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A new audit guide aims to improve supply-chain security and supplier qualification practice.
Early in January 2011, the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) updated its 2000 GMP Audit Guideline for Distributors of Bulk Pharmaceutical Excipients and renamed it the IPEC–Americas Good Distribution Practices Audit Guide for North American Distribution of Pharmaceutical Excipients. Although the new good distribution practice (GDP) audit guide is meant for distributors, brokers, and traders of excipients in North America primarily, it also can be a resource for the audit of distributors worldwide. For the purposes of this article, distributor is defined as encompassing the following: distributors who take possession of an excipient and may conduct a range of activities from repackaging and storage through warehousing and shipping; brokers who arrange for a transaction between an excipient manufacturer and an excipient user but never take physical possession of the excipient; and traders who contract with the excipient user before finding a source of the excipient for the pharmaceutical manufacturer and also never takes physical possession of the excipient.
Growing security concerns
Expectations for auditing excipient distributors have grown significantly in recent years. In June 2009, FDA held a conference on economically motivated adulteration (EMA). FDA's working definition of EMA is "the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production (i.e., for economic gain)." EMA is a concern for excipients, in particular, because their supply chain from the manufacturer to end-user frequently involves multiple distributors and, thus, weakens their supply-chain security. FDA investigators also have recently been inspecting supplier-qualification programs at pharmaceutical manufacturers with the expectation that drug manufacturers qualify their distributors and the excipient manufacturers they represent. Industry expressed great interest in the qualification of distributors at two recent conferences, IVT's November 2010 Life Sciences Forum Supplier Audits and the American Society for Quality's January 2010 Northeast Pharmaceutical GMP/Quality Conference. Attendees discussed how certain audit tools could help assess distributors and their excipient suppliers.
The IPEC–Americas audit guide supports the IPEC GDP Guide for Pharmaceutical Excipients issued in 2006. The audit guide provides open-ended questions that are meant to help the auditor begin a dialogue with the distributor and thereby enable the auditor to obtain objective evidence from which to establish conformance of the distributor to applicable provisions of the GDP guide. The audit guide also provides information on how to develop an excipient distributor certification program (see section below).
New audit tools
Similar to IPEC's 2006 GDP guide, the new audit guide opens with a Matrix of Applicability table (see Table I). An auditor can use the table to identify aspects of GDPs that apply to the distribution operation being assessed. Activities may range from simple to more complex GMP operations, ranging from the transportation of packaged excipients to repackaging and packaging from bulk excipient. The auditor identifies the applicability symbol reflecting the activities conducted at the distributor, represented by a Greek letter that corresponds with the warehouse or distribution activity. The auditor can then assemble a customized audit guide by identifying those sections indicated by the Greek letter that are applicable to the distributor to be assessed.
Table I: Matrix of Applicability.
The auditor can create a customized checklist by selecting from more than 250 open-ended questions that cover 96 audit categories within 13 audit sections. The audit sections correspond with the GDP guide. A customized checklist facilitates a thorough audit of distribution activities. Depending on the range of activities conducted at a distributor's facility, a site audit can range from a half-day to multiple days.
Futher, a site assessment of the distributor is an expectation of FDA for the qualification of distributors for the same reason that site audits are expected for the qualification of an excipient manufacturer. The alternative, which is out of favor at FDA, is a paper audit. A paper audit relies on properly worded questions that solicit truthful, thorough answers from the distributor. Regardless of the veracity of the responses to a paper audit, such audits do not provide an adequate assessment of the risk to excipient quality from the environment, equipment, or improper excipient storage conditions.
Although a distributor audit establishes the distributor's conformance to GDPs, certain distributor activities, such as repackaging and storage of bulk excipient, also must conform to applicable GMPs. The IPEC–Americas audit guide provides questions for the assessor that also target these relevant GMP operations conducted at a distributor's site.
In 2001, IPEC formed an independent auditing group known as International Pharmaceutical Excipients Auditing (IPEA) to facilitate physical audits of excipient manufacturers and distributors. At the urging of FDA, IPEA developed an Excipient GMP Conformance Certification Program. In 2010, this program was accredited by the American National Standards Institute (ANSI). Also in 2010, four excipient manufacturing sites in two countries were audited for conforming to the provisions of the IPEA program and two sites completed the certification process. Upon the approval of an ANSI standard for Excipient GMP, currently under development, certification to excipient GMP will be based on this standard.
The updated IPEC-Americas GDP audit guide provides product-conformity assessment bodies with a foundation for developing a similar ANSI accredited excipient GDP certification program. Companies can develop objective criteria along with expectations for substantial conformance to GDPs that cover the range of industry distribution activities. With such procedures in-place, an ANSI accredited third-party audit provider, with the approval of ANSI, can expand its certification activities to include distributor certification to GDPs.
The demands of the pharmaceutical industry will determine whether certification of distributors is beneficial to supplier qualification and to the enhancement of supply-chain security. Most likely, industry can look forward not only to the certification of distributors but also to the development of an American National Standard for GDPs.
The author wishes to acknowledge that the GDP audit guide is a product of the IPEC–Americas GMP Committee.
Irwin Silverstein is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing (IPEA), a subsidiary of IPEC, tel. 732.463.8710, firstname.lastname@example.org, www.ipeainc.com.