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Unexpected Controversy on Best Practices for Bioanalytical Method Validation and Implementation

From: Tata, Prasad N <Prasad.Tata>
Date: Tue, 27 Mar 2007 13:39:12 -0500

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:///>
<outbind://10/> ). 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.


Received on Tue Mar 27 2007 - 14:39:12 EDT

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