Media Fill and Smoke Studies: FDA's Perspective

In our News dated 30 April 2025, we reported on deficiencies in media fills. The topic is a priority for the FDA! In a recent Warning Letter, media fills were criticised again, as well as deficiencies in smoke studies. What did the FDA criticise?

With reference to 21 CFR 211.113, the FDA complained about unhygienic behaviour, e.g. employees moving too quickly in the ISO 5 area. The unhygienic behaviour was also reflected in two media fills that failed. The FDA criticised the fact that no measures to improve hygiene were derived from this.  

The FDA also criticised the smoke studies in the cleanrooms. Too little smoke was produced to be able to show the unidirectional flow. Furthermore, the smoke studies did not cover the set-up of the system and interventions. In general, the high number of interventions themselves and the design of the room and the filling line itself were also criticised.

The response letter

The company informed the FDA in their response letter that they temporarily suspended manufacturing on the filling lines. They announce an independent review to improve the design. They also promised new smoke studies to identify the risks. An independent consultant has been engaged.

The FDA's demands

The FDA criticises the response letter for lacking oversight of the hygienic behaviour of employees and an investigation into the influence that the unhygienic behaviour practised to date has had on previous products. The FDA would also like to know what improvements are planned in the smoke studies. Specifically, the FDA is demanding:

• A plan that describes how appropriate aseptic practices and cleanroom behaviours will be ensured. This should also include the frequency with which the quality unit monitors aseptic practices and supporting work ("oversight").
• A retrospective review and risk assessment of the impact of poor aseptic practices and cleanroom behaviour on product quality and sterility.
• A detailed risk assessment of all contamination hazards related to aseptic processes, equipment and premises that includes, but is not limited to:
  
  - Identification of all human interaction in the ISO 5 area
  - Details of the equipment placement and its availability, including ergonomic considerations
  - The air quality in ISO 5 area and the surrounding rooms
  - Possible reduction or elimination of aseptic manipulations
  - A layout of the facility
  - Personnel and material flows
  - Timelines and a plan for how and when the results of the contamination risk assessment will be addressed
  - Documented smoke studies (video) under dynamic conditions including the aseptic interventions showing unidirectional flow

Conclusion

Smoke studies should be carried out under dynamic conditions and the usual interventions in the sterile field should be included. The media fills show whether the aseptic process is "under control". And if media fills fail, measures regarding hygienic behaviour must be deduced from this.

You can find the entire Warning Letter on the FDA website.