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


The International Conference on Harmonization (ICH) guidance Q6A and the World Health Organization (WHO) each have definitions for periodic or skip testing as well as skip-lot (periodic) testing (6, 7). These definitions apply to new drug substances and new drug products. The ICH and WHO definitions have the same approach yet use variations of the same terms. ICH guidance Q6A states periodic or skip testing is
the performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on a batch-by-batch basis, with the understanding that those batches not being tested still meet all acceptance criteria established for that product. This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation.

In a similar manner, WHO states skip-lot (periodic) testing is
the performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on a batch-to-batch basis, with the understanding that those batches not tested must still meet all the acceptance criteria established for that product.

This represents a less-than-full schedule of testing and should therefore be justified, presented to, and approved by the regulatory authority before implementation. When tested, any failure of a batch to meet the acceptance criteria established for the periodic (skip-lot) test should be handled by proper notification of the appropriate regulatory authority(ies). If the data demonstrate a need to restore routine testing, then batch-by-batch release testing should be reinstated.

For each excipient batch, it is important to demonstrate that it conforms to all of its specifications. This objective can be accomplished using in-process testing and appropriate in-process controls, and/or finished-product testing.

The workshop participants found that confusion exists because most excipient manufacturers do not conduct all compendial tests because their controls give assurance that a compendial quality material is produced. It was asserted that if an excipient manufacturer does not provide the result for a specification test, it must be clearly indicated on the CoA, and the drug-product manufacturer will need to perform that test (21 CFR 211.84).

The confusion exists because in today's environment of process analytical technology (PAT), one question raised is whether all tests really must be run if excipient manufacturers have the systems under control. This topic was felt important enough to have further discussion with FDA.

FDA comments on skip testing and Type 4 drug master files for excipients. The workshop attendees discussed that opportunities exist for skip testing of excipient batches by excipient manufacturers. Several conference participants suggested that the justification for performing skip testing may be submitted to regulatory authorities (e.g., FDA) in a Type 4 drug master file (DMF)—for an excipient—as allowed by 21 CFR 314.420(a)(4).

In post-workshop discussions, FDA representatives stated that normally, DMFs should not be submitted to the agency for standard compendial excipients unless the material is to be used in new and different ways where there may be a need for additional safety or technical data about the excipient. Normally, the excipient control strategy and test justification should be provided to the drug-product manufacturer. The justification can then be assessed by FDA during CGMP inspections of the drug-product manufacturer or the excipient manufacturer.

In a post-workshop meeting, FDA representatives stated that it considers the practice of skip-testing not to be compliant with CGMPs because for those lots that are not sampled and tested, there is a lack of assurance that the finished excipient material will meet all of its specifications. FDA believes that if an attribute for a finished raw material has required criteria, there must be some measurement or test of the material in each lot to ensure that the criteria are met. This may be a measurement from a surrogate test, from in-process control data, or from testing or measurement of the finished material in each lot. Conversely, FDA representatives believe that an approach, which allows for skip testing based on a satisfactory product quality history alone, is not acceptable from a CGMP standpoint because such an approach does not adequately verify that each lot meets all of its specifications.


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