Orgenesis is combining point-of-care technologies into mobile production units, as in this artist’s rendering.

Part of the advanced therapy medicinal products (ATMPs) class of therapeutics, cell and gene therapies (CGTs) can be either autologous, using the patient’s own cells, or allogeneic, using master banked donor cells. Global biotechnology company Orgenesis focuses on autologous therapies, with processes and systems developed for closed and automated processing that have been validated for regulatory-compliant production at the point of care for patient treatment. This technology could help overcome the limitations of traditionally cost-prohibitive CGT manufacturing methods that do not translate well to commercial production because of complex logistics that ultimately limit the number of patients who can afford or even access such therapies.

To achieve its goals, Orgenesis has developed a point-of-care (“POCare”) pipeline of licensed therapies that are designed to be produced and processed in closed, automated systems across a collaborative network. By combining science, technology, engineering, and networking, the company is working to provide a timely and efficient pathway for advanced therapies to reach patients at lowered costs. The company also draws on the medical expertise of its partners to leverage promising new autologous therapies through either ownership or licensing. The POCare network brings together patients, doctors, industry partners, research institutes, and hospitals around the world with a shared goal of harmonized, regulated clinical development and production of those therapies.

Orgenesis is working to combine POCare technologies within mobile production units — Orgenesis Mobile Processing Units and Lab (“OMPUL”) technology, currently in development (above) — intended for use and/or distribution through the POCare network of partners, collaborators, and joint ventures. OMPUL units are designed for validation, development, clinical testing, manufacturing, and/or processing of potential and approved CGT products within a safe, reliable, and cost-effective environment at the point of care — ensuring consistent therapy production across all locations. The design provides a means for the company to deliver CGTs to many clinical institutions around the world.

After selling its interests in MasTherCell — a traditional fee-for-service contract development and manufacturing organization (CDMO) business — to Catalent Pharma Solutions in February 2020, Orgenesis has expanded its therapeutic POCare processing sites into new markets and jurisdictions. Meanwhile, the company has invested in developing, manufacturing, and rolling out several types of OMPUL units to be used and/or distributed through its POCare network. Orgenesis operates subsidiaries in the United States (Maryland and Kentucky), Belgium, Israel, and South Korea.

Vered Caplan is the company’s chief executive officer. She has been an active life-sciences entrepreneur since the 1990s, founding and leading more than 15 companies in diagnostics, over-the-counter and prescription drugs, biologics, cell therapies, and medical devices. We spoke recently about her company’s point-of-care paradigm.

Our Conversation
Can you explain your company’s focus on autologous therapies? Cell therapies are personalized. Even allogeneic products aren’t exactly off the shelf. There are many challenges related to batch variability and making enough quantities. I do think there’s a bright future for allogeneic therapies, but for acute cases, the autologous approach holds a lot of promise. The challenge here is that these are living cells, so sterilization is not an option. You have to work in a very clean environment — for both collecting cells and making products.

We’ve been doing that for over a decade now, and one thing we’ve learned is that getting people out of the process is essential to reducing contamination risk. The only way to do that is by automation — which doesn’t mean just robotics. In many cases, you can use automation tools that are easily adaptable to biology. What you need to do is think about the process in an entirely new way.

For example, say you need to mix one component with another, which is very common in our laboratories. You want to feed the cells and propagate them, or you want to activate them somehow. Typically, a technician would add in what’s needed carefully by hand. You can even have a system do that automatically, but that doesn’t change the process. But with a continuous-flow system exchanging fluids, media, and other components using sensors that measure the amounts of different components in that fluid, now that’s true automation. You can regularly adapt the process to changing conditions in a closed system.

And closed systems would be key to preventing contamination? Many people think of a “closed system” as a box. But it’s about making sure that all these fluids go in — feeding or activating or combining with cells — without a risk of contamination from the outside. So all the pumps, connectors, and discontinuous movements will not harm the cells. Cells are sensitive to pressure, temperature, light, different chemicals, and so on. They are even influenced by their neighbors through chemical signaling.

If you can process cells in small units close to where they’re needed, that makes a lot of sense. You reduce the logistic burden associated with hauling materials to and from far away, and you eliminate the need to adapt your source materials to different surroundings. So there’s a lot to be said about decentralized processing. But how do you decentralize CGTs efficiently in regard to energy, source material, and logistics? We’ve built up our POCare centers, where we validate biological products using engineering to rethink and optimize our process. I think machines should be serving biology, not the other way around.

In some cases, we can collaborate and work with existing systems and manufacturers, and we’re happy to do so. We work with a number of industry players using ready-made solutions. But in other cases, we use a toolbox of engineering and automation solutions that we’ve developed (alone or in partnerships) or licensed. And we can adapt those technologies specifically to a given therapy.

What innovations are helping you make point-of-care autologous treatments work? Getting a product to market cost-effectively and making it widely available aren’t about engineering alone. How do you build a business model that makes point-of-care supply and validation very efficient? We partner with hospitals because they are running the clinical trials, which are an expensive part of product development. Research institutes license out their discoveries to biotechnology companies that spend a lot of money on clinical programs and getting products to market. Hospitals charge a great deal to run clinical investigations, and once products are on the market, drug companies charge a premium for those in turn — a sort of feedback loop.

But what if we say, “We’ll minimize the cost to you in the future if you commit to minimizing the cost of clinical trials?” Patients will benefit because they can get treated at a lower cost. In our business model, we’ve set up “validation centers,” which are clinical sites of excellence working with researchers to validate therapies and then supply those therapies at reduced cost to our partners. Some people call that an “open-source” model. We invest in industrializing the process for hospitals in our network, and in return we have a low-cost clinical trial and licensing of the technology.

To do that, we combine the “recipe” (the therapeutic research) with the necessary engineering and technology (sometimes with device and engineering companies as partners). So the industry players who are developing devices also benefit. They have a route to market, and along the way their equipment can be validated for CGTs. Finally, the third component is bringing in hospitals as part of that network.

Our business model doesn’t preclude the possibility of other marketing agreements later on, but it does give us a quick path to market through partnerships to get the validation stage done. If you’ve got 10 hospitals working on a product, each with 10 patients, then you can get that validation done relatively quickly and at lower cost [than with only one clinical investigator working on a study]. We’ve got contract research and manufacturing organizations to help us supply materials in support of the investigational new drug (IND) applications, and we have our own internal regulatory department, making us serve as a “biotech back office” to the hospital researchers. Meanwhile, we can minimize the cost of development — and later on, the cost of manufacturing, processing, and distribution. It’s more like a service model than a traditional pharma-company model for drug development, manufacturing, and sales. And many hospital administrators and investigators see the value and are eager to work with us.

That brings to mind the African proverb: “It takes a village” — in this case, to develop a cell therapy. You seem to operate as a facilitator. When you try to do something in a different way, people can react in funny ways. Tell a biologist, “We’ll automate this and that, and we’ll do this and that,” and the kneejerk response is “Oh no, you can’t do that!” I say, “We can. Let’s give it a try together.” Tell some engineers, “We’ll do this to the cells, and this is what happens.” They say, “No way.” And I say, “Yes, that’s what happens.” Tell a hospital, “We’ll set it up here, and we’ll do this and that,” and the doctors will be surprised. But this industry needs those different stakeholders to work together, and that’s what we’re trying to do.

Once we get past the initial shock, then things start to work in sync. When you’re talking about CGTs, they need this combination. It’s not enough to have good biology; you need good engineering around that. It’s not enough to have good manufacturing; you need good clinical validation. In cell therapies, the process is the product, so if you do the biology first and then go back and try to “stick in” the engineering, then it is doomed to fail. By then, it’s already a new product.

You need that combination of engineering, biology, and clinical investigation. That’s what we do as a company. We are very dedicated to bringing all those components together to operate in sync. But people need to be patient, as well. A biologist immediately wants to run to a clinic with the recipe. But we want to work on the industrial side — even as the doctors want to test it. We need to test the engineering along with the biology, so it’s about having the patience to do things in an orderly fashion as they should be done.

And it’s not about making a perfect machine that fits all therapies. We want to map the engineering to the biology — and then bring in the clinical partners and validation centers early on to help us make sure that the patients get the treatments they need. Once you have validated together the biology and the engineering around it into a mobile unit, then it’s easier to expand your supply chain.

How do you make it work in compliance with GMPs? We put tremendous focus on our quality system — I call it our “moral backbone.” We want to put forth the best possible patient treatment in the safest and most cost-effective way. That’s a customer-oriented quality approach. So we need a harmonized quality system across all those centers. Automation ensures that we’re always using the same systems.

As with raw materials, it’s helpful if you’re always working with the same supplier and in the same environment. So we’re investing a great deal of effort in adapting our automation systems into mobile units that can be placed easily wherever they are needed. Different-sized cleanrooms with different air conditioning and cleaning procedures all can have clinical effects on a product. But if it’s always the same “room” — inside the same kind of isolated unit with the same automation in every unit — then you truly are ensuring that everything stays the same. Our mobile units provide for optimal use of the space when we can make sure that everything is measured and monitored by putting the isolated components inside.

We insist on using the same suppliers, the same training, and the same methodologies. They contribute to the fact that you’ll constantly get the desired product every time. That’s part of our validation: making sure that no matter where you’re working, you’re making the same product.

Considering the changes suppliers can make over time, that seems wise. How do vendors fit in? It gives us a better negotiation position. There’s quite a difference between one hospital negotiating with a supplier or a single network of 50 hospitals working with a biotechnology company to negotiate with that same supplier. And that’s not just about price. Let’s say you need something for one center. Now you don’t have to stock up because you can always get it from another center in your network. You can work with your suppliers to get exactly what you need when it’s all monitored. You can make sure that supplies are adapted to the process and the needs of each center. And if you find something to be lacking, then you can supplement from other locations. That’s part of optimizing our processes.

And we don’t need to put our mobile units into existing cleanrooms. We can put them to work anywhere because they’re completely closed. As for cleaning and other such work, we try to make sure that everything is synchronized and very similar. We prefer to do that ourselves.

How large are the mobile units? An OMPUL unit is about the size of a shipping container, and we even talk about “OMPUL-izing” processes. Each one has a manual section and an automated section — isolated from one another. You can validate step by step because you don’t necessarily want to validate an entire automation process as one thing. These units are designed to incorporate the necessary flexibility and adaptability.

What’s the next innovation you’re working on? We’re looking forward to the first approved “OMPUL-ized” product. We do have products that are approved for use, but they aren’t yet fully “OMPUL-ized.” Some are more automated but still in early clinical stages, and some are further along in clinical testing but with less automation. So we want to close that gap. Once we have an approved product that’s “OMPUL-ized” and supplied, then I think that this will be an exciting game-changing moment.

I’m not that old, but I still remember when computers used punch cards. And what is cell and gene therapy if not “reprogramming” cells? For now, that work is done in cleanrooms by scientists with specialized knowledge and expertise [the equivalent of “computer rooms” and programmers of old]. But someday we could have the equivalent of laptops and smart phones for cell and gene therapy. It’s going to influence all walks of life.

When we started this company 10 years ago, there were only about 20 cell therapy products in clinical development; now there are thousands. Today, it’s predominantly about oncology, but there are so many other fields that require solutions, and we’re learning so much so quickly. Maybe we can have open-source companies that can supply that “programming” as a service. That’s what we do at Orgenesis. We license in the code because that’s what the therapy is all about, and we build these really neat “computers” to use that code and make reprogrammed cells.

I think that for anyone who has a disease, we should be able to reprogram cells to make that person healthy again. Hospitals should have the most efficient reprogramming units that are relatively low cost and made available to everyone. And we license the code to ensure that every hospital will have that and every patient gets the opportunity to make use of that code.

Brian Gazaille ([email protected]) is associate editor, and Cheryl Scott ([email protected]) is cofounder and senior technical editor of BioProcess International, part of Informa connect, PO Box 70, Dexter, OR 97431.