Unexpected Controversy on Best Practices for Bioanalytical Method Validation and Implementation

Sylvian: In my personal and honest opinion the controversy regarding the incurred samples as QCs is rightfully justified. as the 2000 Bionalaytical guidance is working fully well like a well oiled machine. Introducing this incurred samples analysis as a requirements throws monkey wrench on the usual way of sample analysis. The merits of introducing incurred samples as additional QC measure for establishing the robustness of the method is that The QC are usually prepared from health subjects but not from the sample population as that of study subjects. Fine... we do method specificity and sensitivity for this same reason, rule out the interferences from OTC products and metabolites of the drug under investigation and metabolites of any other co administered drugs. Having said this, School of thought proposing this incurred samples analysis should be aware of sampling limitations those it mean additional pre-dose blood collection, can we do incurred samples from cancer subjects???, even on theoretical basis there seems to have some merit of doing incurred sample analysis as part of the routine sample analysis, in my honest opinion it is nothing but an academic mulch, with remote and doubtful advantage in the NDA work of New Medical Entities and lignad binding assays for Biotech products. But what is the rationale of introducing incurred sample analysis for generics? It is not an unexpected controversy but it is a controversy generated out of its own roots. I wish someone will take up the issue with the concerned folks to the FDA and other global regulatory agencies to gain exemption from this controversial incurred samples if not in entirety at least for generic products. Hope this explanation helps. Prasad Tata, Saint Louis "Unexpected Controversy on Best Practices for Bioanalytical Method Validation and Implementation" Recently, an AAPS workshop was held to review and consider updates to the guidance for bioanalytical method validation and implementation (Crystal City III meeting, May, 2006; http:// http:/// www.aapspharmaceutica.com/meetings/pastmeetings <outbind://10/www.aapspharmaceutica.com/meetings/pastmeetings> ). The meeting focused on "best practices" for both chromatographic and ligand binding bioanalytical methods. Some of the topics discussed at the included: Standards and quality control (QC) criteria Best practices and acceptance criteria for method validation Acceptance criteria for analysis of study samples Similar topics were also discussed for chromatographic assays except the focus was somewhat different, for example: Spacing of QC standards for analysis of study samples Concerns for the accuracy and reproducibility of bioanalytical results Documentation issues Automated and manual chromatographic peak integration methodology However, the topic that generated the most controversy was a proposal for the "reanalysis of incurred samples". This proposal was presented in the context of a discussion of sample assay reproducibility and "what needs work"?. Reanalysis of incurred samples refers to the reanalysis of a randomly selected portion of the study samples to determine whether the original analytical results are reproducible. The amount of the original analyses to be reanalyzed was not determined. Ideally, the validation of the bioanalytical method would have established reproducibility of the analytical results prior to the sample analysis. This additional effort would be unnecessary, but the "reanalysis of incurred samples" implies additional test of reproducibility for each set of unknown study samples that are analyzed. Although the technical bases for a lack of assay reproducibility were not clearly expressed, possibilities might include: (1)the presence of an unstable metabolite(s) in the study samples that could decompose and release the analyte(s) (2)variability in the sample preparation procedures. Ideally, both of these potential issues would be addressed during the validation of the bioanalytical method and by adherence to good laboratory management practices. However, comments by regulatory agency meeting participants suggested that lack of sample assay reproducibility had been observed randomly, and that additional assurances of study data integrity using incurred sample reanalysis are needed. In summary, this technical discussion of best practices for bioanalytical method validation and sample analysis produced an unexpectedly spirited discussion of the most appropriate way to demonstrate the reproducibility of bioanalytical results. A scientific and regulatory consensus on this issue has yet to be defined, but in the interim, it appears that sponsors are expected to initiate a practice of routinely reanalyzing a subset of incurred study samples. I would like to know what are the members experience with the above and/or comments on reanalysis of incurred samples.