Media Fills in the Centre of US FDA Warning Letters

As last year already, the paragraph 21 CFR 211.113 "Control of microbiological contamination" is under the top Ten. While this paragraph was listed as number 6 in 2004, it ranked third this time.

What does this paragraph mean? It requires written procedures to prevent microbial contaminations in not sterile and sterile formulations. It also requires the validation of the sterilisation processes.

The FDA warning letter report contains overall 8 citations relative to 21 CFR 211.113. However, a citation can comprise several deficiencies. Therefore, the following detailed evaluation mentions more listed deficiencies than the actual 8 citations:

• Insufficient media fills (4x), three of which are due to not being representative
• Inadequate validation of the sterilisation processes (2x), one of which directly mentions "heat penetration"
• Missing or insufficient monitoring (2x)
• No action limit established for the water system
• Insufficient filter validation
• Insufficient "smoke studies" in the clean room
• Missing protective clothing for personnel
• Returning samples into the process
• Design deficiencies for tanks

Deficiencies relative to qualification and validation aspects are mentioned quite often, but most frequent are mentions with regards to media fills deficiencies. They directly influence the validation of the aseptic process. The agency directly referenced an incorrect PQ when a sterilisation process was evaluated inadequate. The qualification of clean rooms pertained to insufficient "smoke studies." Reason for design deficiencies for tanks is insufficient DQ. Further mentioned deficiencies related to unsatisfactory filter validation.

The following European Compliance Academy (ECA) education courses relate to this area:

Environmental Monitoring – Compliant and Reasonable,
18-19 May in Prague, Czech Republic,

The Validation Manager, 3-Day GMP Education Course,
31 May to 2 June, Vienna, Austria,

Microbiology for Non-Microbiologists,
19-20 October in Berlin, Germany

Author:
Sven Pommeranz
On behalf of the European Compliance Academy (ECA)

Source: FDA Warning Letter Report (will be published shortly)