Warning Letter to US Manufacturer of Sterile Medicinal Products - Part 2

An FDA inspection in February 2022 at Calgene 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 FDA reference appropriate chapters in 21 CFR Part 211. In this case, chapters 21 CFR 211.67(a) and (b) and 21 CFR 211.113(b). Part 1 dealt with particulate contaminants. Part 2 of the news addresses inadequate cleanroom behaviour by company employees.

"Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b))."


The inspector observed inadequate aseptic working techniques by operators while performing interventions during production. Observations included the following:

  • An employee leaned into the aseptic filling area, resulting in disruption of unidirectional airflow over open vials. Vials on the line that were at particular risk of contamination were not subsequently cleaned 
  • An employee left the door to the filling area open for an extended period of time 
  • Inadequate operator practices in handling vial tray containers

What was further criticised:

  • (b)(4), presumably sterile forceps, were stored outside the filling area. This storage location increases the risk of contamination 
  • The SOP "Personnel Conduct in the Sterile Core" did not specifically require personnel not to interrupt unidirectional airflow during procedures

Overall, the FDA lacked a robust concept of operations with appropriate procedures and also sufficient staff discipline.

Company response

The firm's response that it had made appropriate improvements in its programme to monitor personnel in the aseptic area was not sufficient for the FDA. From FDA's perspective, what was missing was:

  • For all products on the market within the expiration period, a risk assessment related to inadequate aseptic practices 
  • A statement of whether available videos were reviewed with respect to the inadequate practices 
  • An aseptic behaviour procedure that describes how observations are documented and evaluated to determine if noted aseptic deviations affect the sterility of the drug product

What does FDA expect in response to this Warning Letter

  • A plan to ensure appropriate cleanroom practices during production. This includes steps to establish routine quality oversight on all production batches. Appropriate frequencies of monitoring during aseptic production and supporting activities should be defined. 
  • A thorough retrospective risk assessment to determine what impact inadequate aseptic practices have had and continue to have on the quality and sterility of the drugs produced. 
  • A comprehensive risk analysis of all contamination hazards with respect to the aseptic process, equipment and premises.

Further expected is an independent evaluation with regard to:

  • All human interactions in the ISO-5 room 
  • The placement of equipment and ergonomic conditions 
  • The air quality in the ISO-5 room and surrounding spaces 
  • The building layout 
  • The flow of personnel and materials

It is expected that a detailed remediation plan with appropriate timelines will be prepared and submitted for this purpose.


Overall a very serious Warning Letter which puts the company's global ability to manufacture in accordance with GMP under scrutiny. Repeated deviations to an inspection in 2021 were criticised. The inefficient quality system with regard to cGMP was also criticised, in particular the lack of an efficient quality oversight system. The "recommendation" of qualified consultants indicates that the FDA does not expect an adequate internal solution to the problems. Corresponding sanctions in case of non-fulfilment of the demands were considered.

Source: FDA Warning Letter to Cangene BioPharma, LLC dba Emergent BioSolution dated10/8/2022

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