Qvents

Qvents

Discussion forum for Pharma Quality events, Regulatory Actions

Warning letters, 483s, Recalls, Import Alerts, Audit observations

The USFDA issued a warning letter in January 2025 to Sanofi’s API facility in Framingham, Massachusetts. This followed critical deviations observed during an FDA inspection of the facility in July 2024. The cGMP lapses include:

  • failures to investigate deviations comprehensively to establish root causes and corrective actions (CAPAs),
  • deviations from validated manufacturing processes,
  • inappropriate equipment in the microbiologically controlled environments,
  • and delays in closing deviations.

The FDA also observed that the Quality Unit (QU) failed to function effectively and multiple production deviations went unaddressed until FDA inspectors pointed them out.

Deviations Investigation and Handling: More than 20% of bioreactor runs between January 2022 and July 2024 were rejected due to contamination or other quality failures, yet no adequate investigations into critical deviations including microbiological contamination were conducted. The investigations failed to identify all potential contributing causes and document all investigation activities, identify root causes and adequate CAPA. Sanofi repeatedly deviated from their validated manufacturing processes. Manufacturing personnel used a “Pre-Job Briefing” document to handle deviations from validated manufacturing processes, such as pressure build-up and in process leaking events. More than 84 deviations were observed to be still open, some of them delayed by more than 120 -180 days. No approval for extension of deviations was taken, though this was a requirement of the procedure for handling deviations. In its response to FDA Sanofi identified high attrition of trained investigators and process knowledge gap among new investigators as contributing factors

Improper Equipment and Facilities: Operators in microbiologically controlled areas used mobile carts and had to bent down to the floor to manually lock and unlock the cart brakes, despite this being an identified microbiological contamination risk. Sanofi continued to use equipment with a design flaw to establish temporary sterile boundaries for tubing, though this was identified in an earlier microbiology contamination event investigation. Moreover, in response to the FDA, Sanofi changed the earlier conclusion on the equipment design flaw to design limitation and said this required specific instruction and verification of usage to mitigate risk of microbiological contamination. FDA was critical of Sanofi’s response that the design of mobile cart is fit for purpose when used as per SOP, and also not addressing the design flaw / limitation of equipment. FDA asked Sanofi to implement a CAPA plan to ensure routine, vigilant operations management oversight of facilities and equipment including timely technological upgrades.

Quality Unit Failure: The FDA observed that all production deviations are not reported and evaluated and cited lapses sterile process areas like line touching the ground, operator touching helmet or gown and not sanitising hands before handling sterile manufacturing equipment. These were left unaddressed until FDA investigators informed the facility personnel.

With significant deviations reported in the USFDA 483 & Warning letter, FDA concluded that the Quality Unit (QU) is not able to fully exercise its authority and responsibilities.

Remediations asked for by USFDA: Apart from specific measures to identify the gaps observed, the FDA also asked Sanofi for:

  • Comprehensive assessment of the system for investigating deviations.
  • Retrospective and independent review of all investigations of discrepancies, deviations, complaints, OOS results.
  • For invalid OOS determine whether investigations conclusively or inconclusively demonstrate causative laboratory error. Where investigations conclusively establish root cause, identify all other methods and procedures vulnerable to similar root cause for remediation. Where the laboratory error is inconclusive, perform a production investigation and thorough review of production to identify potential manufacturing root causes and operation improvements to mitigate the same.
  • Comprehensive assessment of all drug production processes and ensure scientifically sound program that identifies and controls all sources of variability
  • Detailed program for designing, validating, maintaining, and controlling each manufacturing process including vigilant monitoring of intra-batch and inter-batch variation
  • CAPA plan to implement vigilant operation management oversight for facilities and equipment including ensuring the suitability of equipment, prompt detection of performance issues, effective repair and maintenance, and timely technological upgrades of equipment and facility infrastructure.
  • Assessment of training program effectiveness of all training given to personnel performing or supporting production activities.
  • Assessment and remediation to ensure the Quality Unit (QU) is given top management support and authority, resources, training to function effectively and provision for QU oversight throughout operations.

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