FDA issues Warning Letter to Cell Gene Therapy manufacturer

In November 2023, the US FDA inspected a CGT manufacturer of CAR T cells used in a Phase 2 clinical trial and has now issued a Warning Letter due to GMP violations. The deficiencies described are of a more fundamental nature.

According to the FDA, the US-based company failed to keep the buildings used to manufacture the drug in a clean and hygienic condition. The FDA describes a case that the company itself had observed: on July 14, 2023, Quality Assurance observed a box of food (dated June 16, 2023) housed in the room with the technical HVAC equipment. The food was covered with fly pupae and was not removed until July 31, 2023.
Following this incident, fly larvae were found in ten environmental and personnel monitoring samples taken in the cleanrooms in July 2023. In addition, a live fly was observed in one cleanroom on July 26, 2023.

Another fundamental deficiency is the lack of adequate particle monitoring in the aseptic area. The US manufacturer possesses neither monitoring of (non-viable) particles in the aseptic work area during the production of CAR-T cells nor active monitoring of viable microorganisms in the air during open manufacturing steps. According to the FDA, monitoring non-viable particles is critical to detecting particles in the manufacturing area because they pose a risk to the patient in intravenously administered products. Microorganisms can sit on particles and contaminate the product. Active monitoring of viable microorganisms in the air is important for the detection of microorganisms around the product exposed to the manufacturing environment.

The FDA also criticizes cleaning and disinfection. For example, the company has not conducted a cleaning validation of the cleaning procedures of the manufacturing equipment. The FDA explains that the purpose of cleaning validation is to establish cleaning conditions that allow effective removal of microorganisms commonly found in the manufacturing environment that pose a contamination risk to the sterile product.
Following the inspection, the manufacturer confirmed in writing that a study had shown that the new cleaning program effectively removes bacteria and fungi from surfaces. This statement is not sufficient for the FDA, as the data and results of the study were not submitted.

A 100% visual inspection of the sterile finished medicinal product is also not carried out.
Due to the lack of testing, it cannot be guaranteed that the drug product is essentially free of visible particles, which is necessary to ensure quality and purity prior to intravascular administration, says the FDA.

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