Now and then I work with clinical trial phase companies who manufacture products for phase I and phase II clinical trials. I was sort of surprised when the leader of one of these groups said that one of the researchers objected to doing media fills (process simulations, or aseptic process validation) for a phase 1 product. I responded that it is normal for scientists to question whether something is mandatory or not. Turns out that the scientist was reading the GMP regulations and noted “nothing in there says you have to do media fills.” Right away, I said to take a look at the FDA phase 1 Guidance that states you have to do media fills for phase 1. Also take a look at the Aseptic Guidance.
If you think about it, performing media fills makes sense from the perspective of patient safety, which is the most important objective for a phase 1 trial. Mostly I work with biologics which require aseptic processing—they cannot be terminally sterilized, and in the case of cell therapies, cannot be filter sterilized either. Therefore, ensuring aseptic processing becomes paramount for safety (sterility) for these products. Media fills give us assurance that all the equipment/plastics/components that we are using for processing are, in fact, sterile. The media fill also gives us assurance that the personnel can manufacture in an aseptic way. Therefore, performing a media fill is a key exercise to ensure that the personnel, the environment, the sterile single use plastics, and the other components all work together to produce an aseptic product.
When explained this way, the researcher acknowledged that performing a media fill was important to have some data demonstrating that an aseptic product could be produced. The process was shown to be aseptic, and all the personnel working on the product also passed, in the sense that no positives were found for the media fill where they participated.
It is important to remember that guidances are seen as the “c” in cGMP—the current interpretation of the regulations, and just because you can’t find a requirement in the regulations, does not mean that a certain requirement does not exist. In general, we should follow guidances. If we think about the reverse, that does not mean we have to follow everything in a guidance—it’s just a guidance, not the law or regulation—but if we are going to go against a guidance, there should be a well though out written rationale, and likely also a written risk assessment for this approach. Remember that guidances are consensus documents, endorsed by FDA, and hundreds, if not thousands of smart people from both industry and FDA put these guidances together, so we should acknowledge that, and carefully consider them.
John Godshalk is a CMC/GMP consultant with JG BioConsult, LLC. He can be reached at john(at)jgbioconsult.com.