Ideally, formal AMV is only a confirmation of the suitable performance of test methods that is usually known prior to validation
execution. If there is a low risk of failing a particular AMV, its completion could be planned accordingly with a lower priority.
Critical production process and product quality attributes must be understood and measurable before a production process can
be truly optimized. The earlier that process variability can be reliably and accurately measured, understood, and ultimately
controlled, the higher the probability of gaining license approvals and operating and maintain a robust production process.
A brief list of high priority AMVs to support process validations and the submission of a license application follows:
- All tests for drug safety, purity, efficacy, and stability
- Advanced, automated, or new analytical technologies not yet commonly used in the biopharm-aceutical industry
- Final container and late-stage, in-process testing
COMPLIANCE THROUGH AMM
Once regulatory approval is obtained and production is running smoothly, all quality systems must be monitored and properly
maintained. Figure 2 illustrates how analytical methods can be readily monitored and maintained within the QC VMP. The gray
boxes identify all new analytical methods that need validation and all compendial procedures that need verification. If a
method is later replaced, a method comparability study must provide evidence that the new method is comparable to the current
and licensed method.7 Successfully completing these steps brings you to initial compliance. The overall AMM for validated test methods is split
into method modifications (in yellow) and method reviews (in green/red).
Figure 2. An Analytical Method Maintenance Program
Critical test system elements such as reference standards or analytical instruments are deliberately listed in yellow (Figure
2) under this maintenance category. Depending on the depth of studies conducted for assay robustness during AMD, some critical
test system elements may have already been identified and understood. By definition, a truly robust assay will remain unaffected
by small changes in operational limits and critical methods elements. In reality, however, AMD studies may lack a meaningful
design of experiments to test for robustness. In addition, many test methods are inherently sensitive to changes and are therefore
not very robust. This is why the suggested AMM program is important — it will help to keep test results within acceptable
accuracy and precision limits. If assay robustness was not thoroughly evaluated during AMD (and AMV), the suggested validation
maintenance program (VMP) should monitor all test system components, as it isn't known which one, when altered, could trigger
a change in the test results. Equivalency studies that compare before-to-after method performance criteria (in general accuracy
and precision) could be used to document that changing a critical test system element leaves the test method performance unchanged.
Alternatively, the test-method-associated assay control chart could be monitored for drifting (after change) or undesirable
spreading of control data points.
Minor method modifications such as replacing an assay control with an equivalent control are usually summarized together with
the overall test method performance evaluation (assay controls charts, number of invalids, etc.) in annual reports to regulatory
authorities. Major changes may not require revalidation, but they will require the demonstration of comparability of results
before and after.7 For example, if a reference standard for a potency test method is changed, the equivalence of the new standard should be
demonstrated by comparing accuracy and intermediate precision results using actual production process material.7 Major modifications may also require regulatory approval before their implementation.7