Sterility test positive rates in PET drug manufacturing - a comparison of the US and EU models

Objectives A comprehensive sterility assurance program contains many components, including validation, microbial controls, microbial environmental monitoring, and sterility testing. In 2009, the FDA estimated that the rate of sterility test positives for all PET drugs produced in the US was 0.05%, or about 25 batches out of an estimated 50,500 batches produced annually. This estimate has not been verified experimentally. The objective of this work is to determine the frequency of sterility test positives across a network of US PET manufacturing facilities. In addition, this sterility test positive rate is compared to results from facilities in the EU to determine if differences in facilities and equipment result in differences in the rate of sterility test positives.

Methods All sterility tests in the US were performed by direct inoculation according to written procedures that define testing processes, sample handling and aseptic techniques. The results of all sterility tests for batches of [¹⁸F]FDG were retrospectively analyzed over a multi-year period. The EU model for manufacturing is in an ISO 8 cleanroom with ISO 5 areas within the manufacturing area for aseptic operations. The US model does not include a classified manufacturing area, however ISO 5 controls are used for aseptic manipulations during manufacturing.

Results In the US, the sterility test positive rate for all facilities was 0.063% in 2008. The rate fell to 0.013% in 2013. This change is attributed to procedural and equipment improvements. In the EU, the sterility test positive rate for all facilities was 0.07% in 2013. This compares favorably to that in the US.

Conclusions The rate of sterility test positives indicates that the facilities and equipment used in both the US and the EU are effective in the production of sterile, injectable PET drugs. PET centers in the US have done an excellent job at limiting the potential microbial excursions while manufacturing in an area that has significantly fewer controls than in the EU. This excursion rate enforces the ability to effectively manufacture PET drugs in a cost efficient manner.