PhM — Broadly speaking, what are the greatest challenges you see facing biopharma this year?
PS — First and foremost, there’s the economy. We’re seeing a lot of companies in “wait and see” mode, where their development efforts are being put on hold. Exciting drugs just aren’t moving forward as quickly as one would have hoped,
There’s also pressure from healthcare reform. It could take many different shapes depending on how it all gets negotiated and agreed upon. A big component of that will be biosimilars. This topic has been a big issue in Europe for a couple of years, ever since they enacted regulations allowing for a separate pathway to biosimilars approval.
PhM — Since Obama supports the concepts what do you expect the timeframe to be?
PS — There will be a pathway for them within the next two years. It may not happen this year. There’s thought that it could be done in an independent bill, but it’s more likely to be rolled into broader healthcare reform package, although it could swing the other way in the next few months.
Prevailing wisdom with former Republican administration was that generics wouldn’t get a toehold in biopharma. Now, the administration has completely changed, and generics manufacturers have compromised a bit on the issue of “years of exclusivity for innovator IP,” going up from zero to five.
But, I don’t think innovator industry will get the 14 years it requested, either. Likely it will be a compromise, something between 7 and 10 years.
We’ve seen how the biosimilars that have been approved in Europe so far are affecting the industry. Entrepreneurs that developed biosimilars there are feeling pain because innovators have dropped prices to rock bottom, eroding the market for those products.
When innovators drop prices, the overall dollar level goes down and biosimilars become unattractive as a business option. It will be interesting to see how this plays out in Europe and the U.S. But those are for simpler products such as epos, growth hormones----not that they’re truly simpler but they’re more straightforward to make than some of the antibodies coming along.
We’ll expect to see more competition here, may take bio similars or bio-better path, in which case one takes the innovator molecule and makes it better (e.g. more potent, requiring less frequent dosing, or featuring less immunogenicity).
They’re already laying plans for how to achieve that within the next five years.
PM — Are you seeing the concept of QbD taking root in biopharma, even though we don’t yet have concrete examples of submissions, as exist for small molecules?
PS — There’s still a lotof talk but we are seeing companies implement and embrace it in some,form inmdevelopment strategy
The challenge is that if you do this too late in development, you’ve lost an opportunity to leverage the most return ….but better late than never.
We are seeing companies involved in QbD push it further down in the development cycle. They understand that it they can do these things sooner they will have better quality product, tighter parameters for manufacturing, and will have a system in place that will make it easier to make changes to a process.
Perhaps the drug industry’s uptake of QbD has not been nearly as widespread as early advocates had hoped…. But big biotech companies are using its principles.
PhM — How about PAT in biopharma? Are you seeing more companies with active programs?
PS — A little lesss, in my experience. They’re still using a lot of offline analytics and waiting a few days for results, so they’re not getting the full benefits of analytics and real time.
PhM — How about the downstream bioprocess bottlenecks. Are there any new technologies or will it just involve incremental tweaks to existing technologies?
PS — There probably won’t be revolutionary changes overnight. Historically, limits were always upstream, defined by the scale of the production bioreactor. Discovery and early stage development groups and cell line development people have done a great job and can now make cell lines to manufacture 2, 5,or even 10 grams per Liter….so much more product can now be made from the same scale reactor.
However, the downstream infrastructure was developed five years ago and can no longer support higher yields….downstream depends on mass, need more capacity to handle.
Among the technologies we’re seeing applied are higher capacity chromatography results, supplied by GE and others, such as Mabselect.
Steps are also being taken to reduce buffer volumes and hold tanks….ancillary things required to support (e.g. WFI, buffer prep, holding tanks, those are hundreds of thousands of liters of capacity in some case)
Continuous chromatography also shows promise….particularly simulated moving bed, used a lot in small molecules and in non-pharma applications….Novasep and Tarpin biosystems are developing such products, which show promise to work with antibodies.
Continuous processes mean that one doesn’t have to make everything at once…can make it in real time so the JIT manufacturing philosophies can apply.
Sometimes there are simple alternatives to increasing upstream deliverables in terms of titers that people aren’t thinking about. For instance, some folks don’t purify at all, to increase upstream titers….this defeats the purpose of achieving those high titers in the first place, and contributes to downstream problems
PhM — Do you see FDA’s draft validation guidance having any impact on the way people approach validation?
PS — Yes, the industry’s approach will change for the better. QbD and validation work well together. You’re not going to get away from the three conformance lots, that’s still going to happen for first approval….but if you’ve implemented based on the Qbd philosophy, you’ll have all your data and will continuously add to that data set so if you do make changes to processes post approval, the SNDA will be much simpler because you’ll already have data to prove that changes won’t impact the manufacturability of your product.
Like most guidance docs, it is sufficiently vague so that first adopters will set the bar on expectations, but we’re optimistic.