A review of the implementation of a Media fill simulation program that complies with FDA regulation

Objectives In April 2012, the FDA published a guidance document on media fill simulations for PET drug manufacturers. Since then, there have been no publications describing the results of media fill simulations in PET drug manufacturing processes. The objective of this work is to develop media fill simulation procedures that simultaneously assess the aseptic quality of PET drug manufacturing procedures, allow for implementation across a nationwide network of PET drug manufacturing sites, meet the expectations in the FDA guidance document and test the worst case manufacturing parameters.

Methods The key steps in the production process that were simulated by media fills included: the aseptic preparation of the product vial subassembly, the addition of solutions required for formulation and dilution of the product, and product sampling for quality control and sterility testing. Each step was simulated or performed using commercially-available, pre-sterilized soybean-casein digest media (SCDM). Media fill simulations must also employ worst-case conditions. To achieve this, simulations were performed according to site-specific, worst-case conditions, including the number of batches, expiration of components, air quality, sample handling, production locations, routine cleaning and production times. Appropriate negative and positive controls were also included in each simulation.

Results The pre-approved protocol was completed by at least 147 operators at 44 manufacturing sites, resulting in 441 valid media simulations. All SCDM samples from the media simulations demonstrated the absence of microbial growth at the end of the incubation period, confirming the successful execution of all media simulations.

Conclusions The media fills results demonstrate that the PET drug manufacturing processes, including personnel, components and equipment, adequately control and prevent microbial contamination during routine drug production. These results have been successfully reviewed during more than 40 FDA inspections since the implementation of the program.