This article provides practical tips on how to maintain test method suitability long after the formal completion of analytical method validation (AMV) studies. Case studies on how to meaningfully derive acceptance criteria for validation extensions and the validation continuum (maintenance) are described as well as an example on how to reduce analytical variability in validated systems.
Analytical Method Maintenance
There are several points to consider when running an analytical method maintenance (AMM) program. Usually, assay control results that are in established limits (e.g., plus or minus 3 s.d.), will yield valid assay results for the test samples. Whenever possible, the assay control should yield a similar assay response when compared with the test sample. Monitoring the assay control will indicate when unexpected assay result drifts or spreads may have occurred. Whenever the assay control results are close or over their established limits, there is a high probability that test sample results are also going in the same direction. This should not be ignored because it causes predictable, although not exactly measurable, errors in test results (cases 1B and 2B).1
Furthermore, controlling and fixing process problems could save more batches from rejection. These steps would also be in line with the principles for quality and process analytical technology leading to faster license approvals and reduced inspections.2–5
From the robustness studies performed during analytical method development (AMD) and the intermediate precision results during AMV, the identity of the method component that may be responsible for changing test results when replaced is clarified.
This should be the main purpose of AMD and AMV reports, to not only provide results for variance components, but to also clearly identify potential bias and how they can be controlled as part of test system suitability. The validation is ideally only a confirmation of something already expected to be suitable from the AMD studies. All method components and operational limits should be sufficiently studied and properly documented in the AMD report.
This information should then be used to set meaningful limits for sample handling and storage during testing, the number of replicates, and the overall system suitability limits in the AMD and AMV report. It will otherwise be more difficult to set limits and control the implementation of new method components without this knowledge from the AMD and AMV studies. Qualifying another instrument, reference standard, critical reagent, assay control, or operator for testing may arise from the need to get test results faster. Often, use of an alternative instrument or operator is inevitable. In any case, whenever critical validated method components are exchanged, equivalency in test results between the validated method component and the alternative component should be verified.
An example for an execution matrix for instrument equivalency is illustrated in Table 1. The testing of various production lots, unlike the obligation to include this for AMTs (current regulatory expectation), should not be involved as this may not help for the purpose of the equivalency studies.1