Acceptable Analytical Practices for Justification of Specifications - Pharmaceutical Technology

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Acceptable Analytical Practices for Justification of Specifications
The concept of Acceptable Analytical Practices (AAPs) was developed by the Analytical Technical Group of the Pharmaceutical Research and Manufacturers of America to share information about how the pharmaceutical industry has implemented chemistry, manufacturing, and controls and quality guidances of the International Conference on Harmonization and worldwide regulatory authorities. The AAP process identifies and addresses critical issues in which guidance is lacking, ambiguous, or contradictory. AAPs were..


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Tests to consider for potential sunset testing
As discussed previously, limited batch data do not allow a robust estimate of process capability. If criteria are to be derived from process capability, then this lends itself to an interim approach that allows industry to gain more experience with the commercial process and better estimate the process capability. Note that limited data can both under-estimate or over-estimate the appropriate limits. The need for interim specifications should be justified based on safety, process capability, and statistical considerations. Industry would prefer a wider limit until more data are available. For example, limited scale experience is cause for manufacturers to be concerned about committing to an official limit for a specific impurity, especially when safety and efficacy are not an issue. Generous interim limits are a desirable approach to the manufacturer that does not want to encounter needless rejection of a batch where there is no risk to the patient. Setting specifications very close to the manufacturing capability also may impact the ability of the manufacturer to improve other aspects of the process (e.g., environmental impact, cost reduction, stability of supply chain). Specific parameters where an interim specification may be appropriate include impurities, degradation products, dissolution (e.g., especially for highly water-soluble drugs or revision or replacement of a test for an existing product), residual solvents, and particle size.

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

The industry considers multiple options viable for specification changes postapproval, including follow-up on interim specifications. One option may be to make a commitment to re-evaluate the specification, but leave the specific timing for this re-evaluation open until data and statistical justification are available. However, providing a protocol at the time of filing with plans for the number of batches, statistical treatment of the data, and so forth is a proposed approach. For example, revision of dissolution acceptance criteria in response to improvements of the dissolution test method for an existing product might best be handled with a comparability protocol covering the expected number of batches to be evaluated before finalization of the dissolution specification. Similarly, for a new impurities method in an older product, a commitment may be needed to define the number of lots needed.

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.


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