Cross Contamination in Steam Steriliser at US Sterile Manufacturer

In October, the US FDA issued a Warning Letter to a US pharmaceutical manufacturer due to numerous GMP violations. The inspection, which had already taken place from March to April 2022, had revealed numerous deficiencies. The main reasons for the Warning Letter were cross contamination and microbiological contamination of products.

In addition to the inspection deficiencies, the FDA admonishes the manufacturer for not having triggered an NDA Field Alert, as required by law in the USA, despite knowledge of the product contamination.

Cross contamination

During analyses, the pharmaceutical company had noticed that cross-contamination between its own and externally produced products had occurred in three batches in a steam steriliser used together. Permeability of the packaging materials was given as the cause.

Deficiencies in the container/closure system for infusion bags were identified, including high permeability of the material. This allowed contamination of the autoclave and ingress into the containers of subsequent batches of medicinal products produced in the shared sterilisation unit.
An investigation was initiated as early as April 2021. However, the procedure continued unchanged. The manufacturer also uses approach and blow-fill-seal (BFS) filling machines as multipurpose equipment. It was not until the FDA inspection, about a year later, that further measures were initiated. The FDA criticises that due to the failure to conduct a timely and comprehensive investigation, the extent of the risk of cross-contamination of the marketed drugs medicinal product could not be identified.

In a response letter, the pharmaceutical company calls the measured cross-contamination negligible. It also said it now runs sterilisation cycles between different products to "clean" the steam steriliser. The FDA disagrees with the response.

The investigation does not address the deficiencies of the container/closure system (including, but not limited to material quality and compatibility with the manufacturing process). There is no evidence of adequate protection against the escape and entry of contaminations. In addition, the FDA lacks an obligation to review the container/closure system for raw material quality and supplier reliability. Furthermore, the investigation does not consider the impact of the permeability of the material on ensuring the sterility of the products.

FDA also criticises microbial contamination

There were two media fill failures where Pseudomonas aeruginosa was detected in the BFS mandrel cooling water. According to the FDA, it is highly atypical for gram-negative microbes to be detected in the aseptic production cleanroom environment or in the media fill. For example, Pseudomonas aeruginosa was detected in a media fill in a large number of turbid units. The sterile manufacturer then performed a single repeat media fill to requalify the BFS equipment for production after the water leak on the mandrel was repaired. According to the FDA, a single media fill is not sufficient to demonstrate requalification of aseptic procedures. In this situation, a comprehensive CAPA investigation should be conducted followed by three successful and consecutive runs to requalify the aseptic process.

And Pseudomonas aeruginosa was also detected in other locations, including routine environmental monitoring and water system samples. For example, after maintenance of the WFI system, several cases of Pseudomonas aeruginosa and other microorganisms were detected, including seven samples that were too contaminated for enumeration. The pharmaceutical manufacturer attributed the results to a laboratory error and declared the results invalid, without, however, being able to provide clear evidence of laboratory error as the cause (samples from the critical ISO 5 range should not normally show microbiological contamination).

Deficiencies in environmental monitoring

In its Warning Letter, the FDA describes further GMP deficiencies in the sterile area. The environmental monitoring is faulty, more precisely the action values for ISO 5, i.e. the aseptic core area. Due to the incorrect limit values, three out of six limit violations were not investigated.

The sampling of the BFS filling machines to monitor viable and non-viable with active airborne microbial collection is also flawed, according to the FDA. For example, the manufacturer did not demonstrate that the method used for sampling (e.g., using tubing of an appropriate length) provided a meaningful and representative sample of conditions during production.
The air sampling hose was pinched between the doorpost and the door to the BFS, potentially interrupting the air flow to the sampling device. The description of the sampling procedure is also insufficient to the FDA.

For more detailed information please also see the original FDA Warning Letter to Nephron on the FDA website.