E63: Gene Therapy Manufacturing: Two Perspectives

Mary Parker:

I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science. Gene therapy is still in its early stages. Since the field is new but booming, the issue of manufacturing has become more crucial. How do we make these tricky products at a scale large enough to help patients without a longstanding infrastructure? Joining me to discuss this issue is Charles River Associate Director of Gene Therapy, Andrew Frazer, and Purespring Therapeutics' VP of Chemistry, Manufacturing and Controls, Amanda Weiss. Welcome, Andrew and Amanda.

Amanda Weiss:

Hi. Well, thank you for the invitation. It's great to be chatting about this.

Mary Parker:

Yeah.

Andrew Frazer:

Yeah, likewise.

Mary Parker:

So Amanda, can we start with you? What's your background and how did you get started with Purespring?

Amanda Weiss:

Sure. So I trained as a biochemical engineer at the University of Birmingham. And the reason that I took biochemical engineering was when I went for an interview down there, I had a look around their pilot plant and I fell in love with their shiny stainless steel bio reactors. I thought, "I just really want to know how they work. And so that's what I did. And my first scientific role after that was as a fermentation scientist at what was then Thorexus, then Cobra, and now Charles River. And there I made plasmid DNA actually for a gene therapy indication. After that, I've worked in a number of CDMOs and product development companies developing bio processors for different biological molecules. As part of that journey, I joined Night Star, which was a retinal gene therapy company, and I really enjoyed that experience and got to know the Syncona Group who put a lot of investment into new startups. And when the opportunity came along to join another gene therapy Purespring, I jumped at the opportunity.

Mary Parker:

So did you figure out what those bioreactors do?

Amanda Weiss:

Indeed, indeed. So I started as a fermentation, so as I say, making plasmid DNA and then ended up designing a lot and in installing quite a lot in the different places that I've worked at over the years.

Mary Parker:

It's funny you say fermentation, it makes it sound like growing these things is the same as using hops to ferment beer.

Amanda Weiss:

And that's exactly what it is.

Mary Parker:

That's pretty cool.

Amanda Weiss:

Yes. That's the guideline.

Mary Parker:

Yeah, yeah, absolutely. So what does Purespring do?

Amanda Weiss:

So we are a gene therapy company and we are leading a revolution in the treatment of chronic kidney diseases. The company was founded on the pioneering research from Professor Moin Saleem at the University of Bristol. He's also Purespring's Scientific founder. Did you know that there's about 840 million people globally that suffer from chronic kidney disease?

Amanda Weiss:

And there's been a real lack of innovation in the treatment of kidney diseases. You need even lots and lots of people with an unmet need. And as we know, many people who have those diseases end up on dialysis. When that fails, it's down to transplantation and when that fails, it fails. So we are really on a mission here to try and do something about this, and that's exactly what we want to do. We want to stop and reverse and cure these chronic diseases and really make a difference to those patients that are suffering from kidney disease.

Mary Parker:

That's awesome. Andrew, over to you. Can you tell me about your background?

Andrew Frazer:

Sure, yeah, of course. So my background is in biochemistry and actually it's interesting to hear Amanda talking about big shiny bioreactors. That was kind of how I started as well. I was quite lucky that during my PhD at Queens in Belfast, in Northern Ireland, we had a reasonably large scale pilot facility actually. So about 150 liter stainless steel fermentor and we used that to produce biocatalysts and that's kind of what I looked into in my PhD. That gave me a really good introduction to what goes on with industrial processing and particularly like upstream fermentation and that type of thing. So quite a similar kind of, I guess, start to what Amanda has.

I then held a role where I worked as a knowledge transfer KTP associate, so transferring knowledge between academia and industry. Working with a CDM in Northern Ireland. We started up a spin out business on biocatalysis and launched some products through that. So again, really wide exposure to different elements within biologics and biopharmaceuticals. I actually joined Cobra Biologics in 2015 as a Process Development Scientist. And really since then I've held a number of different roles within plasma DNA manufacturing and eventually got to where I am today as part of Charles Rivers gene therapy, CDMO business. And my current role, I work very closely with our commercial and operations teams focusing on our plasmid service offering.

Mary Parker:

You both mentioned the bioreactors, which makes me think that more companies who are hoping to invest in the future talent pool should invite schools to come tour their facilities and show up all their most impressive equipment. It's a good way to get kids interested in science.

Amanda Weiss:

Absolutely. I think until they actually see what's involved, you just don't appreciate it. You can't appreciate that from a textbook or a piece of paper. Getting there and having a look, as I said, that's what clinched it for me.

Mary Parker:

Yeah, it doesn't help that most of the pictures in the textbooks are stock photos of scientists playing with colored water and beakers and that doesn't seem very fun, but you show them a big shiny machine and then kids are way into it.

Andrew Frazer:

Yeah, definitely. And that was definitely my experience as well. I remember kind of getting into research and getting exposed to that side of it, all really small stuff on the bench, typically preparing little small volumes that you can barely see. But yeah, it wasn't really until I got to the big stuff that I got really excited about it.

Mary Parker:

Totally. That totally makes sense. So Andrew, how are plasmids used in gene therapy manufacturing?

Andrew Frazer:

Sure. If we look at major uses of plasmid, we can see that it can be used on its own as a direct therapeutic in the case of a drug product. So this would be for things like naked DNA therapies or plasmid vaccines. But I guess the really important one, and the one that we actually do a lot of work around at Charles River currently is the role of plasmid as a critical starting material for onward processing. And this can be for a range of different applications. I guess some of the most common ones that we see are where plasmids are used as transfection reagents for viral vector production. So it'll be in the case of AAV, adeno associated virus or for LVV, lentivirus production, are two of the really big ones within gene therapy and cell therapy, but also as template for messenger RNA production.

And I guess if we think about how they're used and their function and the function of plasmids within these applications, they carry genetic information and this ultimately defines the characteristics of the final drug product. And that is, I guess, irrespective of application. So we think about plasmids, it is very critical to have a very safe and reliable and also cost-effective kind of supply to deliver effective treatments to patients.

Mary Parker:

I was talking with somebody else for a different interview the other day and they mentioned something about how the gene therapies, there's like a limit to the size of the DNA that can be delivered in the drug. And I just thought that was interesting. Do you happen to know what the limiting factor is on that?

Andrew Frazer:

I'm not going to quote numbers off the top of my head, but Yeah, I mean, depending on the different vector that's used, they all have different packaging capacities. So it kind of does, I guess, lend itself to this theme around complexity within advanced therapies.

Amanda Weiss:

You're absolutely right, Mary. So we work with AAV and there is a packaging capacity, so that packaging capacity could limit some of the applications that you want to develop. If you want an analogy, it's a little bit like squeezing an elephant into a mini.

Mary Parker:

I like that image.

Amanda Weiss:

Unless you get it all in there, just not going to work. So yeah, for some therapies, the size of the gene that you are targeting, say I'm talking more specifically for AAV, if it's too big and you can't get it in there, that's a real challenge to develop that at that indication.

Mary Parker:

So Andrew, Charles River has a long history in testing. How does manufacturing now fit into that equation?

Andrew Frazer:

Yeah, you're absolutely correct. I mean, if you ask people about Charles River, typically they'll talk about the history and capability and testing. But more recently through a number of different acquisitions, the company has established a manufacturing network and it's one that kind of spans each of the major areas within advanced therapy. So we've now got cell therapy manufacturing at our Baltimore and Memphis sites in the US. We also have Viral Vector, which is manufactured at Rockville, again in the US. And then on the plasmid side of things, we've got plasmid DNA production at our Calin Oldsley park sites in the UK.

I guess the mission of Charles River at the moment within advanced therapies is to try and combine this testing capability and capacity.

Andrew Frazer:

And really it allowed us to do something that really no other contract manufacturer can kind of claim in that we can do 100% of our testing and also link it to the different stages of clinical development discovery, safety assessment that are present within other divisions within Charles River and try to provide this kind of integrated end to end service offering for our customers and ultimately deliver advanced therapies more quickly and more cost effectively.

Mary Parker:

I have a kind of related question actually that could bring Amanda in as well. When you're talking about going from a test drug or something that you've been researching to it being approved and scaling up for production, what are some of the biggest hurdles in terms of scaling up at that rate?

Amanda Weiss:

Well, yeah, absolutely. That's gauged by a number of factors. So obviously we start off in research, we have to have a proof of concepts, and once we're there, then it comes over to us in developments. And indeed we start at small scale, might be in shape flasks before we go into suspension bioreactors. So this is where it's useful to have a platform process where you've got a baseline process that you can put your product into and try and expedite that development. But there are challenges in scaling up the physical handling of the volumes that you have to deal with. And when I think of things around the transfection stage, that can be quite challenging, particularly in scales as you go larger than a thousand liters. So yes, that can be a limitation.

Mary Parker:

So since gene therapies have only been on the market for less than a decade, how well are their manufacturing protocols established?

Amanda Weiss:

So there's been an awful lot of development efforts into gene therapy technology, particularly over the last five or six years. For example, there's been a number of cell lines developed and the media that they're grown in. So these have had a big impact on viral tied to productivities, which is a great help because obviously that helps with cost of goods. In relation to that, things like cell growth media and transfection reagents that you use to make your vector. And in addition to that, some of the DSP purification technologies have really come on. So we've seen big improvements in process recoveries, particularly around things like 420 enrichment where the aim is to package as much as your payload, so your gene of interest in your final product as you can. So all of these things have contributed to higher productivities and better recoveries, but also importantly, then getting more of a consistent quality of the product. So when you run your process and you have your process parameters defined, you can be more reassured about the quality of the product that you'll get out at the end of it. So there's been lots of improvements of all of these technologies.

Mary Parker:

Is there anything about gene therapy manufacturing that makes it difficult to have that kind of standardization? I'm just curious because when you think of manufacturing, having everything be standardized is a really big part of it. If you buy a thing of cornflakes, each cornflake is about the same size. Is there anything in gene therapy manufacturing that makes that difficult?

Andrew Frazer:

Yeah, I mean, to follow on from what Amanda said, I think we are approaching, certainly for things like AAV that are relatively common within advanced therapies, we are moving more towards standardization and ultimately that that's the goal, particularly for manufacturer. The more we can standardize, the more we can streamline processes, supply chain, all those things, it kind of helps with these main challenges around cost and timelines. But what I would say on top of that is that advanced therapies do kind of include a wide range of different approaches and advancements are being made and new technology is being developed all the time. We typically, even on the plasmid side of things, we're seeing people try different things, amend the way that they're delivering their products, and that ultimately adds complexity. So you've kind of got this kind of seesaw effect where on one end some of these products are becoming much more established. Amanda mentioned that the titers are improving, safety of these systems is improving, but ultimately on the other side then you've got this really, really fast and rapid kind of advancement in the early stage science, which ultimately the benefits to patients are very, very clear. But it does create some rather big challenges for manufacturing, particularly when we think about things like standardization.

Mary Parker:

So from each of your perspectives, can you see any bottlenecks or roadblocks to expanding gene therapy manufacturing?

Andrew Frazer:

Sure. I mean, just to follow on to what I just said, just the inherent complex nature of the products is definitely the biggest challenge within manufacturing. If we think about these types of products compared to things like insulin, they're much larger molecules, much more complex and much more challenging to make. I think when we talk about bottlenecks and roadblocks and expanding manufacturing, what's probably even further behind the science and even the manufacturing or in terms of maturity, are probably the healthcare funding and reimbursement systems that we have. We've seen a number of licensed products within advanced therapies being pulled from market due to commercial viability. And I think it's clear that the very, very high cost to these products, and even though they are in the millions of dollars per treatment, they are curative in many cases. And it probably does need a very different approach compared to more traditional treatments that would be much lower cost and typically require treatments over years for some disease indications.

Mary Parker:

What do you think, Amanda?

Amanda Weiss:

Yeah. Well, indeed. So following on from that, from a process perspective and helping with drive the cost of goods, if we can get better productivities and I talked about the 420 separation, if we can get more product with the payload in it, it might increase the potency and we could use lower doses. So that might help contribute to some of the cost of goods. Because then you could get more for your dollar if you like. Another big challenge as well is the supply chain. So currently a lot of the gene therapies are ultra cold chain supply, so less than -70 degrees. So is there something that can be done around formulation and helping with the shipping of these products internationally? Because that also adds a huge expense. And there's also, we have to do a lot of stability work to assess the stability of these products and how they're shipped. So again, that's another challenge for us. So if we could work around formulations to try and reduce the need for all to cold chain supply, that would be a good thing.

Mary Parker:

I was actually, yeah, I was thinking about that because I remember in the early stages of when they were distributing the COVID vaccines and they had to be kept extra cold and it of course made it difficult to get them to places that don't have strong infrastructure.

Amanda Weiss:

Absolutely.

Mary Parker:

Which is not the goal. Obviously you want these to be able to get to patients who need them wherever they are.

Amanda Weiss:

And also working with the reg authorities as well, getting more regulatory guidance on acceptability of the products, to get a fast track approach, to work much more closely in the development with the regulators on these products so that they understand them better as well, to help with the regulatory authority release process. I think that's something that we need to do better on.

Mary Parker:

Yeah. So do you guys have any questions for each other?

Amanda Weiss:

Yeah, sure. So just talking about costs. So I buy a lot of plasmid and it's still relatively expensive. Well, it is very expensive. So Charles River being a plasmid supplier, Andrew, what are you guys doing, trying to improve on that?

Andrew Frazer:

Yeah, it's a really good point. And then yeah, it is one of which we're very aware. I mean, with regards to things that we're doing actively at the moment, we talked about standardization. We've launched our XP DNA platform, which I guess is an iteration of what we've always done within our manufacturing sites, but in a much more streamlined way. So those cost benefits will start to come through for customers as well as they enter more rapid delivery. We do have a number of pipeline step improvements for that platform as well. The most recent one that we've launched is our off-the-shelf plasmid service offering.

So this is where we manufacture commonly used plasmids. So packaging and helper that are used for viral vector production, we can manufacture those in advance and store them to inventory so that they're available immediately for our customers. That also carries with it efficiencies around productions, so we can manufacture them at larger scales. We don't have to do it on a batch by batch basis the way we typically would for custom manufacture, I guess on your side, Amanda, when you're ordering these products as well, you can also order the specific quantity that you want rather than having to order a batch and potentially have wastage your overage or even under ordering is, I know, a massive problem within in the plasmid space because manufacturing timelines and capacities are quite restrained with all manufacturers. So those are some of the things that are coming. I think it's one of the big advantages to being part of a large organization like Charles River is that we've got that big company back and behind us. There are huge efficiencies that we'll be able to realize moving forward around testing both on timelines and cost reduction.

Amanda Weiss:

Yeah, it's a good point. Getting plasmid quantities right can be a bit challenging, and particularly if you get a batch of vector spoiled and you have to repeat it. If you haven't got enough in stock, then you add timelines, which is quite detrimental, particularly to a small company who's trying to get into the clinic as quickly as possible.

Andrew Frazer:

Yeah, I had a question for Amanda. Haven't worked with Purespring for quite a while now. It is a very well organized company, you have a very clear plan about what you want to do and lots of experienced people working with you. The question for me would be, do you have any kind of key lessons learned that might help other product developers, particularly how to deal with contract manufacturers?

Amanda Weiss:

That's a very good question. For a company like Purespring who outsources all of its manufacturing and critical material supply, it's really doing your homework and due diligence around what's out there, who's supplying what, reputations, cost of course is really important. But once you've identified that it's really working with your CDMO, not as a contractor, but as a partner because your success is only going to be dependent on their success. So it's something that I've found that we don't sign a contract and hand it over to our supply and go, "Here you go. Let me know when it's finished." That is just a recipe for disaster. It's really about building a partnership, building a joint project team, them understanding what you need, when you need it. Being open to them about indications. Often a lot of people who end up manufacturing the goods don't really understand what the final product's being used for. So we've been on site to give seminars about the indications that we're treating and how important their role is in providing and helping us with that solution. Having clear defined goals of where you want to be and when you want to be there. So that relationship is really important to our success.

Mary Parker:

Well, thank you both so much for joining me. I really appreciate your insight into this topic. I find the manufacturing aspect of this really interesting, so I definitely especially appreciate that.

Amanda Weiss:

No, thank you. Thank you for your time. It was nice to speak with you both.

Andrew Frazer:

Yeah, thank you.