Late last year we were fortunate enough to catch up with Christopher Bravery, Director, Consulting on Advanced Biologicals Ltd and a member of the ISCT EU Legal and Regulatory Affairs Committee. We asked him about the reasoning behind the topic of his talk ‘Setting Specifications’ at the Cell Therapy Manufacturing & Gene Therapy Congress on 3rd February 2016 in Brussels:
“I try and think of a topic that I don’t feel has been covered enough each year and choose that as my topic that I try and speak on. Particularly at the Cell Therapy Bioprocessing & Commercialization conference run by IBC in the U.S and Informa Cell Therapy Manufacturing and Gene Therapy congress in Brussels, because I think there are topics that somehow fall under the radar. The thing with justification of specifications is that you rarely have to write much during clinical development, and I often see ‘not applicable’ written for the justification in the specifications, which in many cases, the regulators will pay no attention to.
The ones that people are probably familiar in having to justify, are the things like endotoxin levels, where there is some reasonable guidance to what is a reasonable daily exposure to endotoxins, so you divide that by your dose and come up with a figure to justify the limit you’ve set for your endotoxin. Although, if you’re needing to do some sort of viral testing then it’s usually a no brainer that it is usually not detectable, and you don’t need to justify that specification much either.
Once you get to market authorisation, it is a substantial amount of work and text in the dossier, and I think what interested me when I thought about it was how it draws upon all of development. So I produced a figure actually where I laid out the CTD sections in a mind map, and showed all the links about the dative for justifying your product specification and where it will come from, and your data for your processes will come from.
Potency is a brilliant example of how do you justify your potency specification? It’s probably a bit easier for gene therapy than it is for cell therapy, but it is very difficult. That almost certainly might need to draw on non-clinical data as evidence that something sub-potent, that you’re not getting the effect you want, and that at another value on your potency assay is actually potent. Often the appropriate non-clinical models that might allow you to support that might be missing so you might be relying on in-vitro assays.
But really, I think the main reason I chose it is that in my consulting work I have seen a move towards later stage development. There are certainly more companies thinking now about what they need for market authorisation, either planning or embarking on their pivotal studies. And really if you haven’t done the work on the process you’re taking into pivotal that is suitable for early commercial, then you would have an enormous amount of work to do in phase II. In phase III when you’re supposed to be validating the process, validating the methods and writing a dossier, all those things take a lot of time, so in phase II you really should have your characterisation of the process out of the way; identified your critical process parameters, your critical quality attributes and so on. But, there is always a lot to do!
What worries me is that this work might not be getting done, and then it would be very difficult to justify specifications when you have no data to base them on. Obviously if this is the case, then there is the pressure not to wait, but to get on with phase III, and so suddenly it’s done in parallel and you have six months to do what you really need two or three years for.
And this is why I chose that topic. It has really struck me as being something that we needed to start talking about – how you do that. What I have seen particularly with the cell therapy community, somewhat less with the gene therapy because it’s more like biotech, is really significant deficiencies in characterising the process and understanding what those critical parameters are. Without that characterisation data, you wouldn’t be able to justify those parameters.
I also have fears, as I’ve been through this myself, that decisions get made in corridors or at lunchtime about how you’re going to go about doing things early in development and sometimes if they don’t get recorded, then at the end you’re not sure why you even did it that way, let alone having a justification for the specification!”
Christopher’s talk is on day two of the Cell Therapy Manufacturing & Gene Therapy Congress at 16:00 on the Cell Therapy manufacturing stream, and no doubt will be extremely insightful. See the full agenda and buy tickets at https://celltherapy.knnlab.com/. We look forward to seeing you there!