Deficiencies at Sterile Manufacturer

In May 2022, the US FDA inspected an Indian sterile manufacturer, revealing numerous deficiencies that have now led to a Warning Letter. Among other things, deficiencies in media fill, plant and cleanroom design, and environmental monitoring were cited.

Media Fill

The FDA complained that the conditions of the routine process during the media fill were not simulated accurately enough. For example, a different amount of sterile API (than in the routine process) was added by hand during the media fill, resulting in a difference in the duration of the manual intervention. The filling process itself also differs. Thus, in the routine process, containers can be used that were previously opened and closed again, which was not taken into account in the media fill.
The employees carry out time-consuming, very manual aseptic procedures, which, according to the FDA, is not sufficiently taken into account in the media fills.

Aseptic behaviour of employees

Smoke studies and media fill results demonstrate inadequate employee behaviour in the aseptic area, according to the FDA. Some of the cases cited include:

• An operator touched the product contact surface of a sterile stopper before placing it back on the container.
• Operator movements in critical areas were not always slow and deliberate.
• One operator interfered with airflow during various activities, including reaching over the open sterile container several times, leaning it toward his body so he could see inside while removing sterile supplies.

Deficiencies in aseptic behaviour had been known to the manufacturer since issues with the media fill in November 2021. However, the manufacturer failed to conduct a timely risk assessment to determine whether the quality and sterility of the distributed medicinal products had been compromised by these deficiencies. The recall of affected batches did not occur until five months later.

Cleanroom design

ISO-5 cleanroom areas (aseptic core) used for aseptic drug manufacturing and filling are inadequately designed and lack sufficient safeguards, according to the FDA. For example, the ISO-5 area lacks physical barriers to prevent potential contamination of sterile components, including the sterile API, during intensive, manual operations.
Personnel's bodies and hands are in close proximity to the sterile API during filling and loading syringes into the filling station. Operators also hand-fill sterile components into a container through a large funnel with a wide opening. Smoke studies show unidirectional, recirculating airflow on and around the funnel. The FDA considers this a major contamination hazard to the sterile medicinal product. Fundamental design deficiencies and manual intervention during operation prevent adequate sterility assurance.

Environmental monitoring

The FDA criticizes the lack of an adequate system for monitoring environmental conditions. For example, there is no monitoring of surfaces and air near the aseptic filling area. According to the manufacturer's documents, this area is not considered a "high-risk sampling point" for environmental monitoring. Particularly in such highly manual operations, the FDA considers environmental monitoring to be essential.  

Filling equipment

The FDA also criticizes the equipment used for filling. According to the FDA, the filling equipment used is not suitable for filling the viscous products of the Indian manufacturer. This has led to considerable impurities in vials of an injection solution with foreign particles. The manufacturer itself had found that the combination of its viscous products with the filling equipment caused friction and abrasion, which led to the formation of fine metal particles that could then enter the product vials. According to the manufacturer, the parts damaged in this way were no longer used. However, according to the FDA, two years later these parts are still listed as acceptable equipment in the Master Batch Record and have been used - two years after the manufacturer identified this source of contamination.

These and other deficiencies can be found in the original Warning Letter on the FDA website.