FDA Warning Letter due to Deficiencies in Cleanroom Design and Condition

In March 2025, the FDA identified serious GMP deficiencies during an inspection of a US manufacturer of sterile OTC products and contract testing laboratories. After the manufacturer's response to the Form 483 report was deemed insufficient, a Warning Letter was issued. The complaints focused on the design and condition of the cleanroom. According to the FDA, the area classified as ISO 5 for the aseptic manufacture of sterile OTC products was structurally unsuitable. There were large, partially dirty gaps with grid inserts between the wall panels and the floor, which meant that there was insufficient separation from the adjacent, unclassified storage area. The pressure differential between the manufacturing and storage areas was also not maintained or continuously monitored. This means that there is neither physical nor ventilation separation, which significantly increases the risk of microbial contamination. In addition, the production area was in a poorly maintained condition, with discoloured light panels, flaking equipment, and residues on surfaces.

Environmental Monitoring and Aseptic Behaviour

According to the FDA, environmental monitoring was also inadequate. Airborne microbial measurements were not performed regularly during production, even though this was required by the manufacturer's procedural descriptions. A particle monitor was positioned outside the critical area, meaning that the measurement results did not reflect realistic conditions. Furthermore, the data was not evaluated before batch release.

The FDA also observed serious errors in the aseptic behaviour of employees. Operators blocked the (unidirectional) air flow, wore non-sterile masks and used non-sterile materials in the ISO 5 area, such as paper towels. During filling, an open container was sealed for several days with only a makeshift cover that was neither sterile nor airtight. The FDA inspectors also described condensation in the container.

Inadequate Media Fill Programme & Smoke Study

According to the FDA, the media fill programme (Aseptic Process Simulation, APS) was also inadequate: only a fraction of the intended units was incubated, and the simulation duration was significantly shorter than the actual production time. The validation of the sterilisation processes was rated as inadequate because no biological indicators were used.  Filter integrity tests were not performed on a batch-by-batch basis.

The FDA further objected to the smoke study. It was also inadequate because the unidirectional airflow in the ISO 5 area was not verified. Instead, the manufacturer had switched off the HEPA filtration, filled the room with smoke, and, after switching on the fans, merely checked whether the room had become smoke-free. In addition, the test had been carried out without the production equipment.

Finally, the FDA concluded that the Quality Unit was unable to ensure compliance with GMP requirements. Due to the severity of the deficiencies, the FDA recommended a recall of all affected sterile product batches distributed in the United States. The manufacturer complied with this recommendation, ceased production and initiated a voluntary recall. Before manufacturing can resume, the FDA requires comprehensive GMP remediation and an assessment by an independent, qualified CGMP consultant.

Please see the FDA website for the detailed Warning Letter to the US manufacturer.