Manufacturing can make or break the future of cell and gene therapy. In this episode, Stuart sits down with two expert guests to share how smart design, automation, and closed systems are helping to lower costs, reduce complexity, and make therapies more accessible. From scaling strategies to operator-friendly technology, they reveal why manufacturing isn’t just a back-end process, but a critical part of therapy development from day one.
Guests:
- Professor Mark Lowdell, CSO InMune Bio Inc
- Luc Henry, Founder and CEO at Limula
Cell and gene therapy: progress and growing pains
[00:00:04] Stuart Lowe There's lots to celebrate in the cell and gene therapy industry. New products are being approved on a monthly basis. Over 40,000 patients have already benefited from the curative potential of these therapies. But look behind the headlines and a concerning picture emerges. Patients unable to access treatment are reasons of geography, cost, or supply. It's simply the case that our ability to manufacture at scale has not kept up with the impressive scientific progress. So what can companies do to ensure that their therapies avoid the scaling issues faced by others in the industry? And how can they do this while continuing to meet demanding clinical milestones? To help answer these questions, I'll be joined by two guests who are deeply involved in developing and executing manufacturing strategy to explain their approach. My first guest is Professor Mark Lowdell, Professor of Cell and Tissue Therapy at University College London, and CSO at INmune Bio. He brings a unique perspective. He's been an active part of many cell and gene companies in leadership and advisory roles, and has firsthand experience of integrating manufacturing thinking into process development. Next, I'll speak with Luc Henry. Luc is one of the co-founders and CEO of Limula, a company offering a novel take on embedding scalability into manufacturing tools, supporting therapy companies to make personalized medicines accessible to more patients. And remember, if you enjoy this episode, please leave us a rating and review. Well, it's really great to see you, and thanks for coming on the podcast. Would you mind telling us who you are and what you do in the cell and gene therapy industry?
From academia to industry
[00:02:04] Mark Lowdell Yes, certainly Stuart, thanks for the invitation. So I'm Mark Lowdell. I'm a full professor at University College London and the person who really started 35 years ago making cell and gene therapies and have been doing so ever since. We built the first facility in Europe, possibly even in the world, to manufacture cells as medicines because Europe started that process before anybody else. And we made the first ATMP in 2007 under European regulations. I've been involved in a number of spin outs in that time, one of which is INmune Bio, and I am the co-founder and remain chief scientific officer of INmune Bio and two of the drugs that we're developing are drugs that are invented by me and my team and licensed out from, from UCL originally. So yes, I've been advising companies for a very long time now, but it has given me a fascinating insight to lots of different products that we've made. The first product I have made was a TIL cell product back in 1988 and then an NK cell product later the same year, and I've gone through that with my career and made gene therapies and helped other people and so people have come to us for our advice and how do they take something that's experimental. I suppose that the most challenging one most recently was a product that Novo Nordisk bought in from a university in Scandinavia, and asked us on my facility to turn that into something that would get through phase one trial. And we learnt a lot doing that. But I think we also helped Novo Nordisk learn a lot because it was so different to what they manufacture. So it's been really good. I've made lots and lots of different products, worked lots and lot of different companies and so learnt a a lot through mistakes that I've make, my team's made and indeed the companies I've advised have made. So yeah, I think I've earned my gray hair.
Why manufacturing struggles to keep pace
[00:03:46] Stuart Lowe There's a lot made of this kind of supply and demand mismatch. Why do you think it is that manufacturing hasn't been able to keep pace with the demand or the available patient population?
[00:03:59] Mark Lowdell Yeah. So, so first of all, let's just put this into context. ATMPs are new. So we've really only been developing cells as medicines since 2005, very early in Europe and a little bit later in the United States and elsewhere in the world. And if you look at that, that's 20 years. Well, if you looked at recombinant monoclonal antibodies, it was 15 years from the first description of monoclonal antibodies before the first one was, was clinically available. And that was a process that admittedly was a substantial change from conventional white powder manufacturing, but it still fits into the same business model of single batch manufacturing to treat thousands of patients. And even in the best will of the world, and I'm sure we'll come on to this later on with some of our therapies, most of these products are still autologous, and most of them ultimately I think still will be autologous. The industry made a big thing about, oh, be in allogeneic very very soon without really looking at the science behind that. And even in allogeneic, you're starting off with a human cell. Unless it's a linearly transformed cell line, you don't get to the scales that you get with monoclonal antibody production. So let's accept the fact we're only 20 years into this and there's a lot to be learned. And there was an awful lot of hype around it because of, let's admit it, the substantial success of the early CAR T really, really drove this marketplace. And so everybody an [00:05:24]awful lot of the investors [0.2s] have come into this. Have come in with the idea, oh, well, we'll invest 300 million dollars in X and it'll be sold for eleven point eight billion in two years time.
[00:05:33] Stuart Lowe To be on the market and a great commercial success within.
[00:05:37] Mark Lowdell Yeah. Yeah. So the problem is that these things are difficult. They're very scientifically driven and they tend to be, I think probably a couple of years ago, we looked at this 90 percent of energy therapy trials were in academic settings and they were academically invented. And the pressure on an academic and I've been an academic all my life, the pressure pressure on academic is to publish a paper and the best paper in the highest ranking journal they can, not to develop a drug. And indeed, most of us, I think I'm probably a little bit closer to a drug developer than most of my colleagues, but we're not drug developers. We're not, we don't have that skill set. We don't even have that mindset. And our universities don't want us to be drug developers because let's put it into context, I might publish a really, really terrific trial of a new cell or gene therapy, and if it's really good, it might get into the [00:06:31]Lancet [0.0s] or the New England Journal of Medicine. That's very rare. But even then that's nowhere near the impact factor of a cell paper which would have cost a tenth or a twentieth of the money to actually deliver and without any reputational risk to the university. You start doing early phase clinical trials and there's reputations risk to the University. The way in which grants are funded means that you never get full economic costing funding of your manufacturing product, and so it needs to be subsidized.
[00:07:00] Stuart Lowe So the way that the innovations are coming into the market, they're almost kind of set up to be difficult to translate.
[00:07:08] Mark Lowdell So, you know, because you can make, unlike monoclonal antibodies, you can't make these products very easily, not easily, but technically very easily. You can work in a class to safety cabinet. You can walk in a completely open process. You can manufacture a small scale and still get enough to treat patients mostly, certainly in the autologous setting. And so you can do an early phase clinical trial without too much investment. That means you don't, there's no incentive, in fact there's very little money to actually work out how you would treat more than the 10 patients that you're going to treat in your phase one trial. But years ago when I was setting up my facility in London, one of the very very senior members of staff at UCL said that we're not going to invest in this because you only need to treat 10 patients in these trials, and there's no need to invest in anything more than that. And I said well actually no because if you're going to be able to plan this on. Oh, no, no. You just give it off. You know, we sell it off to a company and they do the rest. And that's been the challenge. OK, the idea being that you can treat ten patients. You can have a manufacturing process that's not fit for purpose, but gets ten patients treated, and then it's somebody else's problem. And so, you know, we spin out a company, and I know I've been involved in a few spin outs, both my own and ones I've advised. And the drive immediately is to get clinical data because that's what drives investment.
Translational gaps and CMC challenges
[00:08:35] Stuart Lowe Thinking about the provenance of most advanced therapies which, as Mark pointed out, originate from an academic setting, perhaps it's not surprising that we find ourselves with innovations that are solid scientifically, but where translational challenges remain unresolved. I asked Mark about the cash implications.
[00:08:54] Mark Lowdell And there's no incentive to spend money on CMC because the people that run the company are going no no no. I've got to go and my shareholders want to see see clinical data my shareholders working. We can't go out and raise money with banks unless you've got clinical data. And so it's very difficult to get investment in CMC. And it's very difficult. I'll be terribly rude and blunt here, but it's very difficult in my experience, and I'm not saying this is always true. In my experience, it's very difficult to get boards of biotech companies to understand the boring regulatory framework in which we live, and they go, oh yeah, we can fix that further down the line. We'll solve that problem at phase two, and all you're doing is building up a history of your product which then won't be usable when you go to BLA or MAA marketing authorization, because it's not the same product.
[00:09:52] Stuart Lowe Your company is going to be bigger and more expensive to run by the time you get to phase two as well. And that time spent on the CMC is more expensive too.
[00:10:02] Mark Lowdell Absolutely. You know, that's a really good point. Your your watershed waterfall, rather, the cash waterfall is now huge. And you say, well, actually, no, we can't do the phase two, three yet because we've still got some problems to solve at CMC. And no, no, no, no we've already treated a hundred papers. We could, you're exactly right there. And so it's this naivety which big pharma doesn't really have because they've got a bigger checkbook, and they can, that biotech is living on in investors cash. And it's running out.
[00:10:33] Stuart Lowe It's pretty galling to imagine a therapy making blistering clinical progress and starting to build hope in the minds of patients being stopped in its tracks by CMC issues when it's too late to change course. CMC stands for Chemistry, Manufacturing and Controls. It's such a key aspect of the product quality and manufacturing consistency that regulatory agencies can withhold approvals until they are satisfied that it's under control. And correcting CMC deficiencies can be a multi-year process. So if CMC is such a potential showstopper, is there a way to weave in thinking about manufacturing earlier on in the development process? I asked Mark for his thoughts. But there are companies who have co-developed CMC alongside doing therapeutic development. So this is the opposite side of the coin. So we've seen the pitfalls of not doing it, but have you seen particular benefits, success stories people have actually done it?
Building scalability into therapy development
[00:11:41] Mark Lowdell I suppose that the only one I can really talk about with any depth is our own with an INmune Bio. So I'd say two of the drugs we have an INmune Bio were invented by me and following my mantra, which is you shouldn't do a clinical trial at any patient unless you're intending that if it's successful to change clinical practice, because I think it's unethical to put patients at risk at early phase trials if you're not thinking.
[00:12:02] Stuart Lowe Thinking of the longer term because it's not, yeah, that benefit isn't worth the risk then, yeah.
[00:12:06] Mark Lowdell Yeah, I think so. But what do I know? And so within INmune Bio, both of the products that we bought in were products that I'd invented as a get-go to sit down, and say, well, we don't really know what dose is going to be needed because there's no informative animal model. So let's look at worst-case scenario. Let's look at how we can manufacture that at scale and what could that drug cost look like? What would the market bear? Let's say that we have x percentage, which is one disease that we're going to target because in biotech that's all you ever get to do. So which is one disease in the first instance and we'll look at what level of impact we might have on that disease. And then what we did with one of our products is say, right, well, this is what we think we might ultimately achieve. Using the worst case, which will be nice in the UK. Price would nice really put on that without us having to go through hoops of claiming special dispensations and everything else. And you know that in cancer a quality adjusted year is about thirty four thirty five thousand pounds. You can guesstimate, they never admit it, but that's what we gues estimate and so how many quality-adjusted life years would you have to get to justify the cost of this drug in there for what?
[00:13:24] Stuart Lowe Then you're kind of back down to the performance of the of the therapy as well.
[00:13:28] Mark Lowdell We do a lot of that modeling, if you like. A lot of it is in the air, but at least we try, and so we're not going to produce a product that costs two million pounds.
[00:13:40] Stuart Lowe Because there is a lot of thinking and what does that thinking allow you to do? Then if you've got even if it's finger in the air, what are you doing with that information?
[00:13:48] Mark Lowdell Few years ago, back in 2014, one of my colleagues at UCL, Sam James, very smart, came to me and said, we've got this lovely data where we've, we we've genetically modified some bone marrow divide MSCs, human MSCs to express trail to the molecule that the immune system uses to kill cancer cells. And we've injected these into mice with mesothelioma, and they go to the lung and they clear the mesothelium. And would like to do a human trial in mesothelioma or in lung cancer, probably lung cancer. And I looked at it and I said, well, actually the way, great, wonderful data, but you couldn't possibly translate that to a human because it's looking at a dose of probably a billion cells. In fact, ultimately the clinical trial was 1.2 billion cells, and you can't make that from one bone marrow, and just go away and look at how many cells you'd have to grow and how many incubators you'd need and blah, blah. So we worked with a small biotech company in Belgium to use a standalone bioreactor for growing mesenchymal stromal cells. And we invented actually a very, very, closed.High throughput system that even in a very small grade C cleanroom, we closed it entirely, we could put out between four and eight billion cells per run, and we could hold four bioreactors going simultaneously. So that was between 20 and 35 billion cells per manufacturing run. And that suddenly makes it affordable. So then you can go back and look at the cost of that. Now a few years later, there was a clinical trial completed at Great Ormond Street using non-modified mesenchymal stromal to treat patients with mesotheli with epidermolysis bullosa, a particularly severe form of it. And we were asked to supply the cells because we could do it very cost-effectively, and we did that as a contractor, not as a sponsor. That trial is now in press, so I can't say anything about the trial outcome, but we have had to look at, well, if it's successful, what would the market bear and could we make cells for the right dose to make that actually fly in the UK, because It was funded by National Institute of Health Research, part of NHS England. And we have an obligation therefore I think morally to make that drug available in the UK if we could afford it. What's the dose these cells, those cells these children will need, and how would you manufacture that at an affordable rate. And it was very easy actually in that setting because you know that we knew the dose really pretty much from the praise one trial to go back and work backwards and say what are these children cost at the moment to the NHS and could we match that or better that. And so, yes, you're able to sit down and do those sort of calculations up front and say, well, what does this mean about my manufacturing process? How efficient has it got to be? Where can I make savings? And so we've done that very, very, certainly in a very grown-up manner.
The power of process closure
[00:16:23] Stuart Lowe And you had to be innovative, right? So you've actually identified a gap as well, which, which wasn't met. It hadn't even been conceived as part of the manufacturing process before you did this calculation. Mark makes a good point about designing therapies with scale in mind. Clearly it makes sense for their commercialization, but what impact might it have in earlier development stages? I wondered. I wonder if you can tell us a little bit about how you are thinking about process closure for INmune Bio or some of the other organisations.
[00:16:57] Mark Lowdell Wearing my old university hat and head of the manufacturer, we set it up for UCL. We had an awful lot of processes that were open because they came very early in their scale and I think the first.
[00:17:08] Stuart Lowe And just try what you mean by by open here, Mark.
[00:17:11] Mark Lowdell Okay, so working in a class A environment with a tissue culture flask, a pipette, fully gowned up, goggles, nuclear biological warfare type kit, really uncomfortable in a room with 60 air changes an hour. Now for people that are biologists who haven't looked into that, let's just say what that means. Sixty air change an hour means the whole volume of air in the room gets removed and replaced with fresh air every minute. Well, what's the problem with that? Well, all of that air has to be filtered, multiply filtered. If you're working an open process and also the monitoring of that, the number of settle plates you've got to put down, that you've gotta go and put into an incubator, and someone's got to count them and see that, and if you've got a positive, someone's gotta investigate that positive. That's what I mean about the running costs being high. And particularly when you then, if you then said that same process, I want to do a commercial scale, you're probably increasing the number of settleplates five or tenfold. And the staff that are doing that, that's all they do. So they're no longer doing some of your QC for you. They're dedicated just to putting little plates in. You've got incubators that take up four labs and it starts to become really, really difficult.
[00:18:25] Stuart Lowe So why are you starting with an open process at all?
[00:18:29] Mark Lowdell Also, when you're starting off with INmune Bio, when we were starting to make INKmune, my first drug product in INmune Bio, the scale at which we were making that from the seed stocks meant you couldn't go into a closed process. So we were doing that in [00:18:44]T-flask [0.0s] until we got to a scale where we could say, right, we don't need the any law, we'll go into a closed system.
[00:18:51] Stuart Lowe Part of the development pathway.
[00:18:53] Mark Lowdell And in autologous settings, it's difficult to get to the number of cells that you need to start. That's why CAR T is relatively easy to close. We close the process which, or to autologous build, or rather, we close that very early on because you're working with a whole apheresis, so it comes in a bag, it is welding, as long as you can do all the downstream bits. So yeah, closing is really good, but you have to have enough cells that can afford to lose some because you lose cells in tubing, even if you try and pump through. And so consequently there is inevitably a lot and cells don't like coming out of bags difficult to send few cells in bags. It's easy to take them out and put them in a in a falcon tube and spin them in a centrifuge but then you're back to an open process. So, you know that your your yield through the process is never as good closed as it was open. No, you couldn't afford to do it in an open setting
[00:19:41] Stuart Lowe That might be an argument for saying actually we should be investing in process closure first off as a priority because of getting out of those class A clean rooms is a priority, right?
[00:19:53] Mark Lowdell Well, absolutely. So, you know, if you look at my, and you're doing one product in a class B clean room at any one time, the thing about the the the CAR-T process that we close with Martin Pule's team, or Martin Pule's team close with a little bit of help from my team. I probably probably the better way. The Martin Pule process, if your like his team's process, we got to a stage where when that's all that's currently running in a class C lab, it could be in a class D, but we don't have a class D. But all of the development CAR-T program at UCL, which is fifth largest in the world, thanks to Martin and his team. That's all in closed system semi-automation and we can run three, four, we haven't got the space, we currently run three bioreactors simultaneously, so three products can be made at the same time. If you had a bigger lab, you could have any number of those and indeed that's what Autilus has done and have labs now with multiple parallel runs. So by closing, it means you can work in a grade C or grade D environment with 10 air changes an hour, those 10 air changes are spread over, you know, it could be a hundred products if you had that much. So it suddenly becomes much, much, much less expensive to run the facility. And gowning, you think, you, you know, the gowning that you need to wear to go into a grade B lab. It's about a third of the cost, probably a quarter of the costs to, for the gowning to go in to a grade C lab. And staff are happier because they're not wearing goggles and booties over booties and head chunk. It's a much, much, much more pleasant environment. So your staff turnover is, is less, and they're not as, not as exhausted. So yes, getting closure and moving into a lower grade manufacturing environment is just such a simple.
[00:21:35] Stuart Lowe You're getting a pretty good return on investment there as well, to take to potential investors as well, because it's a better story to tell that.
[00:21:46] Mark Lowdell Yeah, so when we, you know, we've got two products in the INmune Bio, one is CORDStrom, the umbilical mesenchymal stromal cell product that I talked about earlier on. When we took that into INmune Bio and away from the academic manufacturing, we changed the bioreactor. So the bioreactor is now the same bioreactor we use for INKmune. And the downstream, this is an allergenic product, so it makes life a lot easier, but the downstream process of both of them are pretty identical. They don't use all the same equipment. And so now you can envisage, well, campaign manufacture. One clean room makes batches of CORDStrom until you've got enough for your clinical trial, your clinical use, then you clean down same bioreactors, because they're disposable components, so the bioreactor can change. You can just put different disposables in and you make INKmune. And so the same staff, the same process, the same equipment, so your capex is split between two drugs. And now suddenly you've got a much, much, much better story to go out to investors with and indeed people who want to buy them.
Partnerships and shared expertise
[00:22:50] Stuart Lowe I really enjoyed getting to speak with Mark. He brings such a wide array of insight and expertise, and I think the problems he highlights are central to understanding why the industry is struggling to scale manufacturing. Here are my three key takeaways from our conversation. One, while academia is a very fruitful source of innovation for advanced therapies, the nature of these products means that translation is a much bigger barrier to commercial success than is the case for other types of pharmaceutical product, like small molecules or monoclonal antibodies. Second, you can set your company up for smoother transition to commercial phase by thinking about manufacturing early. Mark shared how his team starts by modeling the cost, dosing regimen, and market fit before even entering clinical trials. That kind of foresight can help identify critical path items in the CMC development. And fosters therapies that are not just effective, but also scalable and affordable. And finally, we learned that moving from open to closed manufacturing systems is particularly impactful. Open processes are costly, slow, and tough to scale. Investing in process closure can reduce risk, cut costs, and could hold the key to making these therapies accessible to more patients. As Mark points out, manufacturing strategy, scale up, and process closure are often areas where partnerships between different types of companies can be particularly beneficial to access skills and expertise not normally found within biotech companies. To find out more about these sorts of partnerships, I spoke to Luc Henry, whose company, Limula, is developing a tool to support therapy development and manufacturing across a range of scales. Would you mind introducing yourself and telling us a bit more about what you do at Limula?
Automation and accessibility in manufacturing
[00:24:50] Luc Henry No, thanks, absolutely. I mean, it's a pleasure to be part of this exercise. And Stuart, thank you very much for inviting me. My name is Luc Henry. I'm the CEO, one of the three co-founders of a company based in Switzerland called Limula. And we're building a fully automated platform for the manufacturing of cell therapies.
[00:25:08] Stuart Lowe Oh, cool. And how did you get into the cell and gene therapy field?
[00:25:14] Luc Henry Myself, entirely by accident. It was actually my friend and long-term colleague, Yann Pierson, who is the brain behind the technology that we're trying to turn into a product and put on the market. So I don't take any credit for the inventive step. He came to me with a logo, the company name, and a very strong concept of the technology. And so because of our past history of working together he thought I would be a good co-founder, so we started the two of us and then invited Tom Eaton to join us and out of the three co-founders we build a team of 20 people now.
[00:25:46] Stuart Lowe And where are you hoping to be in, say, five years' time?
[00:25:50] Luc Henry In five years, we would like to see that tool used in GMP for the manufacturing of clinical grade products that would be used in clinical trials or even, you know, already further down the line, advancing and supporting our customers' advance in their therapeutic development journey.
[00:26:06] Stuart Lowe Thinking about people adopting novel technologies. And there's a lot of kind of established equipment that perhaps comes from the biologics arena. What are the sort of questions that people are asking? What are they, what are the concerns that they have when they're looking at new technologies and perhaps evaluating that for their processes? Can you let us in a bit of those kinds of conversations?
[00:26:33] Luc Henry I think experience told people that automation is only valuable if it's implemented in the right way and at the right moment. And we see that beyond automation, being able to work in a closed system, in a system where the sterile envelope is as small as possible and really only contains the cells will be a very strong cost-saving aspect to any technology, any solution. And so our target is certainly to be able to offer a tool that can be used in lower grade class clean rooms, because a lot of people have been stuck in solutions from previous industries or with designs that were not really thought for low class clean rooms. And they see this as one of the main barriers. So this is something we certainly want to address. Automation then comes on top. It's a cost saving aspect linked to lower labor. But really, if you don't solve for the sterile environment, then I think the value mostly is not realized.
[00:27:37] Stuart Lowe Maybe dive in a little bit to the challenge or the problem that the product is trying to actually solve. So I know you talked about wanting to encapsulate something into a single device, but why is that necessary?
[00:27:50] Luc Henry Two ways to look at it. There are the people thinking modular is better, so they're trying to cover unit operations separately in different devices. We see that a lot of users, especially in clinical centers or early in their therapeutic development value having a very low footprint and something that can sequence those steps to make it matter. And we see our technology really having a very strong differentiator on how we can manage different volumes or the cells in different volumes and so we think that we ideally position to transition between these unit operations without having to to take the cells in and out of a single device. So we think we have enough value to bring with the technology that people would then accept that having a single device covering every step as the right strategy.
[00:28:42] Stuart Lowe And you're hoping that people who use it in R&D will then kind of carry it forwards into their commercial scale manufacturer as well.
[00:28:49] Luc Henry That's again I think a very strong differentiation of what we offer. We've built the same technology or implemented the same technologies in two different products right now. One which is mostly manual, and it's something that we see people use in R&D in the early stage of process development and evaluation. They can collect preliminary data that is already reflecting the potential of the technology for their specific use case. But then we've taken exactly the same technology and implemented it in this fully automated system. So what we've demonstrated already internally is that you can then transfer everything you've learned on the R&D tool into the fully automated platform without having to redo any process development. Then we see this as a very strong factor for accelerating the development because you don't have a tech transfer step anymore. You don't need to rethink how you process yourselves between R&D and GMP. And we see this as a very strong feature.
[00:29:48] Stuart Lowe Luc's clearly been thinking quite hard about how to support companies on their scaling journey, moving processes onto closed systems, and gradually expanding the degree of automation deployed within the process. This makes it easier for early-stage companies to access the device and begin development on systems designed with future scale in mind. One of the things that influences scalability is the selection of where you manufacture the therapy. And I wanted to ask if this consideration had been in his mind when developing Limula's device. In another episode of this podcast, which is going to come out after this one, we're going to be talking a bit about where you actually manufacture cell therapies from a centralized car plant like facility all the way down to a hospital or maybe even the patient's bedside. Now, in your experience, have you come across any models which seem to lend themselves to one decentralized or centralized and how do we consider and how do we decide what is best for a particular therapy or indication?
Centralised vs. decentralised manufacturing models
[00:30:58] Luc Henry I think the jury is still out, right? I think from the beginning of our journey, and I think certainly the journey of cell therapy in general, there's always been this debate, you know, is there a better way to do things? And certainly the pros and cons in this centralized approach, which is very familiar to the pharma industry, the decentralized approach or the point of care approach very much reflects. The fact that those treatments were first developed in clinical centers very close to the patients by clinicians who had the skills and the infrastructure to produce therapeutics on site. I'm very much convinced that both will remain. I think they have different roles. I think there certainly have a role to play at different stages of a therapeutic development. For early clinical trials, I don't think it makes sense to take a centralized approach. Because, you know, of the low number of doses that you need to get to that clinical proof point. So I think it's again about a collaboration. Do pharma industry have the culture to work with hospitals? Do hospitals have the cultural to potentially work with larger industrial players? But also I think, it will very much depend on the final product and commercial state. If it's a product that addresses relatively small patient populations, patient populations that are geographically very distributed across the world, it makes it really hard to think of a centralized model where you would have to deal with low capacity and high supply chain complexity, while for a much more either concentrated patient population or a case where the sheer number of patients is very high, I think the economies of scale start to be attractive. So as a tool provider, we're certainly trying to be smart and build something that has an application in both. We're trying to understand, you know, is the fundamental difference in the tool's design that would prevent anyone in a centralized model to use something that is applicable to decentralized or not. At the moment, because we have this tabletop standalone system that can manufacture windows at the time, we will probably serve the decentralized market first. But we're already in conversations with multiple large pharma companies that see the value not so much necessarily in the product but in the technology. And so it's also a matter of.
[00:33:34] Stuart Lowe Like an OEM version.
[00:33:36] Luc Henry That's right. Deciding, you know, can we also think of a different implementation of the product? You know, we discussed that research use only implementation and then they stand alone and automated. Is there a case for a high throughput, large scale implementation of the very same technology that would facilitate, again, transfer between these different platforms, but that would be more suited for centralized? So it's certainly something we keep in mind.
Designing for ease of use and global access
[00:34:01] Stuart Lowe That's really interesting. And you also have to start thinking about who the who the users are, right? And potentially their familiarity with working under manufacturing regulated environments. But for distributed manufacturing, it seems like kind of skills, and training and ease of use becomes quite important, right.
[00:34:24] Luc Henry Absolutely. And this is why, you know, we always had the vision that Limula would provide a manufacturing device, not a research device. You know, and I think that puts a lot of constraints on the design choices that you made, not just because I think fundamentally some functionalities need to be there that are not necessarily needed for research use or the other way around, but also the kind of environment and profiles that would be manipulating the system that would be operating the technology. And so the way we approached this was to very early on engage with GMP operators, people that don't necessarily are involved in the development of the treatment, but really on the routine production, and ask them, you know, how would you want to see that technology implemented in a product? What would be making your life easier? And so, the user experience and the simplicity in how people can very quickly be comfortable with the machine that, you embedded in the design that prevents from making any mistakes is going to be critical to success. So I don't know, design is hard. I don't know if we have got every decision right, but we're certainly trying hard to meet those expectations.
Key takeaways: planning, flexibility, and partnerships
[00:35:41] Stuart Lowe Another inspiring conversation to round out this episode. Here are my three key takeaways. Number one, like Mark, Luc pointed out the high cost of cleanroom operations. His view, while automation has an important part to play, early savings can be made by implementing closed systems that minimize the need for high-grade cleanroom space. Two, making manufacturing technology accessible can be hugely impactful. The ability to take a common approach across PD and manufacturing means that lengthy additional development steps and costly tech transfers can be avoided. Finally, context matters. If we're going to roll out cell and gene therapies to the mass market, we're gonna have to be at least cognizant of who's going to be operating the manufacturing equipment and in what setting. That's it for this episode. A huge thank you to both Mark Lowdell and Luc Henry for sharing their time and insights. What we've heard today reinforces a clear message. Cell and gene therapy won't reach its full potential until manufacturing is considered as an integral part of therapy development, rather than pushing it down the line. From Mark's experience building therapies with scalability in mind to Luc's work on lowering the barriers to production through automation and process closure. It's clear that smart planning, flexibility and strong partnerships are what will move this field forward. Thank you for listening. If you enjoyed the episode, please be sure to subscribe, and we'll see you next time.
