USFDA 483 (Aug 2021) & Warning letter (Jan 2022) / Aurobindo Unit 1, India /Failure to investigate critical deviations / USFDA Investigator Rita K Kabaso

Observation 2 (Warning letter)

(Cited in the USFDA 483, as Observation 5.3)

Failure to ensure that critical deviations are investigated and resolved.

• During method transfer there was an instance of failure to pass acceptance criteria for inter laboratory precision (Method precision) due to peak splitting. The investigation into the cause for failure was deficient and did not consider all potential sources. The failing result was invalidated without scientific rationale, failure was attributed to column, replaced the column and obtained passing result (on reanalysis). However the failure was not reported in the approved method transfer report. Also controls are not established to ensure acceptable columns are used in future analysis.
• In the first response (to agency after the USFDA 483) the Firm affirmed that method transfer is completed adequately. Further in second response Firm explained there was an ““interaction of [the] sample with the deteriorated column” to explain why standards in the failing sample analysis set did not show peak splitting and only sample did. Further no equipment (column) controls are proposed to prevent peak splitting in future.

Firm is asked to provide a comprehensive and independent assessment of overall system for investigating deviations, discrepancies, out of specifications & provide action plan for significant improvements in investigation competencies and procedures, quality assurance unit oversight.

Firm is asked to provide independent review of all invalidated OOS:

• where root cause for the OOS is conclusively established as laboratory error, identify all other methods vulnerable to similar errors and take remediation actions
• Where root is inconclusive, perform thorough review of Production related causes (Manufacturing investigation) and identify improvements where required.

Firm should also review all analytical and microbiological method transfers for any discrepancies not described in the approved method transfer reports, take actions to ensure methods have been accurately transferred and are acceptable for use.

Observation 2 (Warning letter)

(Cited in the USFDA 483, as Observation 5.3)

Failure to ensure that critical deviations are investigated and resolved.

• During method transfer there was an instance of failure to pass acceptance criteria for inter laboratory precision (Method precision) due to peak splitting. The investigation into the cause for failure was deficient and did not consider all potential sources. The failing result was invalidated without scientific rationale, failure was attributed to column, replaced the column and obtained passing result (on reanalysis). However the failure was not reported in the approved method transfer report. Also controls are not established to ensure acceptable columns are used in future analysis.
• In the first response (to agency after the USFDA 483) the Firm affirmed that method transfer is completed adequately. Further in second response Firm explained there was an ““interaction of [the] sample with the deteriorated column” to explain why standards in the failing sample analysis set did not show peak splitting and only sample did. Further no equipment (column) controls are proposed to prevent peak splitting in future.

Firm is asked to provide a comprehensive and independent assessment of overall system for investigating deviations, discrepancies, out of specifications & provide action plan for significant improvements in investigation competencies and procedures, quality assurance unit oversight.

Firm is asked to provide independent review of all invalidated OOS:

• where root cause for the OOS is conclusively established as laboratory error, identify all other methods vulnerable to similar errors and take remediation actions
• Where root is inconclusive, perform thorough review of Production related causes (Manufacturing investigation) and identify improvements where required.

Firm should also review all analytical and microbiological method transfers for any discrepancies not described in the approved method transfer reports, take actions to ensure methods have been accurately transferred and are acceptable for use.

The case of this USFDA 483 observation and it getting escalated to a Warning letter is interesting and holds learnings for Pharma Quality teams. Overall the industry well understand the significance of invalidated OOS with laboratory error as root cause and how the regulatory auditors scrutinise the same. A similar approach is taken here in the case of an invalidation of an analysis set during method transfer by the auditor and agency. And the Firm is asked to review the entire OOS investigation process and all invalidated OOS, showing concerns of potential deficiencies in identifying root cause and establishing appropriate CAPAs.

It is not unusual for companies to get discrepancies and deviations during method validation / verification / transfer activities, when performing parameters like linearity robustness precision and so on. The method validation protocol and report will have provision to record and discuss such discrepancies. Many times such issues are handled by logging an incident report like a laboratory error report and conclude the activity by repeating the analysis. A comprehensive investigation, assessment is often missed out, failing to identify the root cause for the discrepancy and corrective actions. Recording such incidents in the reports could be left out, fearing additional queries during regulatory review. But for the regulatory authorities and auditors this leaves the concern of similar events happening during routine testing (and what precautions / actions that need to be taken to prevent the same, defining these in the documented method).

Laboratory analysis deviations, whether it is OOS during batch analysis or incidents during method validations / verifications / transfers / certification of standards and so on should be investigated comprehensively. The investigations should focus on the primary root cause. This only can help in preventing the incidents from recurring or else the actions will only be able to correct the current incident. For example, changing a column and repeating the analysis can solve the failure in method transfer; but only when primary root cause is identified, alert or control measures like additional system suitability checks in the method can be taken to prevent the issue recurring. Using an investigation tool like the Why-Why analysis help in getting to primary root cause. And it is responsibility of the independent Quality unit (Quality Assurance) to ensure the investigation is comprehensive, has been able to establish primary root cause and CAPAs to prevent the recurrence of the issue, rather than only addressing peripheral issues to close the current incident.

Another important learning is that all discrepancies and deviations that happen during method verifications / validations  / transfers should be reported in the respective report. With analytical systems and chromatographic systems having secure electronic data controls and audit trails, discrepancies are easily identified when data is thoroughly reviewed. That is, there is no room for escaping the events from getting noticed.  While performing activities discrepancies do happen. But what is important is how it is handled.

Companies and Quality units will do well to review their method validations – verifications / transfers to assess laboratory discrepancies, incidents, deviation etc. are adequately investigated, primary root cause identified, CAPAs are established & also such discrepancies are recoded in the respective reports. If there are gaps, an extensive evaluation can be performed on current date, identify and implement additional actions and document the same as addendums to the method validation/transfer reports. Extend the assessment to invalidated OOS with root cause as laboratory error as well. Where the root cause for invalidated OOS with laboratory error is inconclusive take up Manufacturing investigations, identify required actions if any. Document all such assessments thoroughly.

The QA (Quality assurance) unit should ensure the investigations are comprehensive when incidents and deviations occur. The investigations performed by the primary agency responsible for investigation of laboratory deviations / OOS (e.g. Quality Control, or Analytical Development functions) shall be thoroughly reviewed by QA to see whether primary root cause is established and CAPAs taken to prevent recurrence &  the reports capture the discrepancies and deviations. If issues with execution or performance of the analytical method / analytical accessories or equipment are identified as root cause for laboratory deviations and OOS, CAPA should have appropriate measures for early detection of issues and / or prevent recurrence during routine activities (like additional system suitability criteria). Personnel (QA as well as other functions) should be trained and coached and the team involved in investigation should have the right competencies for the same.