Panel: Phase Appropriate Material Supply

Dan (00:01):
Thank you very much. That was a great start to the summit today. So we're going to move on to the next session now, and this session is really thinking about phase appropriate supply of materials for cell and gene therapies. So I'm going to invite the panel session up. This is going to be more of a panel discussion with some case studies, and some questions, and some questions hopefully from you guys out there as well. So if I could invite Frank Bonnelly up from Encoded, if I could invite Raluca up from Charles River, please, and Mahendra Rao from Pluristyx as well? Thank you.

(00:38):
Yeah, sit there.

(00:38):
So this is going to be an interesting one actually. So we've heard a lot this morning about these different modalities, these different things, and it got me thinking about where does everything start? Everything really starts with the critical materials flowing into those processes, flowing into the manufacturing, flowing into the development arms as well. So really today we're going to be talking about critical plasmid supply coming into things. Plasmid underpins a lot of modalities out there. And we're also going to be talking about critical cellular material coming in as well. So I would say it's a panel session of two halves. We've got DNA first and then we're talking about cells after that. And we're going to try and pull it together at the end with some common themes around regulations, future technologies, stuff like that.

(01:22):
So it's my great pleasure to start with to introduce Frank Bonnelly. Frank can introduce himself in a minute, and Raluca, and Mahendra as well. So what we'd like to do to start with is just spend a couple of minutes each just introducing yourselves, and then we'll move on to the actual panel discussion. So Frank, over to you.

Frank Bonnelly (01:40):
Hello.

(01:40):
That works.

(01:40):
So hi, everyone. First, thanks Dan and Charles River for welcoming myself and having me here. Frank Bonnelly, director of supply chain, alliance management, external manufacturing, small company. We wear multiple hats. I've been with Encoded just over two years, primarily sourcing critical raw materials, so plasma DNA and... I'll preface it, my entire experience has been sourcing DNA for vector production, specifically AAV9. So managing external contracts and really finding those ideal partners to bring our therapy hopefully to market. Previous to that, I was with AveXis, Novartis Gene Therapies, from the early stages all the way to commercialization of Zolgensma. So amazing experience there. Again, sourcing plasmids for AAV9 production amongst other things. Previous to that, most of my experience in supply chain was with a company called Hospira, which was a spinoff of Abbott Labs, which was then subsequently acquired by Pfizer. So again, pleased to be here and looking forward to the rest of the discussions. It's already been worthwhile.

Dan (02:56):
Thanks. Frank.

Raluca Dumitru (02:57):
Hi, everyone. My name is Raluca Dumitru. I'm scientific sales director at Charles River in the cell solutions division. I have been with Charles River for close to two years. Prior to Charles River, I worked at Lonza as well as Thermo Fisher Scientific in technical roles as well as commercial development roles. And before that, I worked in the cell and gene therapy space at two companies developing allogeneic cell-based gene therapies. My postdoc training was in stem cell biology. So cell solutions, we actually worked with a large number of donors each day, donors whose cellular material goes in the manufacturing of these lifesaving therapies. And oftentimes, we talk about difficulties in the manufacturing of these cell therapies, but I think it is absolutely critical to think about the starting cell material, and it is key to identify the right donor for the right technology. So I'm really happy that we're going to have this discussion today. Thank you very much, Dan, for the invitation.

Dan (04:09):
Thank you.

Mahendra Rao (04:12):
My name is Mahendra Rao and I'm the chief scientific officer for Pluristyx. I am an accident member of Pluristyx, because Pluristyx merged with panCELLa, where I was the CEO, which developed stem cell based technologies.

(04:27):
My experience with the... I won't tell you my whole background, but I just point out that the reason I'm on this panel is because of my experience in having to get cell-based therapy towards the clinic and develop appropriate protocols for manufacturing them. So that was a learning, as you heard from Palani earlier, and that meant having to figure out how things get done, how to use new technologies, and how to develop them. And I guess, I went through a trial by fire because I was at the NIH when the NIH decided to make GMP grade iPSC lines, and I was tasked with getting that done with Lonza. So we had to figure out all of those processes and learn how to do it. Luckily, I had the FDA as a sister institute right next door and the FDA asked me to serve on the cell and gene therapy advisory platform and chair it for a period of four years. So I learned through trial by fire as to what the regulators are thinking, and what needs to be done, and then trying to execute it under the NIH mandate.

Dan (05:32):
Thank you, everyone.

(05:33):
So today really we want to get into a discussion around phase appropriate supply, what grade of material is required, what grade of material is acceptable, what's that risk approach to things? So the first session really is thinking about that from a plasmid DNA perspective. I'm going to turn the floor over to Frank who's going to give us his insights and lessons learned hopefully around sourcing DNA for gene therapies.

(05:56):
So Frank, over to you.

Frank Bonnelly (05:58):
Thanks, Dan.

(06:00):
First thing I'll say is, it's great to be here since this is my first conference since COVID. So it's great to be here in person, and no masks, and everything like that. And having supply chain in your title during COVID was a lot of fun, I got to tell you.

(06:16):
But no, as I thought about what I was going to say or talk about, given my experiences over the last seven years or so, really primarily sourcing plasmid for these therapies, I thought about a couple of things, and a common theme kept emerging. So I figured I'll just walk through some of my experiences, some of the lessons learned, and then wrap it all together through the title of our panel here, which is phase appropriate supply.

(06:47):
One common theme that kept emerging was risk management and risk tolerance as specifically geared towards the very aggressive timelines that we're usually on, and rightfully so. We're trying to bring critical therapies to market for patient populations that are desperately in need of them. So inserting risk into that timeline for any reason is something that the leadership that I've seen is never really keen to doing. So when it comes to the plasmid world, in my experience, what I've seen is a couple of things have to be considered. And the first one, I have supply chain in my title, so what is your demand? What does your demand signal say? And that can be very complicated. That's a loaded question. How much material do you need?

(07:44):
In my experience, typically the phrase of building the airplane as you're trying to fly it, your demand picture is not very clear. And it usually does two things. It usually increases and it usually moves further up. So you need more and you need it sooner. There was a saying I had during my time at AveXis, which was, you can never have too many plasmids. That is not a problem that I see. So your demand signal will allow you to make decisions on certain elements. What type of reactor are you going into? What size reactor... Are you trying to solve a current problem or a current demand signal? Or are you looking to secure your supply chain throughout the life cycle of your product by going into a certain reactor that can essentially protect if you eventually get to commercial stage?

(08:44):
The other thing specifically during this time is managing your cash. So a lot of companies are struggling today in having to manage cash a little bit more tightly. So the ideal de-risking situation might not be completely there. So there's decisions that need to be made with how you manufacture, how you source these plasmids.

(09:09):
The third element that, throughout the experience that I had at AveXis and the experience that I'm having now with Encoded, that I've seen is the concept of cross-contamination when it comes to manufacturing plasmid. So do you go into a stainless steel reactor or do you use a single-use train, right? The concern is there and the cost of going into single-use obviously is higher. So that's another element of de-risking your timeline.

(09:44):
So as I wrap it all up together into what I look for in an ideal partner to manufacture something as critical as plasma DNA, we were talking about this earlier, Dan, about obviously the four quadrants that I look at, that I show potential partners. The first one obviously is the quality side. It has to be there. We have to move quickly, but we have to move safely. The quality reg side is the first thing we discuss.

(10:16):
The second thing is the technical expertise, the process. Do you have a small scale that translates to large scale? Are you able to predict what you're going to get out of your full scale reactor when you run your small scale? And I've seen varying elements of success there where I hit the nail right on the head, or it just comes nowhere near it. So that aspect of it will come into play a little bit later when we talk about cost.

(10:44):
But the third quadrant was really the intangibles. What kind of collaboration are we getting into the alliance management side of the partnership? And that is, as I've learned over the past seven years, is critical to a successful partnership. We heard in the previous presentation about the collaborative approach between the client and the CMO where there is no, "We are the experts, we're going to get you what we need." There has to be a collaboration. There has to be that certain element of teamwork between the two.

(11:21):
And then the final one really is cost. I mean, we talked about how critical it is to really reign in the cost of these things. And cost can be looked at specifically when it comes to plasma DNA in several different ways. There's approaches to procuring plasmids as we need a gram, we go buy a gram. There's the element of procuring capacity. We're going to buy a batch. Whatever we get out of that batch, that's what we get for better or worse. But then it's the back to the demand pictures, how much do you need? How much do you actually need, I see a lot of, "Well, I need a gram. So I'm going to go into a 30-liter reactor and I'm going to plug that hole." But what if you could go into a 500-liter reactor and get 10X for 2X the price? So you're looking at cost in terms of cost per batch. And then you also have to look at it as cost per gram.

(12:20):
Obviously, if you don't need that much material, you're not going to do that. But over the life cycle of your product, that's where I mentioned in the demand picture, you're not just trying to solve problems of today, you're trying to solve problems for future stages.

(12:32):
So as I bring it all back to phase appropriate material supply specifically for plasmids, in my experience it's been, once the human element is brought in, you can work up to that point with your GMP source, your HQ, your... There's a lot of names for them, right? GMP-like. But once you are manufacturing, in this case plasmids are going into a vector for potential human introduction, it's full GMP. And that ties it back to the risk element. Why are you inserting risk as minimal as it may be and as overkill as it might be, into your timeline to get this critical therapy to the market? So when you bring in the human element, it's full GMP in my experience.

Dan (13:32):
So Frank, from a phase appropriate point of view then, you'd argue that you can make a lot of plasmids. You lay down a GMP cell bank as early as possible for those. Then up to that clinical interface, you're happy to use phase appropriate supply of plasmid, be that research use, be that high quality, or whatever those GMP-like ones are. But as soon as you move into a first-in-man study, you're absolutely going for GMP. And that's just mainly a risk-based approach that you want to apply, because there's other companies out there that use a different situation to do that.

Frank Bonnelly (14:06):
Right.

Dan (14:07):
But in your experience from AveXis and now in Encoded, you'll always go down that minimum risk approach. And we talked about it earlier outside, do you see there's a difference there between actually the cost of it or the timeline? Which element drives which really? Because you can get some of these phase appropriate ones a lot quicker than you can for GMP plasmids. So again, I just wonder what your comments were around that.

Frank Bonnelly (14:32):
Yeah. Obviously, when you go GMP, it's going to take longer to get the plasmids. And there's elements within the non-GMP side that there's levels of quality within that group. So you can also make decisions there.

(14:47):
But as far as the cost, what I mentioned before about you could be blinded by a certain cost element when you're talking about a cost per gram where if you... I've made it cheaper with GMP is what I'm trying to say. Just by going into a larger scale reactor, your cost per gram actually comes out better than even an HQ or a non-GMP research grade plasmid. And then as far as the timeline, there's ways to manage your risk there. You're trying to move along and de-risk certain situations, and I've seen companies go as far as manufacturing multiple cell banks knowing they're going to throw out one or two of them just to cut that part out of the timeline. And as far as manufacturing bulk plasmids and GMP, it's really that added release timeline that gets you some added time to your program. So at that point, I see it as a business risk really to use the plasmids in vector production. You've got most of your release data already, so cost, I can make it the same. And I could make the same timeline using full GMP.

Dan (16:05):
Sure. Great. Thanks, Frank. That's been really useful insights into the way you think about it.

(16:10):
So I want to switch gears a little bit now and bring in our other two panelists to start to think about phase appropriate supply for critical cellular material. Really thinking about the... Well, not discrepancy, but the challenge of going from discovery all the way through to clinical manufacturing and clinical applications there.

(16:27):
So Raluca, what are your thoughts around phase appropriate? When you are thinking about from a cell solutions point of view, how critical is right at the start and that donor engagement, that donor position? And what is phase appropriate in your mind for that early stage setting into discovery?

Raluca Dumitru (16:47):
Thank you, Dan.

(16:49):
Every cell and gene therapy begins with cellular material. And in the case of allogeneic cell-based therapies, this cell material is really the key raw material that is going to be used throughout process development as well as clinical and commercial manufacturing. And usually sponsors that are developing autologous cell-based therapies use the cellular material in process development and maybe some of it later on for tech transfer and engineering runs.

(17:26):
When sponsors approach us, they approach us early on before they begin process development work. And they are essentially interested in screening donors to identify key donor attributes that will work for that particular technology. Or, if those key donor attributes are known, we have to recruit a large number of donors with those key attributes and bring them over, and over, and over again for process development work. So I think it is critically important to work with suppliers that have a large donor pool. And it's important to have a large donor pool, but it's also important to work with suppliers that have multiple collection sites across the country to capture that tremendous donor to donor variability because perhaps you can mitigate that donor to donor variability when you're making these cell and gene therapies.

(18:41):
Another important consideration is the recall ability of the donors. So once those key attributes have been identified, sponsors usually want to bring those donors back over and over for collections. And donors are just people like us. Some want to come and some are recallable. But sometimes life happens, they relocate. They simply cannot be available for collection. So working with suppliers that have a large number of these recallable donors is also important.

(19:30):
Collections, right? It's not only the donors, but it's the collection. How are we collecting? And there are so many parameters that can be modified during the collection, but suppliers don't necessarily know what works for each technology. So we can adjust collection parameters and collect with plasma or collect without plasma as mononuclear cell only. But I think it's key for us to work with the sponsors in such a way that we optimize these collections for that particular purpose.

(20:10):
Going back a little bit to donor screening, donor screening can be done in multiple ways. And I think it's really important to work with the supplier and choose suppliers that can actually do a robust donor screening in as short amount of time as possible. And usually, I have to say that this early discovery and preclinical work is done with researchers only material. So when sponsors want to transition to clinical manufacturing or even IND enabling studies, they will transition to a material that is collected under good tissue practices for further GMP manufacturing.

(21:01):
And I think there are a few key considerations to keep in mind. So the donors that are going to be participating in these clinical collections, they have to be screened according to FDA regulations. So the screening is a lot more robust than for researchers only material, because we need to meet the 21 CFR 1271 part C specifications. And essentially, you have to think that for one clinical collection, you have to bring at least two to three backup donors, because what if during the pre-screen the donor is positive for CMV or is positive for EBV, and you wanted the CMV negative donor or an EBV negative donor. So it's really critical to line up two to three backup donors for just one clinical collection.

(22:08):
And if you have a number of donors... If you think that you need, let's say, 10 donors for clinical manufacturing, in fact you need to multiply that by two or by three to compensate for the donor loss.

Dan (22:29):
Thank you.

(22:29):
So this phase appropriate way of looking at it, is there a real difference between the way cells are collected for early discovery and the way the cells are collected for clinical applications? Because presumably the donors are pretty similar, but is it the different levels of screening that's in place between those two that drives a different quality approach for a better word then? Because effectively the material is similar, I would say.

Raluca Dumitru (23:01):
The collection itself can be actually similar, but what you need to do is do a lot of donor screening beforehand. And the infectious disease panels, some are much more broadly for clinical collections than for researchers only material. But again, the collection parameters can be changed. So I think it's critical to work early on with the supplier, so that we identify those key parameters that work for the study. So it's also identifying key donor attributes as much as identifying key collection parameters that I think ultimately are going to be one of the determining factors for the success of manufacturing.

Dan (23:51):
Thank you, Raluca.

(23:51):
So I wanted to bring in Mahendra here actually and get your thoughts around this phase appropriate material supply really, thinking about how to maintain that consistency, how to maintain that scalability, I guess, from discovery through to clinical applications as well. And I wondered if you could comment on that really?

Mahendra Rao (24:10):
I'm going to try to lay it out as a background so that everybody is clear on what my experience has been. So when we look at cell therapy, currently we think about cell therapy in two different ways. One is where you collect from a donor and give it to an individual immediately, and either that's autologous or allogenic. But there's very little processing that's done even though it's a manufactured product. And that's really important to remember because the rules for that are different than the rules if I'm making something like from an iPSC where I take a cell from a donor, same process, but I have a long manufacturing process and a lot of time in what I'm doing before I put it into an individual, and the starting material may be different from the final product.

(24:54):
So when we think about phase appropriate material, you heard a lot of the rules and the regulations that apply. They apply differently to something that's going immediately into an individual versus something which is going through an input material for a manufacturing process. So that's a really, really important piece to keep in mind when you're considering all of this. And there are also very specific issues, for example, if you take an iPSC, or a pluripotent stem cell, which is going to be used as starting material or input material all the way for your clinical product and also for your research development, it's the same cell line. So you have to collect it appropriately if that's what you're going to use.

(25:36):
On the other hand, if you don't have a truly immortal cell and you're using it like an mesenchymal stem cell, then you're going to replace donors. So then you really have to worry about equivalence, and you heard all of what Raluca talked about in terms of being able to collect. So phase appropriate means different things for these things. And I'm just going to say that for an iPSC, it is not phase appropriate. You have to collect for a GMP standard. Or, you have to have a strategy where you have both in place and you reduce your cost by using a research bank from that same starting material. But that's collected in a GMP appropriate way.

(26:13):
For an MSC, you really have to worry about your release criteria and whether your release criteria allow you to predict equivalence among different donors to be able to get that done. And there are specific regulations on being able to do that. The same thing applies to plasmids which are being used because a lot of cell therapy is a combination of modifying the cells in some fashion with ex vivo gene therapy, as you heard, in being able to do that.

(26:40):
Again, if you imagine plasmids that are being used at the final stage in the product, you have to worry about integration, consistency, levels of expression. And those are really critical tests and you have to be phase appropriate in what you're doing. And there's a little bit of leeway, but not much. You have to be as close to GMP, as you heard from Frank before.

(27:03):
On the other hand, if I'm using the same plasmid and I'm using it as input to modify my iPS cell line, then all the quality criteria, everything else that I need to use is very different because it's now input material in a biological manufacturing process for which the rules from the FDA are very clear. It's not part of your final product in some fashion. So that's an important difference as well in what's phase appropriate and what you choose.

(27:31):
The last piece, and this is my personal issue with the plasmids has been, when you take an iPSC line and you modify it, or you express it a gene or a growth factor in it, or whatever else you do, you do it once. So is it truly a reliable, reproducible methodology that has to be done in a GMP environment? Or is this something that is input material and therefore my criteria for what I'm going to use is different? And the problem is, all my suppliers of plasmids have no criteria or definition on being able to do it. And even worse, the price that you heard from Frank on quoting for this, I need tiny amounts of plasmid [inaudible 00:28:17], and I need them one time. And I go to my plasmid manufacturer and they say, "I can't do it because I'm not interested, I'm not going to make enough money from this. And it's not a long-term business." So it's not just being phase appropriate, it's also being size and quantity appropriate in being able to get things done.

Dan (28:38):
No, that's a really good point actually. And I think you mentioned the FDA and the regulations around that, and it is a question for all three of you really, do you see differences between FDA and maybe EMA or MHRA as well in this area, especially cells and plasmids around these things? I don't know, Mahendra, if you'd like to-

Mahendra Rao (28:58):
Yes. So unfortunately, there's no harmonization despite the harmonization committees that have been set up for international standards. So there are significant differences where we have found whether it's plasmid or whether it's cells, that what's approved for use in one country is not going to be acceptable. And this problem has become quite acute for viruses because you make them once, and you've got a process, and you've got a site for making it. And it's also a problem for cells which you're going to use long-term because as I said, for a product you've started with an iPSC line, that's the line you're going to use. And if you've manufactured it one particular place with particular indications, that's going to cause difficulty.

(29:42):
And my experience has been, the PTMA seems to be a lot more checkbox. So if it's in the guidelines and you follow the guidelines, it doesn't matter, that's what's going to be approved. They're not trying to do the same risk-benefit modifications that the FDA has been well known for, or pioneering. And the EMEA seems to be a little bit in the middle between these two extremes in that they have much more rigorous quality requirements in some fashion for some aspects of manufacturer compared to the FDA. And if you don't meet them, there's less chance of negotiation, in my mind, with the EMEA.

Dan (30:25):
No, that makes sense. And I guess, the same for plasmid, Frank, as well when you think about it. There's recent guidance out from the EMA that talks about, I guess, phase appropriate principles of GMP for critical starting materials, plasmid being one of those, that can then feed into AAV gene therapies, could feed into production of lentivirus for modified cell therapies, whereas the FDA guidance on it is still not really that clear as which way you should go with it. So when you are sourcing plasmid, and I know you've sourced plasmid from both companies in the UK and the US, as a company, I mean, your strategy is to go to GMPs. You haven't got to worry about that. But if you were going for that phase appropriate thing, do you see that as a challenge? Do you see that as a difference? I mean, you've been in front of the regulators to talk about this in both areas. What's the learnings around that that you can tease out?

Frank Bonnelly (31:17):
Yeah. And I agree with you 100%. I mean, throughout the inspections, I saw one agency spend days talking about plasmids, and another one just look at them and move on. So a vast difference between the two inspections. But as far as we're all learning together, the agencies included. So in one of the inspection that was a couple of days talking about plasmids really looked like a learning experience. Okay, so that's how you're doing that. It again comes back to risk tolerance and management. It's that timeline that we need to keep to get the product to market. So the more conservative approach unfortunately, given that it's as minimal a risk as it might be, this is a starting material for upstream production. You're just trying to de-risk that and not get caught up in a situation where you're delaying your program 6, 12, 18 months.

Dan (32:20):
Yeah, makes sense.

(32:21):
And then Raluca, from your point of view on donor regulations, where do you see that evolving to? Do you see differences between different agencies in that, different territories? Or is there a bit more alignment around that between, say, US and European sites?

Raluca Dumitru (32:36):
I think there is a difference between US, EMEA, and PMDA. Here, in the US, donor screening has to be done according to 21 CFR 1271 sub-party. But in EMA, there are other requirements as well. Donors cannot come from countries that had the TSE, for example. And then PMDA definitely have their own donor testing criteria that are different. So we work with sponsors. Essentially we work early on with sponsors and identify the areas where these clinical trials are going to take place. And then we work with our quality regulatory group to identify the appropriate donor screening for each one of these-

Dan (33:34):
Sure. Makes sense.

(33:35):
Mahendra, you had a comment on that?

Mahendra Rao (33:36):
Yeah. I just wanted to add one more thing to what you said. So I completely agree with what you said, but we found that there's one huge problem with not just the donor consent piece, but ethical review and the IRB panels. And for collection of tissue samples, particularly for self-based collection of material and the testing that has to be done on the donor individual to be able to do this. So that has led to... Actually, on a practical level, what it means is, if you look at most of the companies which have collected tissue samples from making iPSC lines or being able to do a lot of tissue samples for even donor collections from apheresis, most of them come to the US even though they're based in other places. And this has been particularly true for cord blood samples or placenta samples. And the reason I think is thanks to the FDA.

(34:31):
The FDA and the United States Navy actually because of the organ transplant program that had been started, really set up tissue acquisition nonprofits, which collect tissue from various hospitals and make it available. And there's a very clear regulated process with regulated guidances and rules and regulations on what can be done and what is appropriate. So people find it much easier to navigate and get tissue samples in the US than they do otherwise. So we've had many companies come to us, and when we ask them where they're working, and whether they'd like us to collect the tissue in that country, they've often said, "No, we just prefer you do it in the US because that would be easier for us."

Dan (35:17):
Thanks. No, that's useful.

(35:18):
So the last area I wanted to touch on was, you've talked about this phase appropriate supply by either plasmid or cell material coming in from preclinical through to clinical supply. Where do all of you see perhaps it go into? What's the technology development in the area? I mean, people have used plasmids for a long time in things. And you raised the point that actually CDMOs can make plasmids, but they don't make it at the appropriate scale for what you need. So do you see technology moving away from perhaps bacterially-sourced plasmids to some of these synthetic DNA, some of these enzymatically derived DNA, that sort of area? And then in cells in general, are we going to move away from donors completely or not completely, but have banks of iPSCs that we can then draw on differentiating to different ways and regulation change as well?

(36:10):
So I'll open up to you guys, but it'd be really good to get your thoughts on where you think technology's going in this space. I don't know who wants to jump in first on that one.

Mahendra Rao (36:21):
So I'll give you my two thoughts on this is that, for us, bioinformatics and next generation sequencing has allowed testing and screening to be done pre-donor in any stage to be able to get that done. And that's been a huge, huge change in being able to get material and do that. And by the same token, because of next generation sequencing and DNA methodologies, manufacturing technologies and being able to do synthetic sequencing has become cost-effective so that we don't always have to grow in bacteria, but in vitro can be done. And particularly because of this RNA piece that you heard as well, and because that's been moving forward in technology, a lot of the technologies which can be used for RNA can be used for DNA as well in terms of synthesis. So that's been the big change. So it's technology and DNA modifications and sequencing technology.

Dan (37:19):
Sure.

(37:21):
Any other thoughts, Raluca?

Raluca Dumitru (37:23):
Yes. So working with so many sponsors every day, we're looking at the donor criteria that is really requested and asked for. And I think that some of these donor criteria is just so limiting that we worry about being able to supply these sponsors with this cellular material. So I'm even thinking of iPS cells, capturing these key characteristics in iPS cells that we can then differentiate into a variety of cell types. So I think this could be an interesting technology to use to mitigate some of the supply problems.

Dan (38:10):
No, that's great.

(38:11):
And Frank, I guess, final thoughts from you on, do you see Encoded or other companies like that moving away from plasmids themselves and going into more of these enzymatically-derived things for early phase, or maybe scale issues when you get economies of scale later on? It'd be good to get your thoughts on that.

Frank Bonnelly (38:29):
Yeah. So we have a process development and R&D group, we're talking about next gen processes.

Dan (38:36):
Sure.

Frank Bonnelly (38:38):
But right now, we know to a certain degree that what we're trying to get to the market, works. So that's what our focus is at the current moment. We know that an AAV9 therapy can get out there and really impact the lives of these patients. So that that's where we are today. But to answer your question, there's always consideration about what's next and how can we make it better. Not necessarily better, but more cost-effective, more readily available. So right now, hopefully, we'll get our lead therapy for Dravet syndrome to the clinic and hopefully to the market soon.

Dan (39:17):
No, that's great.

(39:17):
So I think it's been a really interesting discussion actually around that. I guess, my take home from it is that there is phase appropriate supply of this material coming in. We need to consider phase appropriate. We've got to balance risk against timelines, against cost, as everyone always does it in that manufacturing environment. Having that consistency pull through from discovery and preclinical through to clinical is important to maintain quality as well as reproducibility of those sort of things.

(39:43):
And the emerging technologies out there, I get asked a lot, what's happening to plasmid? It's going to go away in three to five years, isn't it? And I say, "No, I don't think it is. There's going to be a mix of different technologies coming through." It's the same for cells as well, different cellular technologies coming through iPSCs that will compliment all of this and give us more of a toolbox to play with, I guess.

(40:01):
So I'm going to stop there. I'm going to open the floor up for questions in the last three, four minutes. If anyone's got any questions from the panel, please make your way to the microphone and ask them.

(40:14):
Jesse?

Jesse (40:16):
Great panel discussion. Thank you very much, all three of you. The question's mainly for Frank. I think one of the key drivers for the phase appropriate description in products ordered from CDMOs, really it's the cost and speed. And wondering if you're seeing costs come down such that GMP-like versus GMP are roughly the same, just because the... I mean, over time, through iteration just getting better and better and faster and faster at probably doing full GMP grade PD, is it the same?

Frank Bonnelly (41:00):
Yeah. So it's a great question. Thanks.

(41:02):
So as far as cost, I've been really looking all over the world for plasmid. So I've seen a lot of the suppliers, I've seen SOWs from a lot of different CDMOs. And there's a lot of inconsistency in how these things are priced, even within the same organizations. I moved from AveXis to Encoded, same company sent me an SOW, wildly different. So as far as how it compares from the non-GMP side to the GMP side, what I refer to as being able to comparatively price it is really with the element of cost per gram. So you could go and get the small amounts you need, which is what I would recommend in terms of your R&D and PD side, before you get to your clinical stage, and get the amounts you need in those exact quantities. The cost really is very good there. But when it comes to GMP, that's where you can make some decisions that will make the cost comparative to that non-GMP side. You'll end up with a little bit more DNA, but like I said before, you can never have too many plasmids.

Dan (42:12):
That's right.

(42:14):
And then final question for this section.

Scott (42:17):
Yeah. This is for Raluca and, I guess, Mahendra too. I think that was a lovely summary of the issues with sourcing cells and collecting cells at different stages. And I agree very much about the importance of having multiple collection sites since it's so hard to access the donors with the characteristics that you need. Along with that, what's your take on having the quality system control collection at all of the different sites and what's your take on controlling collection methods or types of collection instruments?

Raluca Dumitru (43:02):
Thank you, Scott, for that question.

(43:05):
The quality of the materials that we're using not only for clinical and commercial manufacturing, but also for preclinical development, I think it has a tremendous importance. And suppliers that provide this material have to have a very robust quality management system where they add the protocols and follow through for every single collection. Again, we also have to be nimble and adjust these collections according to the needs. But absolutely the quality of the material has to have an utmost importance. And working with suppliers that have these integrated and uniform quality management systems across all sites, I think it's absolutely critical.

Dan (44:02):
Thank you, Raluca.

(44:03):
So I'd like to draw this session to a close. If you could all just join me in thanking our panelists today. It's been a great discussion. Thank you, guys.