Severe GMP Violations in the Aseptic Area

Due to numerous and serious GMP violations in the aseptic area, the FDA issued a Warning Letter to an Indian sterile manufacturer in October. The violations concern media fills, employee behaviour in the aseptic area, cleanroom and equipment design, environmental monitoring and CAPA.

Media Fill

According to the FDA, employees carry out lengthy, highly manual aseptic work steps. Therefore, the duration of the process simulation should be very similar to the actual manufacturing process. The FDA criticizes the fact that the processes during the media fill do not sufficiently simulate the real processes during aseptic filling. For example, the quantities used manually differ from the real quantities, such as the quantity of sterile API added manually to the compounding tank. In addition, bags used in commercial production may have been opened and resealed beforehand, which was not simulated in the media fill.

Poor aseptic behaviour
According to the FDA, media fills and smoke studies show inadequate aseptic behaviour among employees, e.g. when adding sterile API to the preparation container. Among other things

  • An operator touched the product contact surface of the stopper. 
  • The operator's movements in the critical areas were not always slow and deliberate. 
  • An operator blocked the laminar air flow during various activities, including by reaching over the open, sterile container several times.

The FDA also writes that there was a serious failure with media fill in November 2021 that revealed serious deficiencies and risks in operation. However, the manufacturer did not conduct a timely risk assessment to determine whether the quality and sterility of the medicinal products distributed were affected by these defects. A recall was not initiated until five months later. The failure to proactively identify deficiencies and implement timely and sustained corrective and preventive actions (CAPA) is unacceptable according to the FDA.

Cleanroom design

The FDA writes that the ISO-5 cleanroom areas used for the aseptic manufacturing and filling of drugs are inadequately designed and do not provide adequate protection. For example, the ISO-5 area lacked physical barriers to prevent potential contamination of sterile components, including the sterile API, during manual operations. Personnel's bodies and hands were in close proximity to the sterile API during preparation and syringe loading in the filling station. Operators also hand-filled sterile components into a compounding tank through a large funnel with a wide opening. The smoke studies showed an undirected, recirculating airflow on and around the funnel. According to the FDA, fundamental design flaws and manual labour-intensive interventions undermine the maintenance of aseptic performance.

Environmental monitoring

According to the FDA, the manufacturer failed to establish an adequate system to monitor environmental conditions. For example, there is no functional environmental monitoring of surfaces and air in the immediate vicinity of aseptic dispensing operations. There is also no monitoring at the point where sterile API is manually added to the compounding tank. However, the manufacturer has not designated this point as a "high-risk" sampling point for environmental monitoring. Furthermore, the data on personnel monitoring was not adequately recorded. Especially for highly manual aseptic operations, the FDA expects a sound environmental and personnel monitoring program.

Equipment design

The FDA also found GMP deficiencies in the production equipment used. For example, the manufacturer used unsuitable equipment for filling vials, which led to significant contamination of injection solution vials with foreign substances. The manufacturer was aware that the design of the filling equipment, in combination with the viscous nature of the drug, generated friction. This friction causes an abrasion effect, resulting in fine metal particles entering the vials during filling. The manufacturer had stated that the affected parts had been withdrawn from circulation. However, the FDA found manufacturing records proving that these parts were still in use two years after the cause of the black particles was discovered.

Deviations and CAPA

The FDA also criticized the handling of deviations. For example, there was a water leak in a cleanroom that was insufficiently investigated. Appropriate CAPA measures were not initiated and the investigation was not extended to other potentially affected batches. In this case, water had entered ISO cleanroom 5 through a leak in the HVAC system in the service area through the cleanroom ceiling. The water had previously collected above the cleanroom ceiling before entering the aseptic filling room. Although the manufacturer had sealed the gaps in the ceiling, they did not adequately inspect the intermediate area, LAF ceiling and HVAC ducts for mold growth and water damage after the repairs. Also, no risk assessment was performed for the sterile product manufactured in this cleanroom since the last preventive maintenance, approximately two months before the leak was discovered.
The Warning Letter to the Indian sterile manufacturer can be found on the FDA website.

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