In this exclusive interview for BWB TV at Biotech Week Boston (September 2018) Jon A. Rowley, PhD, Founder & Chief Product Officer at RoosterBio, explores the decision making process for choosing a manufacturing platform for cell therapies, and how that impacts COGS and bottlenecks. Rowley was speaking to Brandy Sargent, Editor of Cell Culture Dish. Watch the full interview or read the transcript below.
Brandy Sargent: I wanted to start by asking you what drives the decision for the manufacturing platform for cell therapy manufacturing?
Jon Rowley: I feel that the biggest thing that drives the decision making process on what manufacturing platform to use actually has to be driven by lot size. What you have to do is really understand what you're commercially relevant lot size is and then work backwards from there. And then what that does, is it really helps to make sure that the manufacturing platform that you're in is scalable.
At the same time, you have to balance that with the stage of development. If you're just getting into Phase I, the most important thing about getting into Phase I is speed. If you're going to fail, fail fast. Then it's just balancing the phase of development and final lot size.
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So we spend a lot of our time in mesenchymal stem cells, and these are adherent cells and traditionally they've been grown in flasks. Those manufacturing processes are pretty tried and true and you can very quickly get a 10 layer manufacturing process into a clean room and generate Phase I material. That speed to your clinical product in Phase I is probably the most important thing.
However 10 layers for almost all indications are not really commercially relevant source and so then while you're de-risking your product in your Phase I, you will then quickly go down the decision making route, are 10 layers going to take you all the way to commercial, if not when do you implement bioreactors. And then really, it's like getting into bioreactors in Phase II and Phase III is the way to go, but again bioreactors are not 100% necessary in all indications. And so it's really doing that lot size analysis and balancing with phase of development.
BS: And to follow up on that, where do you see the manufacturing bottle necks for cell therapy based products and then how do those shift or adjust as scale up occurs?
JR: Autologous and allogeneic have very different manufacturing challenges, but for allogeneic - or patient specific or universal cell, where one patient’s worth of cells treats hundreds to thousands of patient doses - the manufacturing bottleneck, even at small scales where your lot size is in the billions of cells, is not necessarily in the culture. You could easily double the culture output, but it's really the downstream processing.
If there's anything that we're learning from the field of monoclonal antibody production, it is to really try to anticipate what your downstream processing bottle necks are proactively develop the technologies to address this. Even just clarification and concentration of your harvest. For mesenchymal stem cells, the cells are harvested in trypsin and you can have tens of liters today, easily hundreds of liters of cells in trypsin that you need to completely get out of that residual manufacturing process components and the traditional centrifugation just doesn't do that.
There's been some continuing centrifugation technologies that have been developed, they're being tested and implemented in cell manufacturing today, that could be scalable to hundreds of liters to eventually thousands of liters. But I would say that the majority of cell therapy processes that I know of, currently do not implement that yet, and if you don't get that down it's really hard to fix later on.
So, downstream processing is definitely a challenge today; it's not just in the centrifugation, it's also the formulation, the fill, and even the cryopreservation. For cryopreserving thousands of patient doses there's not really equipment out there to do that today and then how you inventory it and move it into inventory without getting intermittent thaws that happen throughout. That whole backend of the scale up process has a lot of work to do.
Most people talk about scale up and bioreactors and I think that's very important to do and it's hard, but once you're in bioreactors, you don't want to wait another five years for the rest of the technology to come into play. It's really important for equipment providers to be really working on what that downstream looks like.
BS: And how does the manufacturing platform affect the cost of goods for some cell based therapy products?
JR: We've spent a lot of time, coaching different therapeutic companies through this. When you do a 10 layer process, you can actually generate a tremendous chunk of the cost of goods just in labor - labor in media changes, labor in harvesting. Even 10 billion cells can take 10 to 15 people to harvest with a tremendous amount of labor. You can probably save 80% of the labor by moving to a bioreactor and then once you're in bioreactors and you go from say 10 billion to 100 billion, to several hundred billion, because everything is moving via pumps and it's not operators that are moving individual small components, the amount of labor per unit dose manufactured goes down tremendously.
That is a huge savings - that can save you probably up to 30% of the cost of goods. And then as you get into the bioreactors and get into the media optimization and the quality control testing, which can then be distributed out through many more product doses, I think that as you get your lot sizes up to thousands of patient doses, and from bioreactor based processes that you're definitely looking at halving your cost of goods if not more.
BS: I want to kind of ask you a little bit of a tough question. What do you think the biggest opportunities are for standardization in regenerative medicine today?
JR: The standardization on the manufacturing technologies is definitely a big opportunity. Specifically focused on mesenchymal stem cells, MSCs, where we focus, we think that there's a really tremendous amount of opportunity in removing what we see as a significant amount of redundancy throughout the field.
MSCs are being used in lots of different applications, just in regular cell therapies, but then also people are improving upon this traditional MSC that is being used from the gene editing technologies are coming in, it's a great platform for gene modified MSCs. The MSCs are platforms for creating exosomes and extracellular vesicles. MSCs are the raw materials in several of the engineered tissues which are a small component of regenerative medicine today, but I think will be the fastest growing over the next 10 years.
Now, what you have is tens of companies today, if not hundreds of companies over the next few years, that all need essentially the same thing, which is vast numbers of therapeutic grade MSCs. And what we're doing at RoosterBio is actually trying to standardize that - the cell banks that they work from and then the manufacturing process. So if we can help to get everybody into a standardized manufacturing process, generating the same base cell in which they're either gene editing, collecting exosomes from, collecting gene edited exosomes, those cells going into engineered tissues which are a vast number of different types of products. Standardizing the one way to make the bulk MSC, we think that that's probably going to impact a good 30% of regenerative medicine today and what we're trying to push forward as a business.
BS: And I want to close with a question about how big an impact you think that government funded national manufacturing innovation initiatives will have on the industry.
JR: I think these NMIIs, the National Manufacturing Innovation Institutes, are going to have a tremendous impact. There's been two funded by Manufacturing USA: the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and BioFabUSA also called ARMI (Advanced Regenerative Manufacturing Institute), and what they're doing is they're investing in the manufacturing sciences. If you look at the amount of manufacturing progress that was made in the monoclonal antibody space after the first blockbuster drugs were established in the early '90s, that's where the yields went from 100 milligrams per liter to 1 gram per liter, to eventually 10 grams per liter.
But that investment in the manufacturing of monoclonal antibodies in the biologics didn't really happen until companies were making these billion dollar drugs. We don't have a billion dollar drug yet in cell therapy, and so having the US government come in and fund these initiatives to several hundred million dollars, proactively investing in the manufacturing sciences aspect, I think that we will then get to commercially relevant manufacturing processes faster as an entire field.
I think that they're going to tremendously accelerate the entire field. I think it's a really important thing that the government's doing.