Warning Letter due to Inadequate Pressure Stage Concept and Particle Monitoring

An Indian pharmaceutical manufacturer has recently received a Warning Letter from the U.S. FDA due to deficiencies in the ventilation system and the maintenance of pressure levels as well as in particle monitoring in the aseptic processing area. In addition, the microbiology testing was also criticized.


According to the FDA, the pharmaceutical manufacturer producing vials of injections for the U.S. market has not met its obligation to identify microorganisms from the aseptic processing areas. The manufacturer's internal regulations require the identification of microorganisms if they are morphologically different from those already identified. However, according to the FDA, this has almost never happened. In 2019, only one organism of the 6,360 microorganisms isolated in the ISO 7 purity class was identified. Furthermore, the identification was only attempted visually using an incomplete photographic library. Also, a gram stain was often missed, so that the information whether it is was sporeformer is not available.

The FDA also disapproved the endotoxin testing of water samples and criticised the performance of the test by a laboratory employee. He/She did not perform critical steps in the sample preparation and used a non-calibrated wall clock for time-critical steps in the procedure. According to the FDA, both of these can yield false negative test results.

Aseptic production area

According to the FDA, the Indian manufacturer lacks a system that ensures adequate control of the differential pressures between different cleanrooms. The FDA states that pressure differentials are only noted manually and that pressure fluctuations up to the reversal of the flow direction are tolerated. In case of pressure deviations above a certain value, a deviation analysis "may" be proposed. For this reason, the FDA does not have any evidence that the HVAC system is under control during production. Only a prompt notification of relevant pressure fluctuations can prevent air from flowing from a less clean area to a cleaner area.

The particle monitoring system was also criticised. The FDA complained that for the monitoring of ≥ 0.5 µm particles in ISO class 5 (equivalent to EU zone A) no system is in place to initiate action if the action limit is exceeded. As a result, the limit was exceeded in numerous batches of a sterile injection solution. This did not result in any action being taken, as the exceeding of the limit was not judged to be long enough.

The FDA now expects numerous actions to be taken, including

  • An independent assessment for the HVAC/pressure stage system including a CAPA investigation (monitoring, data recording, alarm documentation, deviation investigations)
  • Documentation of all alarms, regardless of their length or location, and the storage of this data
  • A monitoring system that can detect atypical pressure changes in several cleanrooms simultaneously
  • A description of how to ensure uninterrupted power supply for the aseptic area
  • A comprehensive risk assessment of contamination sources with regard to aseptic processes, equipment and facilities. This should include: all human interventions in ISO 5 area, equipment placement and ergonomics, air quality in ISO 5 area and surrounding areas, facility layout including personnel and material flows, and the identification of intrinsic and extrinsic particulate risks to the sterile area.

On the FDA website you can find the Warning Letter to the Indian sterile manufacture Panacea Biotec Limited.

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