10-12 October 2023
The FDA has recently issued a Warning Letter to a large Indian pharmaceutical manufacturer following an inspection that revealed poor cleaning and later detected cross-contamination in manufactured tablets. Further GMP violations were detected like leaking HEPA filters and inadequate smoke studies in the sterile area.
During the inspection, the FDA had noticed insufficient cleaning of non-dedicated equipment in tablet production. Residues of what appeared to be different products inside the exhaust ducts were discovered. The analytical examination later revealed that these were indeed residues of various products. After the inspection, reserve samples were also examined for potential contamination with another product. And indeed, contamination with another API was found in 7 of 268 batches.
In its response, the Indian manufacturer stated that no cross-contamination could be found in 261 reserve samples. Besides, it was not believed that the residues in the exhaust duct did not pose a risk to the products. Obviously, this answer is not sufficient for the FDA. The manufacturer also did not mention that in 10% of the batches tested, unknown peaks eluting at the retention time of a previous product were found in the chromatograms. The FDA now expects a comprehensive investigation and evaluation of the cross-contamination by the manufacturer and comprehensive CAPA measures to remedy the deficiencies. Among other things, the cleaning process should be improved, other possible sources of contamination besides the exhaust ducts and the affected manufacturing equipment should be considered and the cleaning validation programme should be revised.
Another aspect of the Warning Letter concerns conspicuous HEPA filters in the manufacturer's sterile area. For example, 45 of the HEPA filters had side leakages. Often, these filters were adjacent in the same room. The Indian manufacturer had not sufficiently investigated this accumulation of filter integrity test failures. According to the Indian manufacturer, gasket deterioration and lack of timely filter replacement were the most probable causes. In this context, the FDA noted that some filters had been installed many years earlier and that the manufacturer's specified service life had long been exceeded. The FDA emphasizes the importance of the integrity of HEPA filters to ensure aseptic conditions. The FDA also lacks a retrospective view of which products/batches could be affected by the filter errors. The FDA doubts that the manufacturer's CAPA system works and expects an independent evaluation of this system. In addition, the manufacturer is expected to provide complete environmental data for all batches produced in class ISO 5 (and delivered to the USA) from February to December 2018. Furthermore, the manufacturer shall conduct a root cause analysis to determine why so many failures of adjacent HEPA filters have occurred in such a short period of time.
The FDA also disapproved the smoke studies, which are supposed to prove the correct unidirectional flow in the aseptic area. The data could not demonstrate that the protective airflow patterns are maintained during interventions, either because insufficient "smoke" was used or the camera angle was unfavourable. The manufacturer had replied that new smoke studies would be conducted and that the facility would be upgraded with regard to the ventilation system and the installation of particle counters. However, the FDA also expects the manufacturer to carry out a comprehensive risk analysis, which should take into account, among other things: all interventions by employees in ISO 5 areas, the ergonomics of the process equipment, air quality in the ISO 5 area and surrounding room, the layout of the facility, as well as personnel and material flows.
The original Warning Letter from the FDA to Cipla Limited provides further details.