Conversations like this usually happen on the floor of exhibition centers. But with face-to-face events remaining in limbo, BioProcess Insider spoke virtually with MilliporeSigma’s head of cell and gene therapies Jerry Keybl about the future of viral vectors.
Keybl has been looking after the business for over four years and is focused on driving industrialization to make sure that MilliporeSigma has the solution from a product and service prospective.
Bioprocess Insider (BI): What are the complexities of manufacturing viral vectors?
Jerry Keybl (JK): Viral vectors are inherently complex to produce at any scale and the complexity really comes from three places. One is genetic structure, two is their physical structure, three is how they’re manufactured. To make viral vectors that are safe for patients we want to make sure that we don’t produce replication competent viruses. We don’t want to have a virus that once a person receives that treatment may produce more virus that could potentially infect more people. If we were able to put all the genetic information in at once, we would have a much easier time but we don’t do that to make sure that we maintain a safe product.
BI: What about the physical structure?
JK: Some viral vectors, like lentivirus are inherently unstable. What this really means is that as we further process them, we lose some. So, after we produce the viral vector, we must put it through downstream processing to make sure that we are putting a purified product into a patient. Yields through that process of 30% are considered high, which means you’re throwing away 70 to 80% of viruses produced during processing. Some of it is due to the structure, some of this just due to the size. To make sure we have a safe product is to make sure there’s nothing else in the product, so a lot of filtration occurs and often the things that you’re trying to remove and make sure aren’t in there are the same size as the virus you produce. So, it’s a very challenging technical problem.
BI: Can you explain the difficulties regarding the manufacturing process?
JK: We use living cells to produce it, this is not the only biologic by a longshot that’s produced in the industry today but it’s still really complex to solve. It’s relatively early in talking about the development of the whole industry, and so a lot of processing comes straight out of academic labs meaning there’s academic processes. When manufacturing it’s not really scalable, you have to scale up many, many times to get to larger volumes and there’s a real push towards the industry moving into suspension culture, which is much more like how monoclonal antibodies are produced today, which is going to be really, really helpful.
BI: If they are so complex to manufacture, why are they needed in the cell and gene therapy sector?
JK: Viral vectors remain the most effective way of getting cells to express new genes. The industry has spent the last 30 years really understanding trans gene expression, how we manufacture them, and how we maintain safety and stability. We’ve been [working] at this since the mid-90s and really focused on bringing the expertise to customers, I see this as a really important modality, one that’s not going to move away easily in the next decade.
BI: What do you predict the future of viral vectors is going to look like?
JK: I think they’re going to be the dominant modality for the next decade. Part of this is that there’s just such a rich pipeline although the time to see that through is going to take a while. They really do have some strong advantages when we think about inserting genetic material themselves. When we think about modifying cells in the gene therapy industry, we can think about it two paradigms. One is in vivo, where it’s in the patient and we understand that pretty well, I think that’s going to be really, really dominant. And there’s ex vivo where the cells are processed outside of the body and returned to the patient. That’s the one we’re probably going to see newer technologies [emerge] sooner.
BI: Has the COVID-19 pandemic affected the anticipated timeline?
JK: I haven’t seen anyone in the industry decide to slow down, everyone is moving fast or faster than they were initially to see the benefits of these types of theories or treatments. The second thing, though, was there has been some challenges around supply and in terms of the industry overall. Here in the US, there were things like rated orders around materials that affected the entire industry. We’re kind of coming out of that but there is going to be some short-term delays, but I think that’s more of a speed bump and not a change in the trajectory going forward.
BI: How do you believe the industry can reach its potential?
JK: I think for the industry to reach its potential, the technology is going to have to be able to produce more viral vector, we’re going to have to reduce variability in what we produce, and we’re going to have to do it faster.
BI: What is MilliporeSigma doing to tackle the issues?
JK: Late last year, we launched a platform that we believe can cut off at least 40% of the process development time because there’s just less work to do up front versus when customers try and modify their own cell lines. In a two-year period, we’ve been able to increase the virus titer and in addition to being a high performing cell line in terms of the upstream, it also has some real benefits on the downstream and a lot of this comes from the fact that we’re using a chemically defined media.
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