sampled and one of two Copovidone lots failed to conform to the monograph. It was noted that two of three lots of Crospovidone tested high for heavy metals in one laboratory but was found to conform by the other.
Table V: Povidone USP K-90 from Asian manufacturer B.
The results of this study illustrate the importance of adequately qualifying the supplier of components. It is important to confirm the quality of the excipient using a scientific sampling plan and to perform complete testing until there is adequate assurance in the reliability of the manufacturers test data. In addition, it is essential to audit the site of manufacture because no amount of laboratory testing can confirm that the quality system used to produce the excipient meets CGMPs. A site audit also can provide confidence that the manufacturer has the technical ability to produce the excipient in the commercial package.
Irwin Silverstein is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing, a subsidiary of the International Pharmaceutical Excipients Council, tel. 732.463.8710, Irwin.S@verizon.net
1. S. Wolfgang, "Regulatory Perspective on Assuring Excipient Quality," presented at the USP International Excipient Workshop, Washington, DC, July 2009.
2. A.R. Sibille, "Control of Components and Drug Product Containers and Closures, Subpart E" in Good Manufacturing Practices for Pharmaceuticals, J. Nally, Ed. (Informa Healthcare, 6th ed., 2007), pp. 76–77.