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Dear All,
We are analysing 3 analytes simultaneously. However for one of the analyte, more than 20% batches have failed to meet the acceptance criteria . Can we continue with submission of this study to USFDA or do we need to analyse the failing analyte with new method? Can anyone share their experience in such cases for submission to USFDA? Expert views are welcome.
Dr. Mandar Mote
Asst. General Manager Bio-analytical
Bio-equivalence Division
Macleods Pharmaceuticals Ltd.
Mumbai.
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Dear Dr. Mote,
You can two things :
1) Continue analysis depends on therapeutic importance of analyte which is not meeting 20% criteria e.g. active metabolite for parent drug or isomer form of drug. 2) Alternative, you can use different method for that particular analyte and file an amendement with final USFDA report which mandatory GLP requirment for Bioequivalence study.
Hope, it will be helpful to you.
Regards,
Gaj Jadhav
VRA, Dr. Kompella`s lab
School of Pharmacy
Dept of Pharmaceutical Sciences
University of Colorado, Denver
12700(E), 19th Avenue, Room No.4410A,
RC-2, P-15, C-238,
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TO,
Respected Mandar sir,
I appeciated your query regarding the analysis of 3 analytes in single method. As per my opinion, if we have to provide proper investigation and justification for failurity of batches of one analyte ( more than 20%) which also included in study report. Based on that on we will submit to any regulatory agency. However, Failure batch will not created doubt on the performance of method. We also shows method reproducibility based on the experiments performed during the pre- study method validation phase as well as during study phase- ISR ((Incurred sample reanalysis) as strong support for the performance of method for the its intended use. We also compared the % difference in concentration of Repeated batch (accepted batch) as well as Initial batch (failure batch), if % difference within the pre-defined acceptance criteria of ISR, then it will not issue. if significant difference then it should be justified and accordingly batch or concentration shall be accepted and study shall be submitted. Anoth
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Dear Mandar,
it depends on your protocol and the drug. if for example the two analytes are metabolites for the drug then unless the FDA specifically manadates submission of metabolite data with the parent drug you can do without the simulataneous analysis but this has to be decided from when you have written the protocol for your study because otherwise you have to justify not doing so later. if the protocol says you will do the data submission for all three then you have to re-analyze your failed batches.
the data for re-analysis can be using the same method without regard to the results of the other analytes but you have to specifically state this in your documentation for repeat analysis and what your SOP considers as well. you don't create a new method for the analyte unless it is obvious that it is an issue with the method itself which you need to investigate. in this case new method and new validation and analysis for analyte from all batches regardless failed or not.
this is my experience on this circumstance, I hope it helps
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Dear Mandar,
As mentioned by others, the approach forward would need a complete understanding of the 3 analytes i.e If these are parent and metabolites then a conversion/stability over the assay time/parameters could be clue for path forward, In case these are 3 sundry analytes then cross contamination and other possibilities should be evaluated (I hope this would have been evaluated already). If as per your study protocol you need only single analyte for Bioavailability evaluation then you can exclude those analytes. But a scientific justification for same has to be captured in the final report. As you will be aware that these concern was addressed in third American Association of Pharmaceutical Scientists (AAPS)/Food and Drug Administration (FDA) Bioanalytical Workshop. As per the report published
* Characterization of unique and/or major metabolites, should proceed using a flexible," tiered " approach to bioanalytical methods validation. But incase the application is intended for clinical study samples estimation, then a complete validation is recommended.
* If this behavior was not observed during validation and has come up during study samples analysis than the final decision as to the extent and nature of the incurred sample testing is left to the analytical investigator, and
should be based on an in-depth understanding of the method, the behavior of the drug, metabolites, and any concomitant
medications in the matrices of interest.
Finally if you are proceeding for a reanalysis then not to forget;
* In the case of multi-analyte assays (simultaneous measurement of multiple analytes in each sample), when samples are reassayed only for 1 analyte (eg, because the analyte failed to meet acceptance criteria in the original assay), the raw data collected for the other analytes should also be retained.
Hope it would help to clear your concerns,
Regards,
Kuldeep Sharma
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Why are the batches failing? Precision? Accuracy? Linearity? Stability?
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Dear Mandar
As per my experience don't submit this study to USFDA because they may raise so may points during audit example why batches are failed, show investigation report, they will check intial value and repeat value (% difference not more than 20%). so better way to develop new method or separate method for 3 analytes.
chaitanya pednekar
Watson India Pvt Ltd
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