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.
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.
Table 1. Instrument equivalency execution matrix
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
UNDERSTANDING THE RELATIONSHIP OF ALL COMPONENTS
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.
Table 2. Historical process, sampling, assay performance data, and suggested limits for accuracy an (intermediate) precision.
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
- 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).