Lias: We've seen an enormous upswing, both in the physical number and types of vaccines that we're seeing brought into our organization for development and manufacturing. These include not only prophylactic vaccines, but also therapeutic vaccines—a vast, different array of novel vaccines. It's a very exciting time out there.
What does that mean? Well, they all need different production processes. There is really no standard platform for producing many of these novel vaccines. With monoclonal antibodies (MAbs), we've got to the stage where MAbs are well-defined products; we're able to characterize them properly. The regulators are comfortable with that of course, it makes it easier to make changes in the process because we can prove we're developing the same product. Also, the actual production of MAbs has become a platform nowadays. Most companies do it exactly the same way, working with perhaps a CHO cell or NS0, similar bioreactors, Protein A purification, and low pH hold for viral clearance.For vaccines it's very different, because these products are tremendously diverse. So really we are almost stuck in what I consider a 1980s paradigm with vaccines. We're back to the situation where the process really defines the product. That's the way it was with monoclonals and a lot of other recombinants probably 10 to15 years ago.
BioPharm: Do the specific needs of vaccine manufacture cause particular concerns when outsourcing vaccine production, for example, in terms of tech transfer?
Lias: Absolutely. The process is really seen by the regulators as defining the product at this point, and therefore, every time you make a change or you scale up or change facilities, there are particular regulatory concerns for many of these novel vaccine products.
Because immunogenicity is hugely important for vaccines, you run the risk of making changes during tech transfer which could change your entire product and its clinical efficacy. So you got to be extremely careful. And it's much more important when you are outsourcing manufacture, to look for a service provider who can stay with you longer and has the scale you may need for future production, because then you can avoid future tech transfers.
BioPharm: Can you give us some examples of the different types of vaccines you've worked on? And how different are they from one another?
Lias: We have both a service business and a consultancy business, so we have seen a wide range of products. In our UKfacilities, we're doing some work on a virus-like particle (VLP), which we're producing in Pichia pastoris in suspension culture. We also have some interesting technology that we've bought on and applied ourselves for some adenoviral work for vaccine use; it's also in suspension culture rather than having to rely on adherent cell lines. We also worked with whole-cell microbial and recombinant protein vaccines. In our consulting group, we work with live attenuated vaccines. Our management group has particular skills and expertise in this area. They're actually the group that launched in Europe a third generation hepatitis B vaccine, which was expressed in mammalian cells. Because we see a huge range, we have to look at production technologies that vary—cell factories, disposable bioreactors, roller bottles, conventional bioreactors, and fermenters.
BioPharm: For your vaccine clients, do you usually carry out the process development as well, or do the clients often do the process development and transfer it to you?
Lias: For the most part, we do the development. That's actually really what our business is—we're fundamentally in process development, although we do transfer in products as well.
We're doing upstream development, whether it's expressed in a mammalian system or a microbial cell, that's pretty conventional. We do have some particular expertise in doing suspension culture for some of these products, which would be somewhat unusual. On the downstream side, we're developing purification processes. We're getting away from the old days of cesium gradients and trying to put together something which approaches a platform of chromatographic techniques for many of these vaccines.
The key part of it, I believe, is actually the analytical side. We've seen some tremendous advances there. We no longer have to wait three days for a plaque assay result when we're changing a filter in a process. So we can apply some of the newer techniques such as anion exchange and HPLC, and get answers in minutes or hours instead of days.
The other thing to be considered in these days of pandemics and bioterrorism is that although it is difficult to transfer these processes, sometimes we have to transfer them. We may be developing them for developing markets such as the Chinese or Indian markets. So we've got to make the processes more robust and transferable.
Roger Lias, PhD, President and group commercial director, Eden Biodesign, Inc.