Recent FDA Warning Letter Notes Validation Failures for Aseptic and Sterilization Processes
June 10th, 2025 // 2:04 pm @ jmpickett
The May 7, 2025 warning letter to Excelvision Fareva noted several departures from cGMP guidelines. One of them was:
‘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)).‘
Specifically, the FDA warning letter stated that the drug maker did air flow visualization studies AKA smoke studies for their ISO 5 tradional aseptic filing line, which is used to fill products for the American market. However, it didn’t show unidirectional airflow. For instance, the FDA investigator noticed that airflow was observed to stagnate, swirl, and move left and right and upward to the air return vent in the room ceiling.
The FDAers also saw several examples of subpar aseptic techniques during manual intervention. This occurred when a redacted item was connected to the ISO 5 or Grade A filling line. Workers leaned against or blocked the air inside that line and extended unsterilized forearms near the drug product, where the bottles were open.
The ISO 5 or Grade A area is vital because sterile drug products can be exposed and be more likely to suffer contamination. The aseptic manufacturing process must be made and executed to avoid contamination dangers to sterile products. Flaws in cleanrooms and aseptic processing lines, or poor execution of aseptic systems can lead to more contamination in vital areas.
The FDA said the company stated it would do new air flow visualizations for filling lines, and to use long gloves before thre were ISO 5 interventions. But FDA said the answer was insufficient because the firm didn’t state how it would enhance air flow visualization or perform interventions in the ISO5 area.
Components of a Successful Aseptic Processing Validation System
FDA guidance demonstrates that a successful aseptic processing system has these four aspects:
- Sufficient operator training, supervision, and skills
- Effective cleaning, maintenance, and disinfection
- Quality assurance operational oversight
- Microbiological monitoring. Sterility assurance means all factors must be validated or qualified, including the AC and heating ventilation systems, material transfer, cleanroom environment, and all manufacturing process steps. These include all sterilization processes and filtration for sterilization.
Your aseptic processing program should have at least three successful media simulations, which should be followed by media simulations every six months. All media failures must be investigated and a root cause analysis performed. Aseptic manufacturing should be done in a conventional cleanroom featuring container filling and stoppering. There should be Grade A laminar airflow, and a Grade B background environment should be used.
If you are filling 5,000 to 10,000 units, FDA regulations state that one contaminated product should trigger an investigation, and a repeat media fill should be considered. After the investigation, two or more contaminated products should lead to revalidation. Remember that FDA inspections for aseptic manufacturing processes are more common today, especially with FDA’s new AI model Elsa being used to choose inspection sites.
