A Guide for Testing Biopharmaceuticals Part 2: Acceptance criteria and analytical method maintenance - - BioPharm International


A Guide for Testing Biopharmaceuticals Part 2: Acceptance criteria and analytical method maintenance

BioPharm International
Volume 19, Issue 10

This should indeed 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. It is the recommendation of the author that all method components and operational limits are 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/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/AMV studies.

Table 1. Instrument equivalency execution matrix
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.

As discussed, the AMD/AMV report should indicate whatever those "critical" method components might be and what associated risk might be involved when changing particular components. Equivalency can be accomplished similarly to AMT, provided that limits set initially still hold, by using an equivalency matrix and appropriate acceptance criteria for accuracy (matching) and (intermediate) precision.

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.7


Table 2. Historical process, sampling, assay performance data, and suggested limits for accuracy an (intermediate) precision.
There are numerous ways that process and method performance knowledge can be used to monitor and improve overall process and product quality. In reality, unlimited time and resources are not always available and we should first identify the most critical components and maintain committed to implement critical improvements before we get lost in too much data. A hypothetical example is provided below to illustrate how acceptance criteria for AMTs and AMMs could be derived with respect to estimated probabilities for 1A-B and 2A-B. Following from this example, potential improvements are discussed to illustrate what could be done to reduce the undesirable probabilities for cases 1B and 2A-B.

A potency bioassay is used for downstream in-process and final container testing of a licensed biopharmaceutical drug. This method is monitored in our AMM programme. After months of commercial production, transfer of this analytical method to a different laboratory for product release testing is needed. If the downstream in-process stage is yielding inconsistent potency results (Table 2), the following data should be reviewed:

  • process development
  • process validation
  • AMD
  • AMV
  • historical process
  • method performance (assay control) data.

We may want to start with the easiest variance component, the assay variance, as monitored with the assay control. Figure 1 illustrates the relationship between the assay performance and observed recent SPC potency results (last n = 60).

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