Deficient OOS Investigation and Handling, Cites USFDA 483 to Torrent

Out of specification investigation for API products is deficient.

OOS investigation number OOS/IN/A/ST/17/013 was initiated on 03/06/17 to probe OOS results generated during assay testing at 12M timepoint (25⁰C/60%RH and 30⁰C/75%RH).

As part of hypothesis (Phase 1) a redilution study was not considered using the diluent allowed by the method to rule out any dilution error. Additionally a service engineer for the instrument confirmed that there was no instrument failure during initial or hypothesis testing. However instrument error was still suspected and substantiated by intentionally pumping air bubble into the system and the standard injections yielded results higher than the specification limits. Furthermore since the method validation for solution stability was deficiently established (only for short duration) a second set of samples was analysed in duplicate to invalidate the original failing results.

Passing results of other batches from initial sequence were discarded and retested results were reported without a valid justification. No consideration was given to report the average of all passing results when definitive root cause is not identified.

OOS investigations should be comprehensive, not to be hurried through with preconceived notions of errors / causes. The OOS investigation should give the impression that an investigation process was followed and from this possible causes were shortlisted / arrived at. Many QC labs practice long sequences cubbing many samples for higher throughput of analysis, but this can be counterproductive when errors / discrepancies happen in even one of the samples in a sequence.

• The laboratory investigation (Phase 1A and Phase 1B) during OOS investigations shall be thorough, considering all aspects of possible errors. Avoid preconception of possible errors. (Also refer discussion under Observation 1 / USFDA 483 / Torrent,Indrad)
• When solution stability is established during method validation, consider sufficient sample solutions holding time (to cover usual method exigencies, errors) which will allow repeating the test with original solutions in case of errors. Many time, the solutions could be stable for longer hours, even though the verified solution stability time are shorter. (However during regular analysis, avoid striving to utilize the entire established solution stability time by clubbing several samples in same sequence. The solution stability time buffers will be useful for investigations in case of OOS).
• Limit the number of samples analysed in a sequence to a reasonable small number; Be alert that if some analytical error / instrument error happen during the sequence, all the samples may need to be repeated. Analysis is a technique and process with several variables. Getting right first time results with smaller sequences will be much more productive than long sequences with several samples clubbed.
• Rationalise the results of retest. If possible root cause is identified as instrument error l(for example air bubble in this case), it is obvious that all the samples analysed in the sequence will be repeated. In such cases make a comparison table of initial and retest results and in each case provide justification for how the final results to be reported are arrived at. It is also possible to show that the difference between the initial and retest results of non-impacted samples are not materially significant; hence retest results will be reported. Document the rationale adequately.

• Enhancing the OOS procedure and practices (Refer discussion under Observation 1/ USFDA 483/ Torrent, Indrad). Train the laboratory personnel (QC) in proper application of the OOS investigation logic.
• Make a comparison of the results of retest and initial test for non-impacted samples. Evaluate potential impact of reporting only the retest result and rationalize. 
• Review the solution stability time for all established methods. Identify methods where the established solution stability time are short and review possibility for increasing the time. Accordingly take action for improving solution stability times for analysis.