A Guide for Testing Biopharmaceuticals Part 1: General Strategies for Validation Extensions - - BioPharm International


A Guide for Testing Biopharmaceuticals Part 1: General Strategies for Validation Extensions

BioPharm International
Volume 19, Issue 9

Measured results are within established specifications.

  • Case 1A: results are true.
  • Case 1B: results are not true.

Measured results are outside established specifications (OOS).

  • Case 2A: results are true.
  • Case 2B: results are not true.

Cases 1A and 2A are routinely monitored by SPC. Cases 1B and 2B originate from other uncertainties such as imperfect test method performance or poor sampling and are not readily visible by SPC. Cases 2A and 2B are obviously not desirable because the firm cannot process nor sell this product or material. Case 1B constitutes a risk primarily to patients, but also means a risk to the firm if adverse product-related reactions or over- or under-dosing would actually occur. Case 2B constitutes a loss solely to the firm and should also be avoided mainly for profit reasons although other problems may also arise from this situation.

For our validation extension acceptance criteria, we should primarily set acceptable protocol limits from SPC with relation to specifications. We should consider the likelihood and impact for cases 1B and 2B, and avoid as much as possible measurement errors as part of the AMM program. Inaccurate or imprecise measurements will always cause a lower than ideal probability of observing results within specifications. The acceptance criteria for AMV and its continuum requirements must, therefore, ensure the low likelihood for all cases but 1A.

To meaningfully estimate risk to patients and the firm, we must understand our process data and integrate test measurement aspects into our risk-based validation strategies. Good risk management tools will dictate how much assay performance characteristics can deviate from the ideal. This will then set limits on how much we can tolerate over time for a test method to deviate from ideal (100% accurate and precise). It should also now become apparent why it is so important to maintain our validation status with an AMM program. When this is ignored, we negatively affect all four cases. (Negative here means increased risk to patient or firm). Although undetected, negative effects will occur for the "invisible" cases 1B and 2B because measurement errors are not captured by regular SPC. This may also cause the lack of process understanding and control, and may also lead to conflicts with current regulatory expectations (process analytical technology [PAT]) and may impact a firm's profits in the long run.15


Table 1. Analytical method transfer (AMT) execution matrix.
Validated analytical methods can be transferred from one laboratory to another without the need for revalidation at the receiving laboratory.9,16 A typical AMT is accomplished by testing at the sending and receiving laboratories in a round-robin format. Testing is performed on three different product lots over three days, using two operators and two instruments in each laboratory.9,16 Reproducibility of test results, within and between laboratories, is demonstrated in Table 1 by evaluating intermediate precision (different operators, instruments, days and product lots at each site) using an analysis of variance (ANOVA) and by comparing the differences in mean results for each lot between both sites.9,16 For each AMT, preset acceptance criteria for intermediate precision and for the absolute differences between sites are derived and justified from the validation at the sending laboratory.9

The AMT reports should include descriptive statistics (means, standard deviations and coefficients of variance), comparative statistics (ANOVA ρ-values) for inter-laboratory results, and the differences-of-mean values for both (or each) laboratories. Each report documents evidence that the transferred test method is suitable (qualified) for testing at the receiving laboratory.

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