Total Error Concept in Validation of Viral Activity in Cell Cultures

Due to the high variability inherent of experimental recipients, validating biological methods is often a
complex exercise, and following ICH Q2R1 recommendations is not always feasible and/or meaningful.
Linking systematic error and random error to obtain a unique criterion, as defined in ISO guideline, could
be of interest to capture the total variability in biological assays. In this paper, the use of Total Error concept
in the validation of biological assays was for the first time investigated and compared to a conventional
interpretation of the ICH guideline. Both decision methodologies concluded that the assaywas valid from
2.13 to 5.83 log10(CCID50/ml). However, only the Total Error approach using accuracy profile as decision
tool allowed to guarantee that accurate and reliable results will be obtained during the future routine
application of the assay. In addition, the risk to obtain out of acceptance limits results was estimated
using this approach and was found out to be at the most 3.1% irrespective of the concentration level, thus
demonstrating the reliability of the biological assay.