Bringing highly potent cell therapy products to market

insights from industryDenis BedoretManaging Director,MaSTherCell

An interview with Denis Bedoret, Managing Director, MaSTherCell, conducted by April Cashin-Garbutt, MA (Cantab)

What are the main challenges when bringing highly potent cell therapy products to market?

There are two main challenges and both relate to manufacturing. The first one is to make sure you can manufacture therapies with reasonable costs and the second one is to make sure that you can balance the capacity you need with the demands.

This is quite a significant challenge in cell therapy because it encompasses both the need for local manufacturing, and the needs in terms of capacity, as the demands vary a lot with the development stage of the project.

How do MaSTherCell help cell therapy organizations overcome these hurdles?

We do two main things, first is the service offer we have designed, it is a perfect fit to answer these needs, and second, the way we work is also very important in helping our clients to achieve their goals.

In terms of service offer, as part of the network we are in, we offer a global manufacturing service. We have, at present, a MaSTherCell site in Europe and we also have a site in the Middle East (ATVIO), South Korea (CureCell), and one soon to be announced in the US, which will be up and running next year. We answer to the need of global manufacturing and manufacturing close to point of care.

We also offer process development, therefore we don't only manufacture clinical batches, but we also offer the customers the option to optimize the process, which is the best way to answer for the needs of reasonable costs. More specifically, we can make sure that you have a good yield achieved through the use of bioreactors etc.

Lastly, in our service offer, we have in-house quality control (QC), and strong expertise in assay development, which means that we can make sure to develop very good product characterization assays for our customers, which is one of the main pain points when you think about quality of the product. The way we do it is with a very strong focus on the level of quality.

We strive to achieve getting quality done right, and this includes complying with quality guidelines, as well as having amazing manufacturing success rates. Typically, an average success rate of clinical batches is over 95%, which is way over what you see with our competition. This is also key to reducing costs. Instead of failing one batch out of two, if you can achieve to manufacture every batch successfully, that will make a huge difference in terms of cost for the customer.

In our mindset, we are totally committed to the success of our customer, we think about the success of our customer as our success. This is how we motivate our teams internally. We try to have the best knowledge sharing of the two teams on the customer progress because we see ourselves not as a service provider, but we try to become a long-term, reliable partner as well.

Can you please give a case study?

With one of our recent process development customers, we worked on two different aspects. First, we used more efficient bioreactors regarding their process. In doing so, we increased by three times the number of cells produced per batch, but we also combined that with our expertise in quality control development.

We reduced the number cells needed for quality control assays by 50%, very simply through two things. First, because we have all the QC in-house and we don't use external partners, this means that we don't have to send away many vials to other partners and so we can more efficiently use the number of cells available for quality control.

Secondly, we designed new assays using less cells than what they had before, and by combining these two things, increasing the number of cells produced by three times and decreasing the number of cells lost for QC by 50%, we were able to achieve an increase by seven times in the number of cells available for cell therapy, i.e. for administration during the clinical trial to patients.

A change of that magnitude has a huge impact on the cost, and I'm sure that it is key for the customer going down the road, to hit the market with a product that is financially stable.

How important is cell therapy expertise when developing solutions to the industrialization challenges facing the sector?

This is key, it is impossible to get to an industrialized process in our field without very strong cell and gene therapy expertise. We used to say that we don't manufacture pizzas! We work with live materials. It is not even like you can see in chemicals in the traditional way of doing pharma, it is much more difficult.

The expertise in cell therapy helps first to make sure we get a very good success rate, which requires teams with a high level of dedication so that they can, early on during the process, check that everything is okay, and that there is no change, in the cell etc. This means you can act very quickly to make sure that you get your success for the batch.

But even when you pay a lot of attention to success rates, you can still face some failure and typically during the tech transfer. This involves transferring the technology from the customer to our site or from another site to our site, this is very tricky.

When you have enough expertise, you can find the root cause for failure and it is the only way to make sure that when you go to clinical, you don't face this failure any more. This is typically why MaSTherCell has much higher success rates in clinical than other CDMOs, because when we transfer technology, we take the time to do it well and to make sure that we control every element before going to clinic.

Expertise is obviously important, especially in the type of industry we are in, because most of our customers don't have that much expertise or experience with drug development. Most of them are biotech with one or two products in the pipeline. It is very important to able to advise them, not only on the manufacturing side and on process, but also on regulation.

If you are working with a non-European customer, you need to make sure you can introduce them to the right people in terms of authorities or clinical sites and that you support them for the IMPD preparation. All these elements are very important, and you can only do it if you have a very strong, but also broad expertise in the cell therapy manufacturing market.

In what ways is MaSTherCell’s approach technology-focused?

Technology is key when you think about process development to make sure that you can optimize the process as much as you can. Especially because most of these processes come from the academic world, where usually workforce is not that expensive. At least it is not seen as a hurdle for them, so technology is very important to make sure that you can reduce first the costs associated with too much workforce, but also other issues you can sometimes see when too many people are involved in a process, so this is very important.

It is vital that we always remain completely independent, so we can be a trusted advisor. This means that we have no exclusivity with, for example, an equipment supplier. For each process, we provide what we think is the best answer to the needs of the client for this process.

This is important because you see some trends in the market with some equipment suppliers providing CDMOs with exclusivity and exclusive access to some equipment. I think when you go that way, you lose complete independent judgment that is required.

It takes a lot of time to make sure that you are aware of everything that is out on the market regarding technology and that you make sure you can connect the different pieces of equipment the best way, because for some processes, one equipment piece can be better than another one, but if you associate it with another equipment then it changes completely again.

We dedicated a lot of time and resource so that we can continue to provide this independently assessed level of service to our customers. It translates into the fact that we have a small team of people dedicated to technology watch, and make sure that we can work and have an insight on every piece of equipment that is available on the market.

We also have a very good partnership with our partner in Israel, called ATVIO. And that partner is very much specialized in providing tailored equipment. What we do at MaSTherCell, is work with standard piece of equipment, and if we need more tailored approach, we can reach out to our partner in Israel so that they can make sure that we adapt to the small details that is required for a process.

Can you please outline your recent agreement with CRISPR Therapeutics?

We've been very lucky to find an agreement with CRISPR Therapeutics recently. They have appointed us to develop their allogeneic CAR-T platform.

CRISPR is the world-leading gene editing company, and they have very good objectives and goals in terms of the pipelines they can provide and the type of products that they will bring to the market. Thanks to our expertise in immunotherapy, especially in allogeneic products, we have a chance to combine their breakthrough and amazing technology with our expertise to help them bring to market, but first to clinical, a good allogeneic CAR-T product that might change the game in terms of what you see with the immunotherapy market at the moment.

This is typically the type of deal that we look for, because clearly this can lead to a long-term partnership. It is also something that is very motivating for our teams involved. This technology is amazing, so being expert enough to be appointed to work on that is very rewarding for us and for the teams.

How will you help CRISPR to bring their products to market in a fast, safe and cost efficient way?

I cannot be too specific, because a lot of it is confidential information of course. But first, we will work on the process development for them. We have the chance to really change the way the process is done, to make it fast, safe, and cost-efficient.

Typically, we will look at different things, for example firstly we want to make sure the process is safe so that we can close the process as much as we can, which means that you avoid working with open phases which reduces the risk of contamination of the product. We cannot tell how far we can go, but it can go from having a closed system to having a system closed in an isolator, for example.

In addition, regarding the safety, but also speed aspect of the process, we will work on the QC assays again, and make sure that the product can be characterized efficiently with good product characterization assays. This is very important in the cell therapy market. Too often you see products in clinic that are not characterized enough in terms, for example, of the proportion of cells that you have in the product.

It is always for the customer an issue when you get to the dose calculation. If you don't really know what you inject, even if you have proven it is safe, it is very difficult to do a clinical trial that provides you with the best information on the dose needed and then you are stuck for the rest of the development of the product.

Then regarding the cost-efficiency, QC will play a role but we will also have a chance to improve the efficiency of the process using bioreactors to improve the yield of the manufacturing process.

What do you think the future holds for bringing highly potent cell therapy products to market?

Most of the topics we have discussed so far revolve around costs and capacity, product availability, and these are topics that we have heard in the market for years. Even five years ago at conferences you heard about people saying that we should get more reasonable costs, more automation of the process and it should be using closed systems, have bioreactors etc. but optimal process has not been seen so far, therefore I think for the next few years, it is time to stop talking and start doing these things.

Currently there is good momentum because some of these products will hit the market, which will highlight even more the attractiveness of the market, and this may encourage companies to put more funds and to spend more time on process development.

In addition, equipment suppliers will start to provide much better equipment, and so we will have more choice when we try to find the best way to optimize the process.

There is also a change in mindset, product developers use to think that in cell therapy the process is the product, and so they were very reluctant at outsourcing the process development to an external provider. This perception has changed after seeing that most first companies who hit the market with their products fail because costs were too high. And so now they realize that they have to find some support.

I think that companies like MaSTherCell are ideally positioned to connect the dots between the drug developers, the equipment suppliers, and also through the networks of the clinical sites we have. I think it is the best way to finally support customers to bring their cell therapy products to the market.

What is MaSTherCell’s vision?

Our vision is to become a long-term global partner for the cell and gene therapy developers, to help them and support them from science to commercialization. We are now looking into expanding our activities into the sourcing of some critical materials, for example, lentivirus used to engineer cells before injecting them into the patient is something critical that most of the customers have difficult access to and it is something that we consider to provide as a service in the future, to make sure that they have everything in their hands to get there.

The seamless expansion concept, using the different sites we have across the globe to help a customer develop worldwide their product, is very important and is part of our vision. We want to remain a leader in Europe in the immunotherapy market and continue to offer an unmatched level of quality. We provide quality done the right way, because quality is where you need to succeed.

Where can readers find more information?

MaSTherCell

About Denis Bedoret,

Denis Bedoret joined MaSTherCell in October 2016 as Chief Business and Administration Officer. He was then appointed as General Manager in January 2017 with the ambition to pursue the global development of MaSTherCell’s activities.

He previously held the position of COO at Quality Assistance, a leading European analytical CRO where he was also member of the board of Directors. Denis previously served as Engagement Manager at McKinsey & Company, focusing on (Bio-)pharmaceutical projects. Through those experiences, Denis has gained a strong expertise in biologicals, FDA and EMA regulations as well as team management.

Denis holds a degree in veterinary Medicine, a PhD in Life Sciences from ULG and a postdoc in Immunology from Harvard Medical School.

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