OOS observed in Assay test. ..
During investigation when you found any root cause in Preliminary or hypothesis testing, before planing of re-analysis, Review it thoroughly and plan the negative experiment if required to make the investigation more adequate.
Description of Event:
OOS result observed in Assay test.
Result: 92.0%
-Limit: 95.0 - 105.0%.
Preliminary investigation:
During preliminary investigation checked all possibilities for lower Assay results like calculation error (wrong weight, wrong potency etc.), Standard preparation error (recovery factor of standard and control standard is 99.2%) and all other possible causes for lower result, but no error is identified in preliminary investigation. Hence hypothesis testing is planned.
Re-measurement:
Hypothesis testing is performed to rule out instrument error, vial filling error, dilution error etc.
Same vial result is found similar to initial result, hence Instrument error is ruled out.
Refilled (101.9%) and re-dilution (99.1%) results are found well with in specification limit.
Now most of the investigator will plan the re-analysis as vial filling error is identified.
Now the question is ,
Is above investigation and hypothesis outcome is sufficient evidence to plan the re-analysis?
Yes ,we can .
But this may not be acceptable to many of the Auditors.
So what is the additional investigation and efforts are missing.
My take.
In above investigation re-fillled from final sample solution result is with in specification limit and re-dilution from stock solution is also with in limit(slightly lower- about 3% from re-fillled vial) . So there is no issue with the product quality and no error in sample preparation.
There is something happened during sample vial filling.
How final solution gives lower result during initial analysis and with in specification result from same final solution in re-measurement.
So we can say that the analyst might had not mixed the sample solution after make-up the volume with diluent to make it homogenous solution and filled the solution from upper layer which is having less drug concentration in compare to lower solution in volumetric flask.
So the root cause may be the Non-homogeneous same solution instead of vial filling error.
But this is the actual reason for initial lower assay result, we have to perform the negative experiment to proove that this is the actual root cause.
Negative Experiment:
Plan the expanded hypothesis in a similar manner I. e.prepare final sample solution as per STP and do not mix it after make up the volume with diluent. Fill the vial without shaking the final solution and inject all the solution like blank ,SST ,standard and sample as per STP.
It will definitely give lower result, may not be exactly the same ,but near to the initial result.
This experiment will support to our initial root cause.
Our such efforts in investigation will give confidence to auditor.
During investigation when you found any root cause in Preliminary or hypothesis testing, before planing of re-analysis, Review it thoroughly and plan the negative experiment if required to make the investigation more adequate.
Description of Event:
OOS result observed in Assay test.
Result: 92.0%
-Limit: 95.0 - 105.0%.
Preliminary investigation:
During preliminary investigation checked all possibilities for lower Assay results like calculation error (wrong weight, wrong potency etc.), Standard preparation error (recovery factor of standard and control standard is 99.2%) and all other possible causes for lower result, but no error is identified in preliminary investigation. Hence hypothesis testing is planned.
Re-measurement:
Hypothesis testing is performed to rule out instrument error, vial filling error, dilution error etc.
Same vial result is found similar to initial result, hence Instrument error is ruled out.
Refilled (101.9%) and re-dilution (99.1%) results are found well with in specification limit.
Now most of the investigator will plan the re-analysis as vial filling error is identified.
Now the question is ,
Is above investigation and hypothesis outcome is sufficient evidence to plan the re-analysis?
Yes ,we can .
But this may not be acceptable to many of the Auditors.
So what is the additional investigation and efforts are missing.
My take.
In above investigation re-fillled from final sample solution result is with in specification limit and re-dilution from stock solution is also with in limit(slightly lower- about 3% from re-fillled vial) . So there is no issue with the product quality and no error in sample preparation.
There is something happened during sample vial filling.
How final solution gives lower result during initial analysis and with in specification result from same final solution in re-measurement.
So we can say that the analyst might had not mixed the sample solution after make-up the volume with diluent to make it homogenous solution and filled the solution from upper layer which is having less drug concentration in compare to lower solution in volumetric flask.
So the root cause may be the Non-homogeneous same solution instead of vial filling error.
But this is the actual reason for initial lower assay result, we have to perform the negative experiment to proove that this is the actual root cause.
Negative Experiment:
Plan the expanded hypothesis in a similar manner I. e.prepare final sample solution as per STP and do not mix it after make up the volume with diluent. Fill the vial without shaking the final solution and inject all the solution like blank ,SST ,standard and sample as per STP.
It will definitely give lower result, may not be exactly the same ,but near to the initial result.
This experiment will support to our initial root cause.
Our such efforts in investigation will give confidence to auditor.
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