Moderator Nicholas Vrolijk (managing director, BPTG, BDO USA) opened the second panel on therapeutic cell and gene therapy by introducing the participants.
David Chang (CEO, WuXi Advanced Therapies) has 30 years in the industry with prior experience at Celgene, Roche Genentech, Biogene, and BASF. He has worked in cell and gene therapy and biopharmaceutical technical development, manufacturing operations, engineering, and strategy.
Chang: WuXi Advanced Therapies is a globally integrated CTDMO providing front-end research and discovery all the way through development, manufacturing, and release testing. We specialize in virus and cell therapy testing, with most clients in preclinical or early stages. Our innovation center is in Oxford, UK, and our major hubs for process development, manufacturing, and testing are in Philadelphia, PA; Shanghai, China; and Wuxi City, China.
Edwin Beale (senior VP of business development, iVEXSol) has 25 years in the biomanufacturing industry across different modalities. He has worked mainly with large molecules, but also with DNA antisense and cell and gene therapies. He held previous business and marketing positions with Catalent Biologics and Cytovance Biologics.
Beale: I’m excited to talk about challenges in manufacturing cell and gene therapies, with a focus on lentiviral manufacturing concerns. The industry was struggling using transient means and experiencing great variation in batch-to-batch comparability. Not only is it a nonproductive system, but you can waste ~30% of your material for comparability work. If your product fails with materials purchased from a CDMO, you still have to pay for it. So how do you factor that into your risk assessment? Do you make two batches? Do you make three batches? How many are you paying for to ensure that patients will get their material?
The timelines also are complex for that manufacturing system. You have to have the machines in place, plasmids made, a lentiviral vector, and a patient’s cells. It is the most complex supply chain I’ve ever seen, and that extends development timelines, thereby slowing advancements in cell and gene therapies.
We had been working with a technology that went dormant — for a number of reasons. So the original group decided to revitalize it by developing a stable lentiviral production system with all components integrated into a stable producing line (not a stable packaging line). The process makes five to 25 times more product with a production system similar to that used for monoclonal antibodies (MAbs). Production then takes another two to three months to make a stable lentivirus. We’re just launching now, moving on to clinically relevant vectors and signing on our first clients.
Bruce Thompson (VP and technical lead for the cell therapy franchise at Resilience) has over 15 years of experience in CMC development and manufacturing for cell therapies. Previously as VP of process sciences at Lyell Immunopharma, he was responsible for process and analytical development and technology transfer of processes and methods to a newly built state-of-the-art GMP facility. He also held positions at the Fred Hutchinson Cancer Research Center and Pfizer.
Thompson: Resilience is a relatively young company, founded a couple of years ago during the pandemic. National resiliency in the supply chain is critical to the survival of our global population. We want to ensure that we can mobilize CMC capabilities quickly because we know we will have future disruptions — whether from another infectious disease or a war such as that in Ukraine.
Our second observation is that biomanufacturing capabilities by and large haven’t kept up with scientific innovations. We want to ensure that those two are linked and capabilities are leveraged quickly into curative therapies for patients worldwide.
Resilience is applying new and emerging technologies through introducing platform capabilities that enable us to move modules in and out from autologous to allogeneic therapies. We can move from lenti- to retroviruses by swapping in a bioreactor unit operation to a platform process. In partnerships and business models, we do not expect everything to be a transaction. We think like people who are developing programs and products, not necessarily providing turn-key services. Our focus in on velocity and sustainability, ensuring that programs move quickly through development stages. Along with addressing quality and compliance, we are interested in analytics and digitization that helps us to move quickly through production, with quality release by exception. So we learn about our critical quality attributes (CQAs) as we’re developing products and programs with our partners.
Thinking about end-to-end solutions is important. We want to support clients through preclinical into commercial stages, and we’re building capabilities and expertise across the network to be able to do so. Our audacious plan to be able to serve CMC capabilities in cell therapies, gene therapies, nucleic acids, vaccines, and biologics. The Resilience network has 11 sites across those different modalities, supplying capabilities and supporting activities on both US coasts.
Vrolijk asked panelists to identify emerging technologies and associated development and manufacturing challenges.
Thompson: We have yet to pair technology with our understanding of clinical indications and the biology driving efficacy. Autologous cell therapies have shown high efficacy, but we have not demonstrated an ability to scale out. We talk about centralized and decentralized manufacturing, with a number of innovations coming into a decentralized manufacturing space but without a QC testing element. So although we can manufacture at point-of-care, we usually can’t perform quality review release and testing there. Solving for that with new technologies will be critical to our ability to decentralize those manufacturing processes. Another issue is scale: We need to learn more about durability of our allogeneic programs and how to scale them appropriately, also reducing our cost of goods (CoG).
Vrolijk: Edwin, iVEXSol is improving on an already defined technology.
Beale: Unlike a CDMO, we’re starting off in the innovation stage. By contrast, a CDMO moves along with built assets already. It’s a complex, internal chess match to figure out how to innovate and move the industry forward when the biggest challenge is to acquire the starting material (patient cells). The industry has yet to understand how those cells grow from patient to patient. There’s a bioinformatics piece that we need to crack that nut, and that’s going to be important as we move forward.
Chang: I’m a true believer in the cell and gene therapy industry and modality. Right now, innovation is everything — not just to reduce CoG and efficiency, but also to address the needs for future therapeutic modalities.
We need a key AAV manufacturing workhorse to increase titers and purity while bypassing the scalability limitation for plasmid-based processes. We need to improve CoG not only to enable the CAR-T manufacturing platform, but also to fulfill current and future therapeutic development needs. We should not be undertaking incremental innovations (such as with digitalization), but instead, full-on innovations to sustain the industry.
Vrolijk: Bruce, you have partnerships with folks who are exploring novel approaches. Do you have any thoughts about accommodating other practical constraints and limitations?
Thompson: We can talk about technology innovations in instrumentation and applications of new scientific elements. But we also need to couple those with business and regulatory innovations. On the business side, we’re seeing new models of coincubation, equity investment, and aligned incentives that are leading us to think about partnering programs — offering more ownership to excite individuals working on both sides of a program.
On the regulatory side, the FDA has introduced innovative approaches to regulatory filings such as the recent parent–child IND process to explore different modalities within a single clinical indication. That and other innovations expand our ability to move quickly with new technologies. We can introduce new ways of closed processing and analytics with next-generation sequencing to gain information that hasn’t been used from a regulatory perspective. The FDA is open to new approaches to consider disparate modalities and technologies together in a way that might speed us to the clinic.
Vrolijk: David, WuXi Advanced Therapies is accustomed to working with global regulatory agencies. How do you view evolving regulatory perspectives?
Chang: Regulators need to appreciate new modalities and have a strong willingness to work with the industry. From my years in the MAb industry (mainly with Genentech), I know that industry and regulators need to work together to come up with guidelines. The cell and gene therapy segment is replicating that, but not for all delivery platforms. Each route has different kinds of safety and efficacy considerations. Regulators are struggling, as we are, with how to ensure purity and address unpredictable safety events.
A CDMO can generate objective, collective domain knowledge. My company partners with regulators to define, for example, acceptable DNA levels for AAVs. By working with regulators, CDMOs have the opportunity to expedite the process of moving through an IND to a BLA.
Vrolijk: Edwin, based on iVEXSol’s approach of dealing with known limitations, how do you the envision that your approach might apply to other sorts of technologies? Is there a basis for comparison?
Beale: We see many opportunities for innovation. The technologies exist, but they have to be pieced together. In our case, the technology sat for 10–15 years waiting to be developed. We are seeing people take a set of existing technologies and piece them together. Some that might not have worked 10 years ago are being revived and advanced. Regulators are interested in patient safety, but current process steps remain manual and labor intensive. You are setting yourself up to make a mistake when you already have multiple interactions with patients and multiple steps in a process.
Vrolijk: What limitations does Resilience encounter with current technologies?
Thompson: In my large-pharma experience, we would have a new and innovative way to do something but need to apply it to a clinical product to get some feedback. Because Resilience doesn’t have its own product portfolio, we can innovate independently of connectivity into a clinical program. The downside, obviously, is that we don’t get clinical feedback. So we need to have other ways of interacting with the FDA to help regulators understand our approach.
Another aspect of our business is that companies come to us so that we can explore innovations with them. Many companies have pipeline programs, so the first program that comes in is more traditional. The next program might enable us to innovate together. Our partnership model begins to shine when we highlight that we have a new way of performing a certain unit operation, and the partner is willing to try it on its next program going into clinical trials.
Vrolijk: David, where are you seeing some of the best opportunities for improvement?
Chang: So far, the most proven, established cell therapy is that based on autologous CAR-T cells. At my previous company, I oversaw CAR-T manufacture and development, which is far from easy. You can have parallel processing in one suite, with materials from multiple patients passing through. How do you prevent cross-contamination? That’s just a starting point.
We need transformational technologies right now. For autologous CAR-T therapies, we need to integrate automation and move away from manual steps that are prone to error and increase CoG. The challenge is that we need to integrate operations under one automated solution. That is the call to action for autologous CAR-T therapies. We need to produce error-free, CAR-T cells reliably, predictably, and cost-effectively.
The Importance of Innovating in Partnership with CDMOs
Vrolijk: Edwin, how are you seeing CDMOs respond or incorporate new technologies?
Beale: We’ve been so busy pioneering that we haven’t been adding time to innovate, and now we’re overrun. We know that we have to make strides forward and that the therapeutic companies don’t have the time, and they trust us to figure out the next advancements. We’re all trying to move the ball forward.
I’d like to see more cooperation from CDMOs. If I have transposon technology or a piece of a cell line, then I don’t want my competition to have that. As an industry, we need to focus on patients and come together to provide solid solutions. We’ve seen CAR-T therapies scale up from treating 30–100 patients to 30,000 patients, and we just can’t keep up with those demands. So I’d like to see CDMOs come together as an industry to solve problems together.
Thompson: One founding principle at Resilience is the democratization of medicine. That is not mutually exclusive to a business plan that allows us to protect assets, and it has much to do with harmonization. For example, a number of instruments are on the market for closed cell washing. Although some of them address volume limitations and reductions better than others, we probably could harmonize operator training.
Each CDMO has issues with capacity at some point. Partnerships can create opportunities to harmonize technologies. There’s an opportunity to build a community around that “athlete in the field” — the manufacturing and CMC capability.
Chang: CDMOs must be innovators. Our customers come from academia and hospitals. They might have a great idea for a gene sequence with a certain kind of cell phenotype, but they don’t know anything beyond that. They can test it in animals and nonhuman primate models, but they need to go through that process into the clinic.
Innovation is critical, even though 75% percent of the industry is still in preclinical stages with a product that’s at least two years away from an IND. Our customers lack the capability to bring preclinical animal models into the IND stage. I’ve never seen that bar so high and so difficult to reach. But CDMOs play a critical role and need to innovate because customers need the help.
Moderator Nicholas Vrolijk is managing director, BPTG, BDP USA; Edwin Beale is vice president of iVEXSol; David Chang is CEO, WuXi Advanced Therapies; and Bruce Thompson is vice president and technical lead for cell therapies at National Resilience.
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