It was never the intention of Q7A to even suggest that all classical fermentation processes have to be validated. I think if product quality demands that the fermenter be sterilized, than it’s probably wise to sterilize the fermenter and to validate it as such, but if you have a long history of being able to operate the process successfully and maintain product quality in the absence of sterilizing the fermenter, but rather just merely sanitizing it, than that’s probably okay. Let me just say that in the classical arena, when you’re talking about fermenters that could be five stories tall, the whole issue of validating a fermenter of that size becomes almost an impossibility from a product quality perspective and given what you’re doing is normal classical fermentation, it becomes, as you said, an economic issue more that a quality issue. In fact, unless you’re generating a whole broth of material, the fermentation is just the start of the process, and you’re going to go from there into true purification, chemical purification and extraction and clean-up. So from the classical perspective, while it’s a very nice, theoretical concept to want to validate that sterilization, what is going to happen is if you fail to really sterilize, your yields are going to go way down, you probably may even throw away your entire fermentation run if it goes bad, and in reality, will have almost no ill effect on the real product that you’re generating in the classical sense. Some of these fermenters can get very, very large and the sum cost of a batch can become very, very large, and no company wants to lose substantial chunks of a million dollars or more because the fermenter isn’t sterilized. So there can be multiple reasons for wanting to have good quality on the machinery, and product quality is one of them. There can also be valid economic reasons that really have nothing to do with product quality, but do reflect the economics of the situation.
My understanding is that you wanted to file a market application for a product prepared by classical fermentation, there would be the expectation that the critical parameters would have been identified and subjected to whatever level of validation was justifiable. I think it’s important to understand that validation of fermentation is not the same as validation of terminal sterilization autoclaves. Some parts of it certainly may resemble it such as determining whether or not the fermenter can be reliably sterilized, but the parts of the process are just not approachable with the same level of rigor, and even to determine which variables are critical is not always easy. So it’s an area, frankly, where there is not a lot of standardization, there is not a lot of useful guidance and it tends to be case by case. I think in many cases though, the processes are still so complex that it’s really difficult to make progress because the tools of science are just not there. I would go on record as an FDA rep to acknowledge, that validation of sterilization, in situ
sterilization, culture media and the fermentation process is a different animal as compared to a terminal sterilization process for a sterile drug product. Again, you have to consider what are we trying to accomplish here? The real purpose of sterilizing culture in situ, in place, is not so much to achieve total sterility for the downstream, but to try to minimize contaminants in the process in the fermentation broth that may affect your process later on. The intention for drug products is different in that it is to kill all living organisms in the product.
