Warning letter / Centrient India / MARCS-CMS 640196/ 320-23-06/ DECEMBER 07, 2022/ Observation 3

Failure to establish and follow written procedures for investigating critical deviations or the failure of API batches to meet specifications.

Failed to adequately investigate and determine the root cause of black particles in two batches of API. Investigation report stated the black particles were non-metallic charred product residue, but failed to provide data to support the conclusion.

Firms response indicated installation of (system) to limit presence of metal particles. However, investigation remains inadequate because, firm did not provide the data to support proposed root cause or identify an adequate CAPA. The CAPA does not address non-metallic sources of contamination such as charred product residue or inadequate cleaning or fully address metallic sources of contamination such as reactive, additive, or absorptive product contact surfaces.

Firm to provide:

A comprehensive assessment of overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. To provide a detailed action plan to remediate this system – significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

Investigation of Quality events, identification of root cause and CAPA and documentation should be sound and comprehensive. The investigation conclusions need to be objective (how a conclusion like the black particles in API is non metallic charred product residue is made, and what is root cause for such non metallic black particles, and if the black particle is non metallic charred residue what are the CAPAs for preventing such particles). The CAPA should address the root cause and root cause should be an outcome of investigation. (A system to prevent metallic particle contamination may be good to have, but this do not address the specific issue cited in the investigation and hence the CAPA will not be effective to prevent recurrence of the issue).

The investigations should target to identify the root cause and establish CAPA for preventing recurrence. For example, if the cause for black particles is charred product residue, what is the cause for formation of charred residue and what actions are necessary for preventing the same (Why -Why analysis).

FDA has flagged competency for investigation and overall systems and procedures for investigation of all quality events.

• Firms should have well defined procedure for investigation of Quality events:
  
  • Classification of Deviations, OOS, Complaints etc as critical, major, minor based on nature and impact to product quality, integrity and safety.
  • Process of investigation – Investigation team, Investigation tools (such as but not limited to – Why-Why analysis, Process flow chart, Ishikawa diagram, Fault tree analysis)
  • In the case of OOS investigations:
    
    • Phase 1 (Laboratory investigation)
    • Phase 2 (Detailed investigation)
  • Identification of Probable root causes and CAPA for each of the cause. The identified root cause should be scientifically justified, supported with adequate data.
  •  Remediation action on the impacted batch
  • Impact assessment of the quality event (deviation, OOS..) – other potential products, batches that could have similarly impacted; action on such impacted batches. (e.g if the root cause is charring of product, why this happened in the specific batch, whether similar events can /could have happened in other batches or products, if not why; what actions to be taken for remediation of potentially impacted batches). The scope of such evaluation typically should cover all batches within expiry. 
  • CAPA implementation and CAPA effectiveness verification (assess whether after implementation of the CAPAs, the incidents have stopped or there is improvement in the quality and attributes of products and practices.

• Quality unit and the personnel involved in investigations should have appropriate training and competency. 
• There should be a high level of Quality unit oversight and involvement of senior management in review of quality events and matters. There should be periodic quality review meetings (typically monthly) involving Quality head, Leadership team with defined agenda. The agenda should cover review of quality events and investigations, root cause, CAPA and effectiveness of CAPA, repeat quality events.

• Comprehensive assessment of the overall system for investigation – review for example the investigations of last 3 years deviations and deviations on all batches within expiry;  similarly for other discrepancies, complaints, out-of-specification (OOS) results, and failures (Last 3 years to review a sufficient number of incidents to make an assessment of the system). Perform the assessment against a checklist which include (but not limited to) – scope of investigation, tools used, whether root cause(s) are identified, is CAPA and root cause connected and relevant, is CAPA effective, are there repeat incidents after implementation of CAPA. Document the assessment and conclusions. Also identify further actions due to the assessment – reopening the investigation, additional CAPAs, any market actions (such as recall).
• Develop and implement a comprehensive procedure for investigation (of incidents) addressing all the aspects mentioned above (What companies should do..)
• Training and coaching the personnel who will be involved in investigations – QA, QC, Production, Engineering, R&D, others. Engage professional cGMP trainers / consultants.
• Enhancement of Quality oversight – Increasing frequency of internal audits, establishing an IPQA (Inprocess Quality assurance) structure with personnel reviewing and clearing stages of activities and operations.  Establish procedure for Quality management review with defined agenda and frequency. The agenda should also include review of quality incidents and events and their investigation.