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

Acceptance criteria for AMT

Estimations for the true process mean (99 units) and variance (2.0%) were made from the assay control performance and from Equation 1, respectively. For the AMT, both accuracy and precision are areas of concern because several method components (operators, instruments, location and others likely) will change when the method is executed at the receiving laboratory. Tests should therefore be undertaken for the overall matching of the receiving laboratory results to those of the reference laboratory and for equivalent (intermediate) precision. Accuracy and precision limits are treated independently here for simplicity although they both impact all cases (1A-2B).


Table 3. Estimates of release probabilities and measurement errors (cases 1A–2B) for AMT.
The assay performance is at 3.0% (last n = 60)—or potentially higher if control outliers were included—when run under routine conditions with small changes over time. AMV results yielded an intermediate precision of 2.4%. An imprecision higher than 3.0% should not be allowed because the method component is the highest contributor to the overall variance (Table 2). There is already a relatively high likelihood (about 1.73%) of observing an out of specification (OOS) result with two observed over the last 60 (Table 3 and Figure 1). The limit of 3.0% appears balanced between the likelihood of passing to achieve compliance or project advancement and the likelihood for all cases 1A-2B to be continued in the future.


A recovery or matching of the expected (reference) potency of 100 1.5% appears reasonable. Allowing a maximum of 1.5% difference constitutes about one-half of the recent assay variability. The receiving laboratory should not be allowed to test with a greater bias because further increase in the likelihood of OOSs because of the potential shifting in the process mean compared with the target (100 units) may be seen. Overall, recoveries inside this range (98.5– 101.5%) as evidenced by the data from AMV, historical assay control, and SPC should be possible.

Acceptance criteria for AMM

When exchanging or adding a single method component, such as a second instrument, maintaining accuracy or the matching of historical performance should be the main considerations for reasons given above. However, accuracy/matching and precision could both be readily studied to monitor both method performance characteristics. The acceptance criteria for accuracy and precision for AMT and AMM should be derived from the product specifications with regards to assay performance (control) and process performance (SPC data).

As good estimates for all variance components may be present, acceptable criteria (at least for precision) can be derived from the results in Table 2. Acceptance criteria for accuracy (matching) may need to be tightened to avoid a potentially large compounding of bias from several one-directional changes e.g., 99.0–101.0% vs. current system). Unless there was no alternative, a 2.0% increase in test results should not have occurred when the reference standard was changed.

In Table 3, probability estimates are calculated based on the expected rounding of test results to specifications (90–110 units/mL). This leads to more test results falling within specifications as 89.5 is rounded up to 90 and 100.49 is rounded down to 100. The current calculated probabilities for observing passing results (1A) are 98.64% for results above 100 units and 99.63% for below, respectively, for a net total of 98.27%. Given a normal data distribution and the historical process mean of 101.0 units, the probabilities for failing low results versus failing high results do currently not match. The allowed worst-case probabilities for 1A after AMT (protocol acceptance criteria are 100 1.5%) are much greater towards the positive direction and come to the total of 96.73%. Case 2A probabilities are simply the reverse of 1A (100% -1A).

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