Joint Position Paper on Pharmaceutical Excipient Testing and Control Strategies - Pharmaceutical Technology

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Joint Position Paper on Pharmaceutical Excipient Testing and Control Strategies
This article presents collaborative positions among excipient manufacturers, drug product manufacturers, and members of the US Pharmacopeia on key issues pertaining to the control of pharmaceutical excipients stemming from a recent Pharmaceutical Quality Research Institute workshop.

Pharmaceutical Technology

Control strategies concerning excipient functionality and/or performance-related tests should be based on excipient manufacturer's process capabilities and be negotiated between the excipient user and excipient maker. The test parameters and control strategies that are mutually agreed to should be included in contracts between the excipient maker and user. Workshop participants generally agreed with this approach.

IPEC also is supporting the development of educational programs in formulation science. Only through education will the industry have the formulation scientists required by the QbD approach for pharmaceuticals.

Significant change in excipient properties. Communication to excipient users about a significant change in excipient physical and chemical property(ies) should occur in a timely manner, even when the excipient would otherwise continue to meet all of its compendial specifications. IPEC has defined significant change as "any change by the manufacturer of an excipient that alters an excipient physical or chemical property outside the limits of normal variability, or that is likely to alter the excipient performance in the dosage form."

Such changes may necessitate notifying the local regulatory authority if required (as in Europe). Regardless of whether there is a regulatory requirement, the excipient manufacturer has an obligation to notify its customers of a significant change so that the customer can evaluate the effect of the change on the customers' products. Examples of significant change include differences in the methoxylated content of hydroxypropylcellulose, particle-size distribution profile, and change in polymorph or crystalline properties. The issue of change control should be part of the quality agreement between an excipient user and the supplier.

Within a company, a drug-product manufacturer should ensure strong oversight of supply chain management decisions by research and development and other quality assurance and technical groups. There must be improved communication between supply chain management and technical functions as well as improved communication between excipient user and excipient supplier. In particular, it is very important to define and evaluate significant changes to the excipient. Changes to site, scale, equipment, process, packaging and labeling, and specification are considered in the IPEC-Americas Significant Change Guide for Bulk Pharmaceutical Excipients (13). To assess, evaluate, and agree upon such details, audits of excipient suppliers should be a team effort by members such as CGMP compliance auditors and technical personnel. In addition, education programs should be developed with a focus on formulation science and QbD collaboratively between academia and industry.

The closing session of the workshop also identified the need to define significant change in quality agreements as a key issue.

Highlight advantages of increased use of third-party audits

This topic was described to the participants as follows:
Third-party audits of excipient manufacturers, especially outside the United States, are critical to a control strategy for the global excipient supply chain. The use of independent third party audits may provide a cost effective way to accomplish control and ensure quality of excipients, especially for smaller pharmaceutical manufacturers. The concepts and advantages of independent third party audits will be described.

An on-site visit by a drug-product manufacturer's company auditor is the most common practice in auditing an excipient manufacturer. Survey results indicated that 87% of drug-product manufacturers have performed auditing of their excipient manufacturers for some to all of their excipients. Most drug-product manufacturers do not audit every one of their excipient manufacturers but instead have some type of risk prioritization process for selecting the ones to audit. Only 29% of the audits were performed by a third party. This is an opportunity to have third-party auditors provide an alternate view of the excipient supplier and reduce the number of independent audits of excipient suppliers. Of the 17 excipient manufacturers' responses, 1 stated that, on average, they have an on-site visit by their customers every week. Of the remaining responses, 5 are visited by at least one customer once in 2 weeks; 2 manufacturers are visited by their customers every 4 weeks and 8 weeks, respectively, and 7 stated that they have a customer at their site less often than every 8 weeks. The advantages of using independent third-party audits were discussed.


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