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It's time to maintain a thorough traceable excipient trail.
Pharmaceutical companies have spent much time, effort, and money to ensure excipient quality. Whether an excipient travels through a short and direct, or long and complex supply chain, history has shown that, unfortunately, dangerous, often life-threatening changes are sometimes made to the excipient along its path. Consider the following examples:
As a result of the Haiti incident and a subsequent investigation uncovering the involvement of numerous distributors and brokers, in 1998, the World Health Organization (WHO) developed the Good Trade and Distribution Practices for Pharmaceutical Starting Materials (GTDP) guidelines. That same year, the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) published a position paper on vendor qualification. IPEC-Americas, along with IPEC–Europe and IPEC–Japan, have since published numerous guidelines covering such topics as good manufacturing practices (GMPs), good distribution practices (GDPs), the use of certificates of analysis (COAs), and significant-change notification to help manufacturers protect their excipient supply chains.
In spite of these efforts, supply-chain incidents involving excipients occurred agin in China in 2005 and in Panama in 2006. As a result of these incidents and drug-importation discussions with the US Food and Drug Administration, IPEC-Americas and IPEC–Europe released a position paper on proper excipient pedigree in December 2008 (available for free download at www.ipecamericas.org).
Three basic approaches of tracking chain of custody were explored, including paper trail, barcoding, and radiofrequency identification (RFID). Because of the complexity of the excipient industry, the authors (including excipient manufacturers, users, and distributors) deemed that the quickest approach that could be implemented with the least disruption to the supply chain was a verified paper trail. (It's important to note that FDA reviewed the position paper; the authors considered the agency's comments and for most the part, included them in the final version).
Although a single program cannot prevent fraud, a pedigree approach—using existing paperwork (or electronic paperwork) to the greatest extent possible—is a strong deterrent. The IPEC Excipient Pedigree Position Paper is founded on four premises:
The excipient manufacturers' role includes manufacturing the excipient according to the IPEC/Product Quality Group GMPs, as well as following the GDPs for distribution operations performed. Additionally, the position paper states that a manufacturer is expected to provide documentation to verify it shipped the excipient to a distributor if it used this supply chain.
Finally, if the manufacturer is using a distributor, it is recommended that the manufacturer ensure the distributor is in compliance with IPEC GDPs and that the distributor takes appropriate measures to prevent cross-contamination. IPEC and the authors of the position paper believe that verification is best accomplished by auditing the distributor. The paper also recommends that excipient manufacturers and distributors conduct mock recalls to test the effectiveness of their recall procedures.
The IPEC GDP guide calls for a distributor to provide the user, upon request, with a chain-of-custody record for the excipient. This record might include bills of lading or air bills with the financial data redacted. The distributor should also provide a COA for each delivery (a copy of the COA from the original excipient manufacturer is acceptable).
The data reported on the COA, however, must be based on the manufacturer's analytical testing results and include, as recommended by the IPEC COA guide, the identity and location (including country) of the manufacturer. When a distributor provides its own COA, the manufacturer and the site are identified. If the distributor repackages the excipient or packages from bulk, the distributor must sample, analyze, and include its results in its own COA. A distributor-developed COA should identify the original manufacturer and manufacturing location. Traceability of the exipient manufacturer is required to enable the recall of material.
Furthermore, the position paper suggests that if a distributor receives material into a holding tank, only materials from the same manufacturer's site or terminal conforming to the same specifications should be mixed. Distributors that load or package from bulk excipient should follow the WHO GTDP and IPEC GDP principles regarding definition of batches, analysis of material, and preparation of COAs. The distributor also should have an effective change-management program in place.
The excipient user bears the responsibility for all excipients used and, therefore, must know the origin and complete supply chain (i.e., excipient pedigree) for each batch of each excipient. Apart from performing appropriate testing of each incoming excipient lot, the position paper states that the user should audit both the excipient manufacturer and all distributors in the supply chain, or use the results of an audit. FDA has indicated that it is permissable to use a qualified third-party to conduct these audits and IPEC has published audit guides that can be used for this purpose. It's also important for the user to periodically verify the chain of custody described above to ensure the pedigree's accuracy. All these steps can be completed as part of supplier qualification and supply-chain management.
The final topic addresed in the IPEC excipient pedigree paper is labeling. IPEC recommends excipients never be labeled as compendial material (e.g., USP–NF) solely based upon test results. To protect the supply chain, non-GMP material should never be relabeled as compendial grade based solely on conformance to the compendial monograph. The original material must have been manufactured and distributed in conformance with appropriate GMP and GDP requirements, including testing, storage, repackaging, and relabeling.
Verifying the pedigree of an excipient with a paper trail (or electronic paper trail) only works with the cooperation of everyone involved in the supply chain. If a single party fails to adopt these preventive measures voluntarily, verification may eventually be mandated by more burdensome and costly regulations.
Arthur J. Falk, PhD, is president and CEO of International Pharmaceutical Excipient Auditing (IPEA), tel. 908.735.812, firstname.lastname@example.org. The IPEC documents mentioned in this article can be downloaded for free at www.ipecamericas.org.