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Dear All,
Please share your experience on below mentioned topic.
ANDA was intended to submit to the USFDA. Bioequivalence fasting study
analysis was carried out with validated bioanalytical method. As per
the current AAPS/FDA recommendations incurred sample reanalysis was
done by selecting samples from fasting study and results were within
acceptance criteria.
With the same bioanalytical method Fed study sample analysis was
conducted and at the end of the study incurred sample reanalysis was
done. Unfortunately the results are not within acceptance criteria. In
the investigation it was identified that method is not working
properly for Lipemic samples which generally we get in Fed study
because of High-fat breakfast was given to the volunteers before dosing.
Hence the method was redeveloped to address the precision accuracy
issues with Lipemic plasma. And it is planned to use the second method
for reanalysis of Fed study samples.
1. Is it acceptable by regulatory to use different analytical methods
for Fasting and Fed studies?
2. Will they accept reanalysis results of Fed study samples?
3. In this case what are the experiments we should document in
Investigation?
Please share if you have any different way of investigating this
problem.
Regards
Sreekanth
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The following message was posted to: PharmPK
Dear Sreekanth,
Is there any supplier for such blank matrix (lipemic plasma)?
As long as you demonstrate and document that the method is not working
for a particular case (fed subjects), it seems quite reasonable to
adapt the method and validate it.
Have you really ended up with 2 methods (a difficult situation in
clinical practice, where one would need to know the actual fed/fasted
state of the subject of origin before analyzing every plasma sample),
or did you get a new method which applies to both fed and fasted states?
Also, in a general perspective: according to you, does your experience
suggest that any method validation should include tests to cover human
plasma from fasted and fed subjects?
Best regards
Frederic Massiere
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The following message was posted to: PharmPK
There are suppliers providing almost any kind of matrix. Is the drug
to be
taken pre or post meals? It is more likely that the true absorption and
distribution of the drug is more affected by meals, rather than the
actual
assay of the drug.
Each of these factors should be tested but to develop, validate and
apply
two methods to compensate for interferences will be a great and unwieldy
application in clinical trials. As Frederic noted- how accurately
will you
know which patient samples falls into which category for which
analysis? Or
will you assay all samples with each method and use only those which
best
fit your hypothesis? Not a favored approach. That is why for most
biomarkers and clinical assays and TDM there is a fasting requirement.
How do you know it is the method and not the sampling that contributes
to
the results you are seeing?
Usually in method development and validation there is an opportunity to
compare the effects of feeding or fasting on assay performance.
You do not want to develop two assays for the same material, rather
you want
to define collection or dosing.
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1) Is it the method, dosing or sampling?
2) At what point/concentration does the lipemia affect results?
3) Will you run a test for lipids then use results from that to direct
use of a particular assay? This will be unwieldy at best.
4) Would you not be better served by dosing at a set time after a meal?
5) You should order grossly lipemic matrix then modify the extraction
such that spikes into either matrix give equivalent recoveries.
6) The differences may be due to separation of lipids during repeated
freeze-thaws and inadequate homogenization of the sample prior to
analysis.-See five above-.
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Hi Sreekanth,
To me it is a simple matter of showing interference by the fats in the
blood, which led to the erroneous results.
Milind
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The following message was posted to: PharmPK
Hi
As a part of investigation following experiment i can suggest -
1. We have to prove specificity experiment by comparing STD BL and
LLOQ with lipidemic plasma lot.
2. We have to prove phospholipid experiment and ion suppression
experiment.
3. We have to prove at least one accuracy and precision batch with
re-validated method.
4. ISR again we have to prove with re-developed method for fasted
samples.
5. Reanalysis of fed samples can be accepted if 1st case falls within
acceptance.
kanchan
veeda clinical research
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Run recovery curves in buffer, normal matrix and lipemic. Compare
against buffer
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