Excerpts from PharmaAQ Expert Forum – “OOS/OOT Investigations – Overcoming Challenges” held on October 22, 2021, online. In this form, several experts addressed several issues raised by the industry participants. Some of those questions have been given below for the reference of other colleagues. In case you are looking for answers to any of these, please do drop us a mail from the contact us page.
- 1. OOS was first reported about 30 years ago in the US and the guidelines have been there for more than 20 years. Why there is still a lack of clarity regarding the same?
- 2. If the root cause is identified based upon literature, then why the experimental study is required as proof?
- 3. If we had two OOS re-occurrences and the root cause given was “X” and during the third re-occurrence, the root cause was identified as “Y” i.e. not similar to the root cause given earlier. How to handle such types of OOS investigations?
- 4. Can we revise the limit of impurities in intermediate while ongoing plant validation?
- 5. It has been observed that in the industry most of the OOS is closed as invalid as compared to valid. However, the auditors contradict it citing a lack of scientific justification.
- 6. What is the recommended approach for handling OOS investigations in case the additional study/re-measurement study results are passing but borderline?
- 7. How to handle OOS due to transient malfunction of instruments?
- 8. If OOS is reported for unknown impurity at a value of 0.24% while the limit is not more than 0.2%. We understand that the unknown impurity has to be characterized and validated. Apart from that what else will be required for OOS closure.
- 9. If glassware contamination reoccurred for the same test by the same analyst, how to justify/rectify it?
- 10. Is OOT is considered for stability only?
- 11. If there is OOS in PSD test for X customer but for Y customer PSD is OK. Then can we dispatch that batch to Y customer?? What do the regulatory auditors expect for that?
- 12. If OOS is observed in the hardness test due to instrument malfunction, how to do an impact assessment on previously released batches.
- 13. If an impurity is reported below the trend in manufacturing batches, does it trigger OOT?
- 14. We were able to identify the reason but were not able to conclude the exact root cause. How to handle such OOS. For example – we are able to conclude OOS is due to contamination but the exact source of contamination was not identified.
- 15. If the limit of impurity is 0.10% and the result of the analysis is 0.09% (OOT batch), shall we dispatch the material?? What is the expectation of regulatory authorities in that case?
- 16. In case of the root cause of transient instrument error what would be the preventive action.
- 17. Is it mandatory to have a correction, corrective action, and preventive action for all OOS, as preventive action taken can’t have the same root cause?
- 18. If no root cause is identified in the laboratory, manufacturing process, sampling and then we send the sample to ARD and after analysis of the samples on LCMS or ICPMS we conclude that impurity was not ionized. In that case how we can close the OOS? Earlier analysis was done on HPLC.
- 19. If an investigation identified that the root cause was the quality of chemical used for analysis and specific that too once a lot of the chemical. How regulator will take it as an impact on previously analyzed batches using same make of chemical and other lots.
- 20. In the case of stability OOS, if the hypothesis study confirms laboratory error, but there are no additional samples for conducting repeat analysis. In such cases, can hypothesis results be considered for final reporting?
- 21. If there is OOS in PSD test for X customer but for Y customer PSD is OK. Then can we dispatch that batch to Y customer?? What would the regulatory auditors expect for that?
- 22. What are the criteria to be considered for OOT instability, eg: Assay and Related substance?
- 23. What is the strategy to do an investigation for Temp excursion in the stability chamber?
- 24. Statistically how many data points are required to decide OOT criteria?
- 25. How to set OOT limit for dual and triple content formulations?
- 26. If OOS is observed in hardness test due to instrument malfunction, How to do an impact assessment on previously released batches?
- 27. If stability specification limit is 95-105%, OOS result of 94% was obtained, and results obtained during re-measurement study/additional study is 95.5%. Can we proceed for repeat testing or can we consider this as a 1.5% difference, which is obtained from the original failure result, is within the 2% analytical variation
- 28. If OOS is triggered in a contacting lab, in that case, is triplicate analysis required from their end or we can consider single analysis only?
- 29. What is the maximum allowable variation from preparation to preparation in an assay method with a specification of 85% to 115%?
- 30. For OOS, can we use fresh sample/preparation for hypothesis, e.g. for water content, assay by titration, etc.?
- 31. If no root cause is identified at phase 1 and phase 2 investigations, does replicate preparation data suffices the batch disposition though it is a part of the procedure. What is your opinion on that?
- 32. As per regulatory guidelines, we cannot blend the OOS batch, but can we blend the OOT batches and dispatch those materials?
- 33. RPN calculation in risk assessment depends upon the thought process of every reviewer/auditor so what will be the standard parameter where both i.e. auditors/reviewer should be in the same platform. E.g. if the company calculates the RPN and puts the risk in a low category but for the same auditors will consider it moderate or high risk. How to justify this?
