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The author explains the background behind the excipient pedigree and how to implement its use.
Verification of an excipient's pedigree and comprehensive incoming inspection data are important elements of supply-chain security. Without adequate implementation of both components, a pharmaceutical company can be exposed to nefarious activities comparable to a computer user whose Internet activities are unprotected by a firewall and antivirus software. As demonstrated by recent global supply-chain breaches, excipients are vulnerable to contamination, counterfeiting, and adulteration.
In May 2010, the International Pharmaceutical Excipient Council (IPEC) published criteria for excipient pedigrees (1). Pedigree criteria is based on good distribution practice (GDP) guides from the World Health Organization, IPEC, and the Product Quality Group (PQG), and cover auditing, Certificate of Analysis (CoA) data, distribution and holding, and more. The specific criteria can be implemented using the checklist for supply-chain security (see sidebar, "Checklist for supply-chain security"), and can be supported by the supply-chain security flow diagram shown in Figure 1. Use of these materials can help industry confirm that a purchased excipient arriving at the receiving dock has been produced in substantial conformance to excipient good manufacturing practice (GMP) and minimizes risk that the material has been tampered with or otherwise adulterated en-route.
Checklist for supply-chain security
Authenticity and quality
The first task in establishing excipient-pedigree authenticity is to identify the path from receipt of material back to the original excipient manufacturer. Unless the excipient is shipped directly from the manufacturer, the excipient user must trace the material's path from the final shipping point upstream to the manufacturer. This process can involve several stops along the distribution supply chain. At each stop, the pharmaceutical user should confirm through review of the shipping papers (i.e., papers included in the US Bill of Lading or Airway Bill) that the excipient lot in question was handled by the distributor and is traceable upstream to the previous stop. The path ends when the excipient manufacturer's shipping papers are identified, thus confirming the identity of the manufacturer and the full supply chain.
Figure 1: Supply-chain security flow diagram. GMP is good manufacturing practice; GDP is good distribution practice; CoA is Certificate of Analysis. (FIGURE IS COURTESY OF THE AUTHOR)
The second step in implementing the checklist involves performing an assessment of the manufacturer to confirm that the excipient was produced using an excipient GMP compliant quality system (2). In addition, each stop in the distribution supply chain must be assessed to confirm that the excipient was handled in compliance with applicable GMP and GDP requirements (3).
Industry best practice is to visit and audit the original excipient manufacturing site. Relying solely on responses from questionnaires no longer meets regulatory expectations under current GMP for supplier qualification. In a recent conference presentation, FDA announced that pharmaceutical users may soon be expected to audit their excipient suppliers themselves or to use a qualified third-party auditor (4). The pharmaceutical user should assess the third-party provider and confirm that it is qualified. At the conference, FDA said pharmaceutical manufacturers would be expected to audit their suppliers or use an accredited third party or qualified third party to do so. The American National Standards Institute (ANSI) has accredited an organization to provide certification to excipient GMPs that is accepted by FDA.
Before any on-site audit, it is advisable to send the supplier a pre-audit questionnaire that includes a request for the manufacturer to list the applicable quality system under which the excipient was manufactured. The pre-audit questionnaire can also facilitate the site audit by providing applicable background information. The questionnaire should identify the scope of operations conducted at the site. For the manufacturer, the response should identify contract operations, which also require auditing.
For the distributor, the response to the pre-audit questionnaire must identify the scope of its operation and whether other on-site operations might affect excipient quality. For example, the distributor may package bulk excipient or repackage excipient into smaller packages. The pharmaceutical manufacturer also must confirm that the distributor samples and tests the excipient to confirm there has been no contamination or degradation of the material. Once the pre-audit questionnaire is completed, the pharmaceutical user can finalize an audit plan and schedule the on-site audit.
Packaging and labeling
A secure supply chain can be achieved when all parties are confirmed to be in compliance with excipient GMP and GDP requirements. It is also crucial to establish procedures to ensure the quality of the excipient upon receipt. Current industry practice for approving/accepting an excipient from a qualified supplier is to confirm the quality of the excipient based on the CoA and identification testing. Industry best practice is to expand this approach to include confirmation that the excipient has not been tampered with at any stage of its distribution cycle.
A tamper-evident seal for each excipient package can help provide such assurance. However the individual responsible for receiving an excipient often must deal with different seals because each supplier should use a unique seal. An authentic photograph from each excipient supplier showing the tamper-evident seal should be available to the receiver so that he can confirm that the package's original seal has remained in place while en-route. Authentic photographs of both the excipient package and label can provide additional assurance that the excipient was not repackaged.
Overall, receipt of excipients involves satisfactory completion of the following steps:
1. Confirmation according to shipping papers that the excipient came from the approved supplier
2. Verification that the package has not been tampered with by comparing the package and its seal with authentic photographs and packaging descriptions. This step includes determining whether:
a. The excipient was received in the approved packaging (contact packaging and secondary containers)
b. The authentic tamper-evident seal is in place
c. The authentic label is in place.
3. Scientifically justified sampling of the excipient packages and confirmation that the excipient passes appropriate identification testing.
4. Verification that the CoA demonstrates that the excipient meets the compendial monograph or appropriate specification.
Periodically, the pharmaceutical user also should verify that the qualified supplier produced the excipient and that the CoA is authentic. Confirmation of the manufacturer can be accomplished by using shipping papers to trace the supply chain. CoA authentication can be achieved by sending the CoA to the excipient manufacturer to verify that it is unaltered.
Recent incidents have sensitized the pharmaceutical industry to economically motivated adulteration and excipient vulnerability. Many presentations and papers have addressed supply-chain security, but the practice of receiving and approving excipients must be strengthened to fully ensure drug product safety.
Irwin Silverstein is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing (IPEA), a subsidiary of the International Pharmaceutical Excipients Council (IPEC), tel. 732.463.8710, firstname.lastname@example.org, www.ipeainc.com/.
1. A.J. Falk, Pharm. Technol. 34 (3), 78-70 (2010).
2. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients (2005).
3. IPEC, Good Distribution Practices Guide for Pharmaceutical Excipients (2006).
4. B. Hasselbalch, "Public Health Challenges for the Quality of Human Drugs," presented at FDA–Xavier University Global Outsourcing Conference (Cincinati, June 2010).