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Hello,
I have a question to pose regarding acceptance of parts of bio-
analytical runs. I believe it is not OK to accept parts of runs,
here is the scenario:
LC/MS/MS run:
12 total QC samples are analyzed, 3 replicates at diluted (1:200),
Low, Mid and High
ranges. Calibration curve looks acceptable.
All replicates at the low, mid and high QC pass but all 3 replicates
at diluted (1:200) QC fail.
The thinking is to accept the analytical run for any samples that
were not diluted and reject any samples that were diluted.
I disagree because the guidance clearly states that you cannot have
multiple failures at the same level. Here, I am talking about 100%
failure (all 3 replicates failed) for diluted QC.
Any suggestions will be helpful.
Thanks
Anila
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The following message was posted to: PharmPK
You have fulfilled the guidance's requirements for an acceptable run
for only those samples that were NOT diluted. Your QC's passing
proves that both your sample prep and analysis for regular samples is
valid. The failure of your diluted QC says that there may have been
an error in the preparation of your diluted samples.
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In my opinion it does not meet the guidance criteria and the whole
batch should be repeated. Diluted QC should be treated as regular QCs
and acceptance criteria does apply to diluted QCs as well.
The right way to do is to identify the cause for dilution error, fix
the problem and rerun the whole batch.
Best regards,
Sue
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The following message was posted to: PharmPK
Dear anila
Let me know whether have you performed dilution
integrity parameter during the validation process.
Based on these results you need to dilute your study
samples, then there will be no issues about the
dilution. The other possibility, the dilution may be
wrong. You need to run the whole batch again.
Wish you goodluck
G.Venkatesh
PhD Research Scholar
Drug Research Centre
University Science Malaysia
Penang,Malaysia
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We just had an audit recently and this was brought up. Another point
I want to make as explained to me by an auditor is that if the
question is about dilution integrity then working standards are
diluted from the stock as well and therefore dilution integrity
applies to standards in the similar manner as the diluted QCs and
diluted standards. In summary, the whole batch is questionable. The
whole batch should be repeated.
Sue
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Regarding the situation where the all regular QCs and standards
passed for a run, but diluted QCs (1:200) failed, from the limited
information in the message, it appears most likely that there was a
problem with the dilution process for QCs and samples. What does
your SOP on run acceptance/rejection say that you do?
If you have no SOP, then it would be best to reject the run (and
write the SOP). If you have an SOP, but it is ambiguous or silent
regarding this situation, you could investigate, and document the
conclusions of the investigation, and accept the undiluted samples
(assuming the conclusions support it), but be prepared to be
challenged by auditors and others. If your SOP or method allows
acceptance of an undiluted portion of a run and rejection of data
from the diluted portion, then make sure you haven't overlooked
anything and document clearly what was accepted and what was rejected.
As others have already noted, other questions besides dilution of the
samples and QCs may lead you to decide it is simpler to reanalyze all
the run samples.
Thomas L. Tarnowski, Ph.D.
Bioanalytical Development
Elan Pharmaceuticals
ttarnowski1.aaa.aol.com
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Dear Anila,
The scientific judgement to accept the batch or the
part of the batch lies with the procedure to process the samples. If
they are processed in batches, then only that processing batch can be
rejected. Second best answer is that you have proved in method
validation that they pass very fine. If yes then they should meet the
acceptance criteria. The other best way to proceed is to check the
aqueous part first or the extracted QC samples in test run. If they
are ok, then they should be bulk spiked.
Regards
Deepak jain
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Hello Anila,
I did not think dilution of QC's was required for the Bioanalytical
validation process. However the question really is if the dilution
was 200 times for both analyte and internal standard (which I presume
is in use). the dilution being consistent would render a similar
ratio for analyte area/internal standard area as for the non-diluted
samples. If not a factor needs to be applied.
Anisha
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