Warning Letter to US Manufacturer of Sterile Medicinal Products - Part 1

An FDA inspection in February 2022 at Cangene BioPharma, LCC in Baltimore, a subsidiary of Emergent BioSolutions, resulted in a serious Warning Letter by the FDA on August 10, 2022. Warning Letters by the FDA reference appropriate chapters in 21 CFR Part 211, in this case 21 CFR 211.67(a) and (b) and 21 CFR 211.113(b). Part 1 of the News addresses particulate contamination while Part 2 covers inadequate cleanroom behavior by company employees.

"Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and you failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and (b))."


Inappropriate equipment in aseptic manufacturing resulted in particulate contamination. Customers complained about foreign particles (i.e metal particulates) in the medicinal products. Investigations into this issue revealed that the cause was tray units. Metal and other particles were attributed to the manufacturing process, but further measures were not deemed necessary. From the FDA's point of view, the procedure for maintaining the tray units was inadequate. While the relevant SOP called for visual inspection of trays prior to use, there was no specific requirement to document activities such as inspection / identification / segregation / repair, etc. of defective trays. 

Response from the company

The company responded to the effect of initiating an improved inspection of all tray units and repairing or replacing all defective trays. The SOP should be revised accordingly.

This response was not sufficient for the FDA. The authority lacked evidence that the tray units were fundamentally fit for their intended purpose. It also lacked a systematic review of the preventive maintenance / servicing programme, particularly to effectively identify and track the tray units. Further, the FDA missed specifically addressing particle contamination and how to adequately assess and investigate it. 

FDA expectations in response to this Warning Letter

  •  A CAPA plan to implement routine monitoring of facilities and equipment. This should be followed by effective repair management and appropriate preventive maintenance. Facilities and equipment should be brought up to current standards in a timely manner. 
  • A CAPA plan, based on retrospective assessment, that includes corrective actions for cleaning processes and practices. The cleaning programme should be improved. 
  • A comprehensive, independent review and remediation plan for equipment design, control, and maintenance. 
  • A revised process for trays that includes both tray identification and maintenance traceability. 
  • An independent review of the classification and investigation of particulate contamination in the product. 
  • A comprehensive assessment and remediation plan that ensures the Quality Unit has the necessary authority and resources. 
  • An outline of how top management will support quality assurance and proper operations and how resources will be provided in a timely manner to proactively address emerging manufacturing and quality issues. Continuous quality monitoring should be established.

Source: FDA Warning Letter to Cangene BioPharma, LLC dba Emergent BioSolutions dated 10/8/2022

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