GMP Deficiencies at a PET Manufacturer

During the inspection of a manufacturer of PET drug products in June 2025, the FDA identified numerous GMP deficiencies and violations of 21 CFR Part 212. PET drugs (Positron Emission Tomography Drugs) are short-lived radiopharmaceutical injection preparations used in nuclear medicine diagnostics. Due to the very short half-lives of the radionuclides used, these products are often manufactured close to the patient and administered immediately after production, which poses particular GMP challenges.

The FDA's findings focused on significant deficiencies related to facilities, aseptic process control, and microbiological monitoring. According to the FDA, the manufacturer's facilities were not suitable for reliably preventing contamination of sterile PET injection solutions. Critical aseptic connections were performed in open work areas without an appropriate aseptic environment. In addition, a so-called 'Hot Cell', used for the production and filling of radioactive injection preparations, was found to be in poor condition. Hot cells are shielded work cells designed to provide radiation protection when handling radioactive substances and to serve as the primary barrier for aseptic activities. Rust was observed on the manipulation devices/gloves within the hot cell, as well as visible residues in the immediate vicinity of the filtration point of the finished product in sterile vials. The FDA further criticised the fact that repairs performed on the equipment were not accompanied by a systematic assessment of facilities, processes, and equipment to identify potential contamination routes.

Additional deficiencies were noted in environmental monitoring. According to the FDA, adequate monitoring of the critical aseptic area within the hot cell was not conducted. The alert and action levels defined in the manufacturer's SOPs were considered by the FDA to be significantly too high, resulting in an unacceptable risk of contamination. Furthermore, the FDA found no coherent strategy for defining appropriate sampling locations and monitoring frequencies. The FDA emphasises that close microbiological monitoring of the aseptic environment is essential for PET drugs, as these products are often released and administered before monitoring results and sterility test data are available.

The FDA also criticised the gowning worn by personnel working in the aseptic area. Inspectors observed exposed skin and hair during manufacturing operations, including activities performed in the hot cell and under laminar flow conditions. In addition, two operators had not been requalified annually as required by media fill simulations for several years, despite continuing to participate in manufacturing activities. No retrospective assessment had been performed to evaluate the potential impact on batches manufactured during this period.
Furthermore, the FDA observed inadequate aseptic practices during sterility testing, including the opening of sterile components outside the laminar airflow hood. In addition, improper handling of sterility test sample tubes was noted, which could interfere with the visual detection of turbidity, microbial colonies, or other indicators of microorganisms.

Overall, the FDA concluded that the identified deficiencies represent a significant risk to product sterility and, consequently, to patient safety, and that they require a fundamental review of aseptic processes, environmental monitoring systems, personnel qualification programs, and overall regulatory compliance.

Please see the FDA website for the detailed Warning Letter issued to the PET manufacturer.