FDA Warning Letter to Swedish Company - from Microbiology to Maintenance

During a CGMP inspection at Rechon Life Sciences in Sweden, the FDA identified a number of significant violations, as a result of which the manufactured medicinal products are considered ‘adulterated’ within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In addition to the general finding that the company failed to implement and follow appropriate written procedures designed to prevent microbiological contamination of drugs that are considered sterile, including validation of all aseptic and sterilisation processes, the extensive Warning Letter lists a number of more detailed deficiencies. The following summary lists the four main deficiencies in the order in which they appear in the letter, including the most important sub-points.

1. Inadequate control of microbiological contamination (21 CFR 211.113(b))

Observations:

• Operator touched critical surfaces with gloved hands during setup of the aseptic line.
• This practice was permitted in the SOP at the time.
• Videos of the smoke studies showed similar actions (touching critical areas with gloves).

FDA criticisms:

• Contradiction between company presentation and SOP/contents of smoke studies.
• Revised SOP still allows direct contact with gloved hands.
• No trend analysis on environmental monitoring submitted.

FDA requirements:

• Comprehensive risk assessment (including human interactions, air quality, personnel/material flows).
• Remediation plan with time frame.
• Improvements in aseptic practices, QA audits, environmental monitoring.
• Assessment of possible impact on product quality and sterility.

2. Inadequate investigations of deviations and OOS results (21 CFR 211.192)

A. Environmental monitoring (EM)

• Recurring contamination with Gram-negative bacteria and spore-forming organisms since 2022/Inadequate trending
• Inadequate root cause analysis (e.g. ‘conversations in the ISO 7 area’ or ‘sick employees’ as explanation).
• No complete evaluation of all possible sources of contamination.

B. OOS investigation results

• Example OOS investigation for one batch –  explanation of the deviation due to a ‘defective syringe’ without reliable evidence.
• Laboratory result declared invalid without manufacturing verification.
• No retrospective review of  stated identity, strength, quality and purity and other invalid OOS data.

FDA requirements:

• Independent evaluation of the overall system for deviation/OOS investigations.
• Improvements in root cause analysis, QA monitoring, CAPA, SOPs.
• Revision and validation of environmental monitoring.
• Retrospective analysis of all invalid OOS results for US products.

3. Deficiencies in the cleaning and disinfection system (21 CFR 211.42(c)(10)(v))

A. Decontamination procedures

• No validation of the decontamination process (neither coverage nor effectiveness against microorganisms sufficiently documented).
• Repeated contamination with spore-forming organisms such as Paenibacillus provencensis/shunpengii/urinalis, Bacillus infantis, Niallia circulans complex, Metabacillus halosaccharovorans,

B. Residues in production rooms

• Sticky walls/floors to which fibres adhered.
• Residues due to possible interactions between new cleaning agents and surface materials.

FDA requirements:

• Retrospective evaluation and CAPA plan for cleaning/disinfection programme.
• Improvements to cleaning validation, including worst-case scenario analysis.
• Validated SOPs for cleaning procedures.
• Evaluation of possible drug contamination due to residues.

4. Deficient maintenance of facilities (21 CFR 211.58)

Observations:

• Peeling paint, rust formation, blisters on door in ISO 7 room, access to aseptic filling.

FDA requirements:

• CAPA plan for regular, structured plant monitoring.
• Early identification of problems, effective repairs and preventive maintenance.

Accordingly, the FDA requires a CAPA plan for handling OOS results, based on a retrospective assessment of the cleaning and disinfection programme and the implementation of routine, careful monitoring of the operational management of facilities and equipment. Among other things, this plan should ensure the immediate detection of performance problems with equipment/facilities, the effective implementation of repairs, compliance with appropriate preventive maintenance plans, timely technological upgrades of equipment/facility infrastructure, and improved systems for ongoing management review.

Further details can be found directly in the FDA's Warning Letter.