Warning letter / Glenmark, Goa, India /FEI 3004672766 / MARCS-CMS 637314/ 320-23-04/ NOVEMBER 22, 2022/ Observation 3

Failure to have appropriate procedures for the integration of chromatographic peaks and for the review of chromatographic data processing.

An example of manually entering timed integration events into the processing methods and reporting passing results without adequate procedural controls or justification was identified. Analyst manually modified the processing of chromatographic data of impurity peak. The impurity results would not have met release specification if the automatic integration processing had been applied in the same manner as they were to the standard and other peaks.

Chromatographic data integration procedure is inadequate because it does not indicate when the analyst can manually input timed integration events, how these events should be used, or how they should be reviewed. The procedure does not require supervisory approval for manually entering timed integration events, a review of the original system integrated chromatogram and justification for manually entering the timed events.

(The citing of the deficiency in the USFDA 483 (Inspection May 12-20, 2022) reads that : Even though the analyst is manually setting where the integration lines will be placed with the percent liftoff and percent touchdown, the practice is not captured in the requirements of CM/QC013 for manual integration. Manual integration requires supervisory approval and capture of the original system integrated chromatogram and the chromatogram after manual changes for justification. However when the analyst manually entered the timed integration events into the processing method, the original Apex Track integrated chromatogram was not saved for review and justification of the changes. Only the final chromatogram is saved.

USFDA 483 / Glenmark, Goa, India /FEI 3004672766 / Inspection Dates: May 12-20, 2022/ USFDA Inspectors Justin A Boyd & Jose M Cayuela)

B. The calculations for setting the minimum area for peak integration of related substances are not recordedor reviewed by quality. During the inspection, an analyst was asked to calculate the minimum area for analysis of a batch of tablets. The minimum area which was used during analysis was calculated incorrectly. The change in the minimum area did not change the reportable result. However, since the calculation is not recorded, the reviewers could not detect if the wrong minimum area is calculated and used in the analysis. There is a lack of assurance the required peaks of interest have been integrated in the chromatographic analysis.

In response, firm performed a retrospective review of a subset of U.S. finished drug product to verify the minimum area used in the processing method against the actual calculated minimum area. Numerous finished drug product samples were identified in which the minimum area used was greater than the calculated minimum area. However, no results were observed to be out of specification.

Your response is inadequate because you did not commit to performing a retrospective review of all chromatographic data associated with setting the minimum area for related substances to include materials such as active pharmaceutical ingredients.

In response to this letter, firm to provide:

A comprehensive independent assessment of the laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Include an assessment of all test methods and procedures used by the firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of laboratory system.

A management strategy for the firm that includes the details of global CAPA. The detailed corrective action plan should describe how the firm intend to ensure the reliability and completeness of all data generated by the firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

A copy of the analytical method validation report for (specified) tablets. Indicate if the method validation included manual integration and rationale for this practice in commercial batches.

A copy of force degradation studies for (specified) tablets.

Failure to have appropriate procedures for the integration of chromatographic peaks and for the review of chromatographic data processing.

An example of manually entering timed integration events into the processing methods and reporting passing results without adequate procedural controls or justification was identified. Analyst manually modified the processing of chromatographic data of impurity peak. The impurity results would not have met release specification if the automatic integration processing had been applied in the same manner as they were to the standard and other peaks.

Chromatographic data integration procedure is inadequate because it does not indicate when the analyst can manually input timed integration events, how these events should be used, or how they should be reviewed. The procedure does not require supervisory approval for manually entering timed integration events, a review of the original system integrated chromatogram and justification for manually entering the timed events.

(The citing of the deficiency in the USFDA 483 (Inspection May 12-20, 2022) reads that : Even though the analyst is manually setting where the integration lines will be placed with the percent liftoff and percent touchdown, the practice is not captured in the requirements of CM/QC013 for manual integration. Manual integration requires supervisory approval and capture of the original system integrated chromatogram and the chromatogram after manual changes for justification. However when the analyst manually entered the timed integration events into the processing method, the original Apex Track integrated chromatogram was not saved for review and justification of the changes. Only the final chromatogram is saved.

USFDA 483 / Glenmark, Goa, India /FEI 3004672766 / Inspection Dates: May 12-20, 2022/ USFDA Inspectors Justin A Boyd & Jose M Cayuela)

B. The calculations for setting the minimum area for peak integration of related substances are not recordedor reviewed by quality. During the inspection, an analyst was asked to calculate the minimum area for analysis of a batch of tablets. The minimum area which was used during analysis was calculated incorrectly. The change in the minimum area did not change the reportable result. However, since the calculation is not recorded, the reviewers could not detect if the wrong minimum area is calculated and used in the analysis. There is a lack of assurance the required peaks of interest have been integrated in the chromatographic analysis.

In response, firm performed a retrospective review of a subset of U.S. finished drug product to verify the minimum area used in the processing method against the actual calculated minimum area. Numerous finished drug product samples were identified in which the minimum area used was greater than the calculated minimum area. However, no results were observed to be out of specification.

Your response is inadequate because you did not commit to performing a retrospective review of all chromatographic data associated with setting the minimum area for related substances to include materials such as active pharmaceutical ingredients.

In response to this letter, firm to provide:

A comprehensive independent assessment of the laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Include an assessment of all test methods and procedures used by the firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of laboratory system.

A management strategy for the firm that includes the details of global CAPA. The detailed corrective action plan should describe how the firm intend to ensure the reliability and completeness of all data generated by the firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

A copy of the analytical method validation report for (specified) tablets. Indicate if the method validation included manual integration and rationale for this practice in commercial batches.

A copy of force degradation studies for (specified) tablets.

The FDA observation and the Warning letter asking for a comprehensive assessment of laboratory practices and methods calls for a radically different way of looking at control and oversight of laboratory practices.  Firms need to look deeper into the practices and control and procedures to address all possible areas that could be left out – e.g.  is it detailed when and how manual integration can be performed, how manual integration is controlled, whether the raw data review cover all checkpoints or variables due to human discretion (like setting of minimum area or area reject or integration events). And not only in review of chromatographic data, but all other areas where human discretion and related variability is a possibility. Also the Warning letter shows how responses to 483s need to be comprehensive without leaving open ends – eg: when the observations indicate gaps in procedures and practices citing few sample instances, the response should address Firm’s commitment to review all possible impacted areas; if a reduced evaluation is proposed (that do not cover 100% of past events) it should be supported with firm logic and justification. No room for shortcuts!!!

Specifically,

• Procedures for Manual integration in chromatography should be well defined, when manual integration is allowed to be performed (possible scenarios with pictures / screen shots of chromatograms), how and what type of manual integration is allowed to be performed and what is not allowed.
• Ensure adequate controls on Manual integration – Supervisor &QA approval through a Manual integration request, request shall explain reason for manual integration; After manual integration there should be a review of the original integration and manual integration and approval by supervisor and QA. This should be captured in procedures and implemented well. Have specific check points in analytical review checklist which checks aspects such as:
  • Whether any manual integration is performed
  • Is the Manual integration authorized
  • Is the manual integration appropriate and justified.
  • Is both original integration and manual integration chromatograms saved/printed.
  • The rationale and justification should be detailed enough and clearly explain why the system integration (autointegration) is not a true picture of actual level of impurities / quality; Provide comparison table between system integration and manual integration results where relevant and elaborate.
• The minimum area (or area reject) is an important chromatographic integration parameter which can make a difference between a passing and failing batch. Document the basis for minimum area, calculation involved where applicable (e.g. if minimum area is on the basis of a dilute standard injection, document the details). Review of the chromatographic integration events including minimum area should be part of analytical documentation and review with a checkpoint in checklists.
• Analysts and reviewers should be well trained and competent in chromatography analysis, integration. There should be a proper mechanism for competency evaluation and qualification of the analysts. (Many times, simple procedures are adopted for qualifying analysts by providing simple, easy to analyse samples; A good qualification process should involve complex samples and possibly qualification samples with both passing and failing results).
• Make sure the responses to FDA on inspection observations is comprehensive and without loopholes which agency may pick. Then the issue or deficiencies becomes more complicated than original 483 itself. Investigate all possible aspects / areas (like impacted product batches, raw materials), document what is investigated & evaluated; and if certain aspects are not required to be investigated, provide a rationale for the same. Provide all supporting information – e.g. chromatograms in normal view as well as zoom, integration events, audit trails. The agency should not get an impression that investigation is not thorough, not open and transparent. 

• FDA is calling for an independent assessment of laboratory practices, procedures, methods, equipment, documentation, analyst competencies, assessment of all methods, method validations. Independent, competent GMP expert(s) will need to be engaged for a comprehensive review of all aspects FDA has asked for with a detailed documentation of each area assessed. Perform the assessment with a protocol and checklists looking at – what are the gaps, what are the strengths, what remediation actions will be implemented against gaps for further strengthening the system and timelines for the same in each area.
• The remediation plans to include enhancement of the chromatographic practices and procedures, manual integration procedures, enhanced monitoring of the practices with elaboration of documentation and analysis review checklists. Improve the analytical documentation, documentation review and review checklists covering all gaps – manual integration, minimum area, other system suitability criteria
• A comprehensive program for enhancing competencies of analysts and reviewers, training and coaching, requalification of analysts with complex samples, competency tests.
• As a global CAPA FDA has also asked for measures to ensure reliability and completeness of all data generated by the firm. This will require a documented assessment of current systems, procedures, controls in different areas (such as but not limited to Microbiology, Manufacturing, Engineering), identify potential areas of weakness and areas that can be further strengthened and identify actions with timelines.
• Review the specific method for the tablets and the forced degradation data with regard to the specific peak(s), reason for the peak being present both in initial analysis and retest – is it a new degradant / impurity, or it is a sample matrix peak due to complexity of sample matrix, any additional measures necessary (such as but not limited to improving the method, system suitability criteria). Also investigate all raw material analysis defining the scope well (e.g all raw materials within expiry, raw material lots used in finished product batches within expiry).
• Review the procedures and practices for method validation, especially robustness and precision of the method. It will be good to establish where manual integration may be necessary, document it as part of method validation as well as in test procedures. Where the methods give difficult / complex chromatograms – baseline issues, peak resolution issues – review the possibility of improving the methods.