Conforming to the IPEC CoA Guide - Pharmaceutical Technology

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Conforming to the IPEC CoA Guide
Past IPEC-Americas excipient qualification committee chairs highlight changes to the IPEC guide on certificates of analysis for bulk excipients.


Pharmaceutical Technology
Volume 37, Issue 3, pp. 28-31

Based on FDA's comments, a user should no longer consider data from periodic (skip-lot) testing by the excipient manufacturer as sufficient to release the excipient for use in a drug product, regardless of the amount of historical data that may exist. This position is a paradigm shift for the pharmaceutical industry. Many companies use reduced testing programs and rely on their supplier's CoA data and, in the past, have accepted supplier statements that the specifications for a particular test were certified through the use of in-process or skip-lot testing. In addition, historically, pharmacopeias such as USP have allowed for this type of approach to be used by excipient manufacturers in their general notices and ICH Q6A has allowed for skip-lot testing of the drug product and drug substance. However, based on recent comments from FDA, they will not allow users to rely on in-process measurements to justify a specified test parameter without documented evidence (e.g., site audits) to demonstrate that appropriate procedures are in place to assure compliance. Although historically excipient users may not have established this level of documented evidence, but rather, may have simply relied on "un-justified/un-confirmed" data in their reduced testing programs, FDA made it clear during the PQRI discussions that this is now considered inappropriate (14). "According to FDA representatives, an appropriate determination to ensure that each lot conforms to appropriate specifications could involve some combination of the following approaches:

1. End-product testing

2. In-process testing

3. Continuous monitoring of an attribute with statistical process controls

4. Documented rationale that, based on the method of manufacture, the test attribute cannot be present and therefore the test is not applicable (e.g., residual solvents)" (14).

The CoA Guide refers to bullets 2–4 (above) as "other than finished excipient testing" and results derived from other than finished excipient testing should be clearly indicated in the CoA. For example, the test name can be footnoted to indicate the test result is obtained from other than finished excipient testing.

The CoA Guide also makes reference to ICH Q6A in this section, which allows for skip-lot testing of the drug product and drug substance. As mentioned above, FDA has additional expectations related to the use of supplier skip-lot testing results listed on a CoA for determining raw material compliance by pharmaceutical companies. FDA has stated that skip-lot testing by an excipient manufacturer by itself does not provide sufficient data for excipient users to justify reduced testing upon receipt and this lack of data was the basis of the PQRI discussions. Appropriate skip-lot testing can provide the basis, however, for an excipient manufacturer to certify compliance to a specification because the excipient manufacturer has significant process knowledge and understanding beyond what is available to the user. This is allowed for in the USP General Notices chapter, and there is no requirement for the excipient manufacturer to test each batch for all tests listed in their specifications when other controls can demonstrate ongoing compliance.

Verifying test results and measurements for specific parameters. Before releasing an excipient for use in the manufacture of a finished drug product, it is the excipient user's responsibility to ensure that a conforming test result was obtained for each specification parameter either by sampling and testing the finished excipient for each parameter, using qualified supplier test results from the CoA, or relying on "other than finished excipient testing" to support compliance to a particular parameter where qualified as noted above. The excipient CoA should identify these "other-than-finished excipient testing" results. Excipient makers should consider the impact on excipient users of any skip lot or "other-than-finished excipient testing" that is being used for product release at their site and inform excipient users accordingly.

Before accepting any test results from the CoA, the excipient user must qualify the excipient maker to ensure that the excipient is manufactured and tested in a manner consistent with applicable excipient GMP guidelines and excipient user requirements. The qualification should include a site audit of the excipient maker or supplier who provided the CoA by either the excipient user or a qualified third party to verify that the data provided on the CoA are generated using appropriate methods and are reliable. Periodic reassessment is also necessary to verify that the excipient maker remains qualified.

Whenever an excipient user relies on CoA data in lieu of incoming testing, it is suggested that an appropriate quality agreement be in place between the excipient maker and excipient user that clearly defines the responsibilities of each party. In such cases, the excipient maker serves, in essence, as a contract laboratory for the excipient user.

Analytical method reference. It is necessary that the excipient user know the analytical methods used by the excipient manufacturer to test each lot when CoA data are used for batch release. Analytical method references should appear on the CoA or be linked to a specification document so the analytical method used for each test is clearly communicated to the user. In the case where the analytical method is included on the linked specification instead of the CoA, the excipient user must be provided with the specification document.

Identification testing. USP General Notices 5.40 Identity states "A compendial test titled Identity or Identification is provided as an aid in verifying the identity of articles as they are purported to be, e.g., those taken from labeled containers, and to establish whether it is the article named in USP–NF" (17). Furthermore, 21 CFR 211.84(d)(1) states "At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be performed" (18). Similarly, for excipient users whose drug product is marketed in Europe, the EU legislation states, "The identity of a complete batch of starting materials can normally be ensured only if individual samples are taken from all the containers and an identity test performed on each sample (19)."

There has been confusion within the industry regarding reporting of identification tests on the CoA of excipient products. The IPEC CoA Guide clarifies that this reporting is not required when an excipient manufacturer has other control procedures in place that provide adequate assurance that their product will meet the identification test, if tested. In additon, the user must perform an identification test on every batch received regardless of whether the supplier has performed the identification test or not.

Summary

In summary, the CoA Guide is expected to be a crucial tool for manufacturers, distributors, and excipient users by providing clarity on additional regulatory and industry requirements related to supply chain transparency, authenticity of the CoA and testing requirements to name a few and by providing a suggested format that includes all necessary information.

Juanita Garofalo is global manager labeling and packaging at Avantor Performance Materials.

David B. Klug, MS, is senior manager, GMP audit at Sanofi and IPEC-Americas Chairman.

David R. Schoneker is director, global regulatory affairs at Colorcon.


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