USFDA 483 to Jubilant cites poor OOS Investigation

Observation 1,1

Failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. OOS was reported in the batch testing of tablets at Contract Testing laboratory (analysis on 28 Sep,2021), the laboratory investigated and no root cause was identified. The investigation report stated that the test was not carried out in an environment where relative humidity is maintained below (stated values) and based on this contracted lab retested new sample and invalidated the result. The test procedure (effective 6 Jan, 2022) do not mention running the test under specific humidity (%RH) conditions. In addition, review of temperature and humidity record confirmed that the contracted lab only maintained the temperature (20 -25 °C) of the lab and did not record/maintain the lab humidity. SOP No. QC059 RB (Effective date 30 Apr, 2022) Temperature Monitoring in Quality Control Department confirmed that only temperature is maintained for the quality control lab. There is no assurance that the (specific parameter) results recorded for the (specified) batch numbers manufactured at the Jubilant represents the true values. The respective CAPA PR#l31905 stated to revise the testing procedure, by incorporating a note “Avoid prolonged exposure of sample in the environment”. It is not sure how this would have changed the outcome of (specified) test results when the test procedure did not have any provision for ensuring the humidity.

 (Redacted information in the 483 in italics)

Observation 1,1

Failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. OOS was reported in the batch testing of tablets at Contract Testing laboratory (analysis on 28 Sep,2021), the laboratory investigated and no root cause was identified. The investigation report stated that the test was not carried out in an environment where relative humidity is maintained below (stated values) and based on this contracted lab retested new sample and invalidated the result. The test procedure (effective 6 Jan, 2022) do not mention running the test under specific humidity (%RH) conditions. In addition, review of temperature and humidity record confirmed that the contracted lab only maintained the temperature (20 -25 °C) of the lab and did not record/maintain the lab humidity. SOP No. QC059 RB (Effective date 30 Apr, 2022) Temperature Monitoring in Quality Control Department confirmed that only temperature is maintained for the quality control lab. There is no assurance that the (specific parameter) results recorded for the (specified) batch numbers manufactured at the Jubilant represents the true values. The respective CAPA PR#l31905 stated to revise the testing procedure, by incorporating a note “Avoid prolonged exposure of sample in the environment”. It is not sure how this would have changed the outcome of (specified) test results when the test procedure did not have any provision for ensuring the humidity.

 (Redacted information in the 483 in italics)

When OOS are invalidated and batches are released, the investigation should establish a very strong rationale for the invalidation of the OOS results. If there are root causes or probable root causes identified, corrective and preventive actions (CAPA) should address the root causes. Mere possibilities cannot be concluded as conclusive root causes; they need to be supported with sound scientific rationale. (For e.g  When lack of humidity controls is identified as root cause for the OOS, adequate rationale / correlations need to be established to show how humidity conditions can influence the specific test parameter and cause failing results; and if this indeed is cause for OOS, CAPA should address requirement for humidity monitoring or control in the QC laboratory).  Companies should have in place several measures to avoid getting into such situations:

1. When specifications and test procedures are being established, adequate validation of the test procedures should be performed. If there are special precautions required for specific products and specific tests, this should be captured in the test procedures. Accordingly, facilities should be provided.
   • (As in the cited case, Forced degradation studies (eg: neutral hydrolysis), study by exposing product to humidity (open petri dish studies) in humidity chambers and to laboratory conditions can help establish susceptibility of the product to humidity conditions. And where drug products results can be impacted by humidity conditions of the lab, appropriate humidity controls should be specified in the test procedure. Where humidity controls are specified for testing, the laboratory should maintain the required humidity conditions. Facilities should be provided for the same in the laboratory and records of humidity in the testing laboratory should be documented and maintained).
2. OOS Investigations should be able to establish most probable root cause(s). In laboratory investigation when direct causes are not identified, investigation can take up hypothesis testing to evaluate probable causes. But a strong and convincing correlation should be established between the discrepancy and proposed root cause(s).
   • (For e.g, in the cited case, Hypothesis testing could have been performed by performing tests at higher humidity (%RH) conditions to show humidity impact on analysis. In the Investigations, earlier batches tested and released could be reviewed, how these batches were not impacted (Was laboratory humidity in better control – time / date / season, are there alternate environmental humidity data). 
3. When no specific & direct root cause /assignable cause is identified during laboratory investigation, detailed Phase 2 investigation (Manufacturing investigation) should be performed and documented. It should look at all other possible causes for a product failure – Manufacturing, Packing, Storage and Handling. The investigation can also look at whether other test parameters of the batch support the invalidation of the initial OOS results -e.g. the batch reported OOS results for  assay, but no increase in impurities / no failure of uniformity of dosage units, dissolution tests etc can lend support to possible laboratory error / sampling error proposed). 
4. Invalidation of the OOS and batch release should not be hurried; Adequate Phase 1 (1A & 1B) and Phase 2 investigations should be performed. An extensive sampling and testing of the batch(es) taking all precautions to avoid any interference of results by proposed causes ( in this case humidity) may also be performed to establish that the batch itself is not impacted and only the specific test result / samples would have been impacted.  The investigation and efforts to establish possible causes should be thorough that an impression is not created the Firm was looking at the shortest root available to invalidate an OOS result and release a batch.

Several of the below measures should be considered as CAPA:

1.    Start recording humidity of Quality control laboratories along with temperature. Define appropriate control on humidity for the laboratory. Perform a risk assessment of %relative humidity (%RH) of Quality control lab on various tests performed in the laboratory. The humidity controls should be in line with the risk assessment. Where humidity controls are important for tests, revise the test procedures with appropriate instructions, notes, specifying the conditions.

2.   Reopen investigation into the cited OOS. Establish strong scientific rationale between humidity during testing and the test results.

3.    Hypothesis testing against protocol, for e.g.: by exposing product to humidity, keeping high humidity conditions during testing with extended exposure to establish correlation between humidity during testing and test results.

4.      Review other batches of the product – with results of the test parameter, date / time of testing of the batches. Review for any correlation of humidity with test results.

5.  If investigation concludes humidity control during the testing to be the root cause, actions to be initiated to ensure all future testing will be performed under appropriate humidity controls. This will require immediate short term measures and also long term measures (eg: portable dehumidifiers for lab, controlling humidity in specific sections of the lab and ensure testing of the product is performed in such controlled areas, upgrading the humidity controls for the entire Quality control lab, specifying the humidity controls in the test procedure for the product and documentation of the humidity during analysis, revising the procedure (SOP) for environmental controls in the Quality control and so on.

6.   In case the review of the investigation is not able to establish a correlation between humidity during testing and OOS results, extend the OOS investigation to establish other possible root causes. Accordingly establish appropriate CAPAs. This will also require evaluation of the impact on all distributed batches of the product.

7.      If the review indicate batches in distribution could be failing to meet specification, take up remediation actions including Recall, Stop distribution, Market withdrawal.

8.  Review the OOS investigation procedure. Enhance the procedure for improving OOS investigations, addressing Phase 1A, Phase 1B and Phase 2 detailed investigations, Hypothesis testing (In line with USFDA / MHRA guidelines for OOS investigations; Also refer discussions under Warning letter / Glenmark, Goa, India /FEI 3004672766 / MARCS-CMS 637314/ 320-23-04/ NOVEMBER 22, 2022/ Observation 1).

9.    Review the procedures and practices for Method validation, Forced degradation studies, Establishment of test methods and procedures. Factors which can impact test results should be evaluated during method development, method validation; such factors should be defined in test procedures with precautions that need to be taken.