Data Integrity issues
- Analysts documented testing processes and recorded passing results for identification testing by chemical analysis in the Packing Material Laboratory though they were physically not present during testing.
- Viatris acknowledged that both its site and global quality organization were aware of the data integrity issues and Senior Quality management officials violated data integrity policies. The company committed to implementing a data integrity remediation plan and appointing a Data Integrity Compliance Lead.
The response was found inadequate by FDA. FDA asked the Firm for:
- Complete assessment of documentation system throughout Manufacturing and Laboratory Operations
- Comprehensive investigation to find extent of inaccuracies and failures (including interviews with current and former employees)
- Risk assessment of effect of observed failures for potential impact
- Declaration whether persons responsible for the DI issues are still able to influence cGMP data (Or in effect a confirmation whether they have been replaced or relocated)
- Global CAPA plan and management strategy to ensure the reliability and completeness of all data generatedÂ
OOS Investigation – Lack of rigor to identify root cause and evaluate impact
- Instances of Out of specification and Out of Trend reports (OOS, OOT) were observed where analysts had aborted the chromatography sequence without recording sufficient justification. OOS results were invalidated without scientific rationale; An OOS assay result was attributed to column leakage though the instrument audit trail did not record any such error. Viatris acknowledged laboratory investigations on OOS incidents were inadequate and committed to perform extended evaluation of the laboratory practices and control.
FDA considered the response inadequate and pointed out the Firm repeatedly accepted such OOS conclusions despite insufficient justifications. It asked the Firm for:
- Independent retrospective review of all invalidated OOS for last 3 years
- identify whether the investigations conclusively or inconclusively demonstrate causative laboratory error.
- For investigations with conclusive laboratory error, identify all other methods vulnerable to same root cause and extend the remediation
- For investigations where laboratory error is inconclusive, perform comprehensive manufacturing investigation including evaluation of deviation history, complaint history, adequacy of process and manufacturing steps and process capability.
- Comprehensive review OOS investigation system and remediation plan
- Comprehensive review of system for investigating all failures – deviations, complaints, discrepancies, OOS
- Independent assessment of CAPA program and remediation
- Independent assessment of all lab practices, procedures, analyst competencies, equipment, methods and remediation plan
Data integrity issues and deficient OOS handling are frequently cited deviations in FDA audits. A deeper evaluation of the root causes often reveal systematic gaps that create the grounds for such failures.
- Inadequate supervision and monitoring of shopfloor / laboratory activities.
- Inadequate document review system which fails to identify lapses
- Ineffective Internal Audits – frequency could be too low, auditors lacking competency to audit the functions
- Weak management controls – Lack of conviction and will to take prompt and bold corrective measures.
- Predetermined conclusions of OOS incidents like such as deeming OOS as invalid, attributing the root cause to laboratory error often lead to investigation efforts being narrowly focused on confirming these assumptions.
- Weak Quality Culture orientation
A robust quality system must ensure data integrity, effective control over facilities, processes, operations, and prompt identification of deviations and discrepancies and firm corrective actions. It requires Firms to:
- Strengthen supervisory and shopfloor control and monitoring
- Implement effective in-process quality assurance (IPQA) checks.
- Effective internal audits, unannounced audits with competent audit & compliance team.
- Strengthen Quality management leadership who take prompt actions when deviations are observed.
- Have consistency in OOS investigations – evaluating all probable causes, extensive hypothesis testing rather than concluding the OOS with only select evaluation and testing of predetermined assumptions. Strengthen the OOS investigation system, procedures and checklists and build awareness in the team. Case studies using internal OOS incidents, industry Form 483s and Warning letters are a very useful tool for imparting awareness and enhance the team skills
- Similar enhancements must be taken up with all deviation investigation systems and procedures like complaint investigations, failure investigations to prevent skewed investigations and assignment of predetermined root causes. Afterall OOS is also a deviation.
- Foster a strong Quality culture with regular programmes to build awareness, small group workshops to identify underlying issues and corrective actions. Engage a team of internal and external experts, to coach, guide and mentor the team.
Critical data integrity failures and lapses in OOS investigations that fail to identify root causes with scientific rationale require a comprehensive assessment of systems and processes. This assessment must identify vulnerabilities in the quality system, the extent of failures across operations, their impact on product quality and safety, and implement effective remediation measures. The measures shall include:
- Assess Documentation Systems: Evaluate SOPs, protocols, and associated documentation practices against a well defined protocol and checklist to identify gaps and corrective actions.
- Investigate Failures: Conduct detailed reviews of all cGMP documentation across manufacturing and laboratory functions. Objective of the review is to detect data manipulation and / or inconsistencies between activities documented and attendance records of personnel, electronic records from equipment and instruments etc. This shall cover all cGMP document generated over a defined period of time – batch records, analytical records, calibration records, maintenance records, logbooks…so on and so forth.
- Risk Assessments: From the above investigation, list out all the failures / gaps identified. Analyse the impact of each failure on product quality, patient safety, and regulatory compliance. Evaluate secondary or alternate control which could reduce or eliminate the risk of observed failures. Identify actions to address the risk (e.g. product recall where product quality and safety is compromised) as well as the mitigation actions to prevent recurrence of the issue
- Redeploy /Replace Individuals responsible for DI issues: Promptly redeploy or replace personnel involved in data integrity violations such that they will not be able to influence cGMP documentation
- Review Invalidated OOS: Segregate investigations into those where laboratory error is conclusive and where it is inconclusive. Conclusive laboratory errors are those in which a link between the projected root cause and OOS result is clearly established. For example a column deterioration giving a series of chromatograms with poor peak shape resulting in OOS result or an obvious dilution error resulting in abnormal assay like 50% or 150% of expected results are OOS where laboratory error is conclusive. Projected causes like column leakage, air bubble in the HPLC system or analyst error in sample preparation etc. are all examples of inconclusive laboratory error. Where laboratory error is inconclusive manufacturing investigations must be performed to assess whether the OOS is due to any manufacturing related causes. Even where the laboratory error is conclusive, identify all other similar test methods and procedures vulnerable to similar error and extend the identified CAPAs to all such methods.
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