Tests to consider for potential sunset testing

The industry supports the use of interim specifications, where appropriate and when safety is not an issue, at the time of filing. This could be justified at the time of regulatory filing with an interim limit up to the safety threshold. In turn, FDA expects a specific Phase 4 commitment from the new-drug-application holder that defines the number of batches or the time frame over which further experience will be obtained, together with the data-analysis plan to facilitate a timely justification of the final specifications.

Postapproval acceptance criteria changes

Periodic or skip testing

Periodic or skip testing involves performing specific tests at predetermined intervals, rather than on a batch-to-batch basis, for release of the drug substance or drug product. Those batches not being tested still must meet all acceptance criteria established for the drug substance or drug product (1). The obvious benefit is significant reduction in the cost of testing and release cycle time. On the other hand, the sponsor assumes the risk that if a product fails to meet specifications at a given test point, products released to the market since the last testing point may potentially be considered out-of-specification. Depending on the outcome of an OOS investigation into root causes and an evaluation of product impact, there is a potential for product recall from the market. Thus, skip testing can be used only when extensive experience shows that there is low risk of failure and that a potential failure would result in low risk to the patient. The use of process analytical technologies (PAT) for in-process monitoring may be an acceptable justification for consideration of skip testing in that particular case.

Although the concept is recognized in the ICH guideline, skip testing of finished drug products is not in widespread use because of a perceived regulatory risk or reluctance of regulatory agencies to approve skip-testing release protocols (1). Most firms, however, do use skip testing in conjunction with supplier certification programs for the release of excipients. Risk is limited because the qualification or certification process usually requires the supplier to test these materials on a batch-by-batch basis, and each batch has been tested at least once. Unlike raw materials, finished products are at greater risk because actual batch analysis data are not available on skipped lots. This risk may be limited by the availability of data from related tests or by in-process testing or by data from process analytical monitoring.