Cross-Contamination at Indian pharmaceutical manufacturer

The US FDA inspected an Indian pharmaceutical manufacturer from 26 August to 6 September 2024 and found serious GMP violations. The deficiencies relate in particular to the cleaning and maintenance of production equipment, the structural condition of the facility and data integrity.

Insufficient cleaning and maintenance of production equipment

The FDA found that there was significant contamination in the ventilation ducts of multipurpose equipment used to manufacture finished drug products. Although filters were installed to prevent contamination, insufficient cleaning and maintenance rendered them ineffective. During the inspection, swab samples were taken from the ventilation ducts, which showed residues of several previously manufactured drugs and a microbiological load that was too high (‘too numerous to count’). The FDA emphasises that airflow over contaminated surfaces can lead to cross-contamination and that thorough cleaning and regular maintenance are essential.
In an initial response to this inspection deficiency, the manufacturer had examined retain samples and, although cross-contamination was found, the risk to drug safety was classified as low based on MACO calculations.
However, according to the FDA, cross-contamination is not uniform, and testing limited retained samples alone cannot ensure that products are free of contamination. While MACO calculations are helpful in a cleaning validation, they cannot be used if no cleaning has been performed or the exposure is not uniform. In addition, the MACO calculations were incorrect according to the FDA.
The FDA is now calling for a comprehensive evaluation of cleaning effectiveness to determine the extent of the cross-contamination risk and a complete revision of the cleaning validation programme, taking into account worst-case scenarios (difficult-to-clean or toxic active ingredients).

Inadequate facility maintenance

During the inspection, the FDA discovered contamination from bird droppings and feathers in the area of the air handling units (AHUs), particularly on ventilation ducts, on a tank and on floors in production areas. According to the FDA, these unsanitary conditions pose a significant risk of drug contamination as the AHUs channel air into the production areas. The manufacturer stated that birds had entered through gaps in the outer walls and that immediate action was taken to block the entrances with netting. However, the FDA does not consider the nets to be sufficient, as there is no guarantee that smaller animals such as insects cannot get in. In addition to structural measures, the FDA is calling for regular inspections and preventative measures to recognise and rectify structural defects at an early stage.
In addition, the HVAC systems were not properly maintained. According to the FDA, this led to filter failures and leaks, resulting in an increased risk of contamination. The Indian manufacturer then stated that damage to the HEPA filters had been confirmed by the equipment manufacturer and that this may have led to an increased pressure drop. The manufacturer had suggested monitoring the pressure differences to determine when cleaning or replacement of the filters was required. This response is insufficient for the FDA as the causes of these deficiencies have not been addressed. According to the FDA, the Quality Unit does not have a clearly defined responsibility for inspecting critical ventilation components such as the HEPA filters. There is a lack of effective controls over filter replacement, which meant that damaged filters went unnoticed. In addition, leaks in the ventilation system were not recognised, allowing potential contaminants to enter the production areas.

Deficiencies in data integrity

During the inspection, the FDA found a large amount of torn GMP documents in at least 15 plastic bags, including printouts of analytical balances and manufacturing and test data from drug production. The manufacturer argued that these documents or their destruction had no impact on product quality and cited several causes for the problem. For example, SOPs were inadequate, particularly with regard to data integrity requirements, and there were misunderstandings among employees about existing procedures. The FDA is now calling for a complete review of data integrity practices and refers to its guideline "Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices".

The detailed Warning Letter can be found on the FDA website.