E60: From Development to Manufacturing in Biologics

Mary Parker:

I'm Mary Parker and welcome to this episode of Eureka’s Sounds of Science. Today I am joined by two innovators who are working in the same issue from different angles, how to design and manufacture drugs quickly, easily, and most importantly, safely. Ian Wyllie, Director of Operations for Charles River's RightSource testing platform. And Jesse McCool, Co-founder and CEO of Wheeler Bio. RightSource offers basically a lab in a box that can be adapted to run for all kinds of quality control needs. Wheeler Bio specializes in small batch production of biologics and GMP grade reagents with their open source platform, portable CMC. Both platforms aim to make drug production more accessible while maintaining high standards of safety and efficacy. Welcome Jesse and Ian.

Jesse McCool:

Thank you, Mary.

Ian Wyllie:

Thanks, Mary.

Mary Parker:

Glad to have you both here. So let's start with Ian. Can you tell me a bit about your background and give me the elevator pitch for RightSource?

Ian Wyllie:

Yeah, absolutely. So my background's actually more on the business and economic side. I studied at college in Boston, mostly focused on economics and started my own company coming out of school, a small game company. Since then, actually landed at Charles River working on our mergers and acquisitions team. Then in our safety assessment business, and that's been for about past five years, and then moved into biologics two years ago to start off RightSource. Now the easiest way to explain what RightSource is that it's Charles River biologics testing outsourced, but at your doorstep. So we take everything that you typically find at one of our outsource labs and bring it right next to the manufacturing floor for our clients. So what this does is it basically allows the client to have the best of both worlds from both an in source and outsourced perspective.

They get everything they would get if they sent their sample out, the depth of scientific experience, the existing SOPs, quality system methods on site they would have gotten outsourced while having the dedicated team as if they'd hired their own QC lab.

Mary Parker:

That makes sense. So you're basically packaging up Charles River employees and equipment and dropping them off at a client's location?

Ian Wyllie:

Yes, exactly. And the biggest piece I think that differentiates is that it includes the quality component where it really allows the client to focus on their manufacturing piece and know that the quality control is taken care of, and if for some reason something did go wrong, Charles River's the one on the hook, not them. And that just provides that reassurance of really putting ourselves out there and putting our name on the line to show that we're willing to commit to this.

Mary Parker:

Same question for Jesse. How did you get involved in the industry and what is Wheeler about in a nutshell?

Jesse McCool:

Okay, thanks, Mary. Well, I got involved 20 years ago essentially. I'm a scientist by training. I did my PhD in microbiology at the University of Massachusetts, and then went on to a postdoc at Dartmouth. And then from there jumped into industry.

And what I have found over the years, I was a CEO at another CDMO, there's a lot of venture backed biotechs out there that really need a lot of support during the translational stage of their company moving from bench to bedside for the very first time. It's a really dicey time.

And I met an investor in Oklahoma City who was getting involved in life science and was basically starting a venture studio. And so I know the three things that venture back biotechs need to get to the clinic, it's access to capital, it's access to clinical trials, sites and patients, and then it's CMC. And so we put our heads together and reached out to some of our network on the coasts and really put together an interesting model that's a lot different. And it's really basically a CDMO inside of a venture studio. And so there's this sort of a network effect that happens with our customers. They come to talk to Wheeler about doing small batch manufacturing, but we can also make some introductions to venture folks and maybe help them get connected to sources of capital. And then we can walk them down the street to Stevenson Cancer Center, which is an NCI designated cancer center.

So we have this little ecosystem happening in Oklahoma City. And so that's really what Wheeler is doing, it's laser focused on large molecule therapeutics. We're partnered with Coastal Discovery CROs in a really unique way, and really just providing a turnkey solution for venture-backed biotechs to have access to a really high quality, well-characterized, phase appropriate platform that gets into first in human. And the fact that we can partner with Charles River on the QC side just makes it infinitely easier for us to focus on delivering high quality drug substance services. And then Charles River can be right there with us right down the hall, literally, so that they can do the QC testing.

Mary Parker:

Jesse, could you describe the portable CMC? What does that mean and what does it mean for it to be open source?

Jesse McCool:

A portable CMC is our platform for mAbs drug substance process. It's a standard workflow CMC development workflow that gets you from four lead molecules into a tech transfer document. You can take that tech transfer document to any CDMO in the world to do your scale up and your manufacturing.

Mary Parker:

How would each of you describe your approach to drug accessibility versus drug safety? How do you balance those two? What do you think, Ian?

Ian Wyllie:

Sure. So I think to start off with, we always have to lead with safety and quality. There's no point in making a drug more accessible if it's not safe, or people can't have confidence in that drug product or drug substance. But our whole model is creating a scalable model that we can replicate over and over again, which does make it more accessible. So we have the weight of Charles River quality behind us and the expertise that entails to be able to design these programs but by being able to replicate it multiple times. So obviously we have the lab at Wheeler, we have another lab going in London, and we have some other labs in the pipeline. All of those labs utilizing the same scalable platform allows that cost to be spread out over multiple groups.

So every time we spend investing into that model, making it safer by building in more quality by design, more tech infrastructure that makes mistakes less possible to happen. All of that builds in the quality, which then builds in the safety of that potential drug product, drug substance. But by doing it in a scalable way that drives accessibility.

Mary Parker:

Yeah. What do you think, Jesse? How does Wheeler Bio balance accessibility and safety for drug manufacturing?

Jesse McCool:

So safety is definitely top of mind. Quality, it's a given these days. CDMOs have to deliver quality product. We've intentionally designed our facility, our operations, our quality system to be phase appropriate for early clinical phase. But phase appropriate is, it's appropriate, what is reasonable, what's feasible for the manufacturer of drug substance and products for the use in human clinical trials at each phase of clinical development. And so we are intentionally focused on serving the needs of venture backed biotechs. Therefore, we're not offering commercial manufacturing capabilities or costs to these customers. We're giving them an option and access to something that's very appropriate for what they need just to get to first in human.

Mary Parker:

Somewhat recently there was a news story about contaminated eyedrops harming patients. As of this recording, we don't really know details, but Ian, can you tell me how stories like this reaffirm the importance of quality control?

Ian Wyllie:

Yeah, absolutely. So with quality control, it's some of those things that can be very easy for us to take for granted, especially because bio manufacturing is around for a fair amount of time now. So we've got pretty good processes in place, and thankfully now these types of things happen more rarely than they might have used to. But when stuff like this does happen, it brings back to the forefront why we do this. On the off chance that something were to get contaminated, we'd be there to catch it.

And it goes back to your earlier question around accessibility. We do want to keep getting drugs out to patients more cheaply so they can afford it, so they can get the lifesaving treatments that they've been looking for and the reason that everyone's here developing them in the first place. But like we said earlier, we don't want to do that at the risk of patient safety. And I think a lot of people speak for myself, especially, we go into a pharmacy, whether it's a sterile product like an eyedrop, or you go to the pharmacy counter to pick up a prescription, we just assume that's going to be safe. That when we put that into our body, nothing bad is going to happen outside of maybe some side effects that are listed or of the intended effect. So again, oftentimes you're proving a negative that nothing bad happened. But it can be something that's easy to take for granted because over and over again, you're proving a negative that didn't happen.

Mary Parker:

Yeah, that's a good point. Jesse, one of the things you brought up when we were talking earlier was the importance of geographic flexibility in manufacturing. And we want treatments to be available to patients everywhere, even if local infrastructure is underdeveloped. So can you talk about how Wheeler can approach this issue?

Jesse McCool:

Yeah, in the short term, we're starting up a new business and in the United States, it's fairly easy to contract with a manufacturer in any zip code. It's a little bit early for me to comment too much on plans in the future, but the spirit of portable CMC actually refers a little bit to our desire to democratize access to manufacturing technology. We are intentionally leaving portable CMC as a transparent process. So when customers come to Wheeler, they actually get access to all of their batch records, all of the data that has factored into the bio process models. This is important for their IND filings for talking to the FDA and presenting sort of the cell line history, the process history, why certain process parameter ranges are set with certain range, what's the data that sort of backs that up and in an essence that all of that is open source.

And our desire is to deploy portable CMC to multiple locations.

Mary Parker:

I love that. I love that approach to science as a collaborative process beyond economic considerations. And I also make sense that you'd want to really fine tune small batch processes because there are, as we at Charles River know very well, there's a lot of rare and orphan diseases out there that don't affect millions of people, but would greatly improve the lives of thousands and hundreds of thousands of people when you add up all the rare diseases together. So I really like that approach.

Jesse McCool:

Yeah, that's right. I think one of the benefits of democratizing access to standard, well-characterized platform processes is it eventually, if more companies do this, you're essentially lowering the cost of developing drugs early on. You're solving for this, generally it's a two to three year process going from your lead molecule to your first in human trial. But of course, as I mentioned before, there's fundraising, there's tech transfers, multiple vendors are involved. There's not really at that translational stage. There's not really one way to do it. And furthermore, there's just not a lot of information available about your molecule at that point in time. So developing some specifications for early phase programs is very, very challenging. So the sooner you can get into the manufacturing process, really, the better it is for everybody.

Mary Parker:

What has the pandemic taught each of you about the importance of flexibility in the supply chain? Or are there any other lessons from the pandemic that you want to talk about? Jesse, you want to go first?

Jesse McCool:

Sure. I think that the biggest lesson learned from pandemic is that the FDA and the regulatory agency, as long as the science is there, they are open to alternative approaches that are, again, phase appropriate. I go back to that term. FDA is very much in favor of a risk-based approach for develop development of pharmaceuticals. But really the onus is on the sponsor. The onus is on the manufacturer to bring that data and connect the dots for the FDA. But the FDA's very open in other regulatory agencies as well to new concepts.

Jesse McCool:

The agency is continuously publishing guidance documents and getting feedback and change is slow, relatively speaking, which is not surprising when we're talking about protecting the health and safety of patients. It's not that surprising. But there is this, I think there was this inflection point post pandemic that there are new possibilities that might be more accelerated now and better positioned for being more broadly adopted.

Mary Parker:

Yeah, definitely. What do you think, Ian?

Ian Wyllie:

Sure. I think we could probably have multiple podcasts on pandemic. But I do think one thing actually reminds me of a dinner conversation I had with Jesse and one of our colleagues one night was around focus. So I think when the pandemic hit, everyone's priority is aligned, it was very clear what needed to happen. Maybe it wasn't clear how we were going to get there, but it was very clear what had to happen. And that level of focus, along with what Jesse was talking about with the FDA being open to doing things, as long as the data was there and the science was there, allowed us to move so quickly. And I think we'll never have the level of focus and priority we did with the pandemic, and that's probably a good thing. But I do think it speaks to our business models, both of ours, that are around focus. Jesse is laser focused on the translational gap there on that manufacturing process.

Whereas my team's laser focused on the quality control and how we make it more scalable. I think my team's probably sick of hearing me say it when every time we bring up a new piece of instrumentation, a new piece of data, a new method or SOP is can we make it so that it is simpler? Can we make it so that when we add the 10th site that it'll be easy to add that site? So we're always thinking about that with that focus, and that's allowing us to be good at what we're doing and eventually to move faster.

Mary Parker:

All right. Are there any bottlenecks in either of your work that you can't control, and do you have ideas for how to fix them?

Ian Wyllie:

I can take that one to start. So for me, one of the things that we're thinking about a lot right now is especially around computer system validation and automation. As we become more and more automated, there's more and more computer systems, there's more and more updates. Things are running much more without input from a human, and there's a lot of power in that, but there's a lot that needs to be managed and controlled and set up properly. So for me, that's one of the biggest things, I guess I'd say that can be a bottleneck, is your desire to get some of those programs in place and the actual ability to execute on that.

Having completely automated lab of the future, I think everyone would say they want that in certain aspects, but getting there requires not just the robotics and the software to do that, but all the levels of validation and knowledge of computer system, the laboratory quality, all in one, which can be really difficult to find and train, and it's constantly changing.

Mary Parker:

Yeah, it's funny you should say that. I do have a friend who doesn't trust robots at all, and so I don't think she would want everything to be automated in the future, but she doesn't work in pharma, so she doesn't need to worry about it.

Ian Wyllie:

Well, it's interesting though that you mentioned that because we deal with this all the time on change management and that there are groups that don't trust them as much. But the whole point of the computer system validation is to provide for that trust, is to literally test the system, challenge the system, see if they can hold up to things going wrong, and what does it do? Does it handle it properly? Does it flag it and challenge it? And a really well validated process is very good. It's just making sure that that happens and that you have the resources in place to be able to do that.

Mary Parker:

That's excellent. That's very logical. I'm going to argue back with her on that one. Thank you for that argument point. How about you, Jesse? What do you think? What are some bottlenecks?

Jesse McCool:

There's three bottlenecks that one is data management. Two is supply chain and making sure we have raw materials in place at the time we are starting a manufacturing run. And the third is analytical capacity and being able to plan for testing capacity, testing resources. So I'll start with the last one. The last one we've solved with partnering with Charles River and implementing RightSource on premises. Being able to have a QC testing partner that's focused on QC, focused on solving for demand planning, specifically just for QC, we simply have to project our needs to Charles River and they adjust, the headcount, the resource planning. And so to some extent, the Charles River RightSource is solving probably our biggest bottleneck. Analytical is generally the biggest bottleneck in manufacturing. Just takes a long time to test and release data. Going backwards from there, supply chain, since we're focused on mAbs, we essentially take the same 60, 70 raw materials, convert them into drug substance. We can stage for our demand by having on hand inventory of all those raw materials and consumables at point of use.

The first thing I mentioned data, I saw a talk last fall. Michelle Lee from the US Patent Trade Office also at Amazon Web Services, stated that companies use about 10% of their data in a useful way. And I think that's probably even less for bio, for biotech and for biopharma. That's changing. Pharma companies are really focused on data science, machine learning, data and information management in a new way and in really raising the data science ownership in functional area up to the same level as other functional areas in the company. So that there's a significant emphasis on how important data science is.

And we've done that too. Our company started from back of a napkin, and that was one of the main components when we thought about how we're going to organize ourselves, is really want to invest in data science. And so we actually have a dedicated department that just does data science reporting up to manufacturing. We've partnered with Synthes. This is a London-based company that basically creates middleware for laboratories and they help you build a digital lab. So we've worked with them for the last two years to make sure we have as much digitalization embedded in our development labs, because that's where it gets really expensive. Basically generating data points to feed into bioprocess modeling is very expensive.

We just finished our 500th bio campaign, and this generates a tremendous amount of data. We can actually have one scientist running 24 individual cell culture experiments because of the robotics that we have in place, coupled with the automation and automatic data contextualization that we've got with the Synthes software. So we've been able to reduce our costs to generate data, and that has been a really purposeful investment we made. And it really has paid off because a year later, a year and a half later, we have a really robust, well characterized platform process for antibodies.

Mary Parker:

That's great. I love anything to do with machine learning. But speaking of robots, what do each of you see as the main concern for your industry in the next 10 years? Probably not robots, but...

Ian Wyllie:

I think actually going on that train of thought that we talked through about on the computer systems aspect as well is managing that transition. I think as we get better and better at doing some of those routine assays more digitally or more automated, is also then managing the shift in skillset required to do that. And it's a big pivot, and I think there must be plenty of roles and jobs to had to do that. And it's just making sure that as a company moving through that shift that you can keep everyone engaged, keep everyone working towards the same goals, and doing it in a way that is compliant and adds value to the clients.

Mary Parker:

What about you, Jesse? What do you think Wheeler is going to be focused on in the next 10 years?

Jesse McCool:

Reducing the time to get to first in humans, that's really where we're focused. We want to stay in this early clinical phase space and scale out and be able to accommodate a lot more venture backed biotechs in antibody space. Biopharma is going to be growing to 800 billion in the next seven, eight years as an end market. There's a lot coming down the pipeline.

I saw a report somewhere that 70% of the discovery or clinical pipeline right now is made up of non-traditional antibodies. So we have to be ready. And early on, there's not a lot of... You can't walk away from your manufacturing facility. There is a tremendous need for deeply trained and experienced talent. So we're going to struggle, I think, as an industry to keep up with the workforce development needs that are there. So we have some interesting projects around workforce training in our region of the country. With a recent EDA award, we got a 35 million grant to build out bio manufacturing training in Oklahoma City.

Mary Parker:

Excellent.

Jesse McCool:

And so there's a lot coming, but there are opportunities to automate, opportunities to really reduce cost. Right now, it takes 2.6 billion in 12 years to get a drug to market. And that's got to come down. So I think there's no shortage of jobs for human beings and there's, but there's also no shortage of roles for robots, automation, AI and it all needs to be working sort of together in continuously improved approaches.

Mary Parker:

Yeah, it's a really great goal to be supporting these companies, especially in the early stages because there's so many biotechs out there with really good ideas about how to treat a rare disease or an orphan disease or even better treatments for common diseases. It would be a shame for companies like that to not get to the next level because of something like funding. So that's an excellent goal to have. Thank you both so much for joining me. This has been a fantastic talk. I really appreciate both of your time.

Ian Wyllie:

Yeah.

Jesse McCool:

Thank you, Mary.

Ian Wyllie:

Thank you for having us on.