Non Compliance Report in Radiopharmaceutical Manufacturing

Recommendation

18/19 June 2024
Copenhagen, Denmark

Environmental Monitoring
Compliant and Reasonable

The manufacturing of radiopharmaceutical products confronts the producing establishment with a collection of challenges. On the one hand there is the challenge by the contradictory requirements of quality and safety guidelines of pharmaceutical products and the standards of staff safety and radiation protection. On the other hand there are issues of small batch sizes and short shelf life. The short shelf life necessitates fast transportation and application to the patient. These circumstances mean that classical requirements like sterility testing before release and application cannot be fulfilled.

But with international guidelines like in PIC/S Guideline P010, Annex 3, the establishment can find necessary requirements and state of the art recommendations for manufacturing radiopharmaceuticals in a good practice.

On 15 December, the Italian Medicines Agency published a "Statement of Non-Compliance with GMP" for an Italian manufacturer of Radiopharmaceuticals, IASON Italia SRL. The Agency wrote about the nature of Non-Compliance in their report:

"During the inspection 19 deficiencies were identified, 3 of them were rated as critical deficiencies and 11 as major deficiencies. The main deficiencies were related to the Quality Management and the Quality Assurance Systems also in terms of sterility assurance and risk of contamination/defects of the final product. One critical deficiency was related to failure to fully investigate and document out-of-specification results for microbiological environmental monitoring in class A isolator and class B/C surrounding areas, in manufacture of radiopharmaceuticals aseptically prepared. The company didn't carry out an appropriate and full-scale investigation to determine what caused the OOSs. An appropriate level of corrective action analysis was not applied during the investigation and the true root cause(s) were not determined. Failure to address the root cause due to ineffective CAPA revealed a lack of the quality assurance framework system. Another critical deficiency was reported with regards to production processes which were considered not satisfactory controlled: it was found that for the manufacture of some batches of the radiopharmaceutical Pcolina (Iasocholine) a non suitable reagent was used (expired dibromomethane). Moreover, for some batches of released RPs master batch documents were incomplete. No adequate review by QA or QP. Furthermore, preparation of the starting material set for radiopharmaceuticals was performed in condition not appropriate to guarantee an adequate level of chemical and microbiological containment. The inspection's team has rated also as critical the observation related to the number of personnel in force to the manufacturing site, which were considered not appropriate to conduct all the activities in accordance with the GMP and to maintain the quality management system and its effectiveness. The remaining major deficiencies were related to specific aspects of the Quality Assurance System with regards to PQR assessment, revalidation and recalibration of critical equipment, data integrity in the context of HPLC management, storage of materials and documentation system."

Following the inspection and documented deficiencies, the company suspended the manufacturing of some 18F-products and the manufacturing authorisation was suspendend by the responsible authority. All details about this report can be found in the Statement of Non-Compliance at the EudraGMDP website.