The commercial success of a cell-based therapeutic depends on a scalable, automated manufacturing process. But how can companies ensure their manufacturing processes are up to meeting the needs and market demand of the rapidly evolving cell therapy field?  Our annual breakfast briefing at the Phacilitate Leaders World conference in Miami tackled this and other current topics with a panel of industry luminaries.

David Hodl, Invetech’s Head of Business Development, Cell Therapy who chaired the panel, opened the discussion by highlighting one of the prevalent topics of the conference: how to scale up. With the Alliance for Regenerative Medicine estimating up to half a million patients in the US alone in the coming years, how can cell therapy companies meet market demand?

Hodl said, “That very much becomes a question for companies that either have an approved product or they’re tracking toward approval – what do we do with our manufacturing process? We have approval, but now, how do we meet those market challenges and how do we meet the manufacturing needs to treat 500,000 patients in the near term?”

The panel, comprising of Ken Kotz, Associate Director of Drug Product Enabling Technologies (bluebird bio), Isaac Erickson, Director of Bioprocess Engineering (DiscGenics) and Greg Bonfiglio, Founder and Managing Partner (Proteus, LLC), discussed their vision for the coming era of industrialized cell therapy production.

The panelists first discussed the challenges they have faced scaling up their manufacturing processes. Isaac Erickson from DiscGenics talked about centralizing operations and obtaining available technologies to help automate their processes as demand grows rapidly. DiscGenics is projecting they will provide allogenic therapy for up to a million chronic low back pain patients a year within this decade.

Erickson said, “Meeting that demand is a significant challenge. As far as the scale up, we had to change the paradigm of what we were doing altogether. Moving to suspension bioreactors is really the only thing that made sense for our process to get to the type of unit numbers per lot that we needed. But the technologies we found… it’s trying to get them to work for our process. That’s been significantly challenging.”

Ken Kotz from bluebird bio, which has recently been approved for Zynteglo in Europe said, “From early on, bluebird spent a fair bit of time very carefully picking and choosing the technologies that were going to work. We have the same incredible patient to patient variability challenges. So how do you build a process that’s flexible enough to deal with that?”

He continued, “What can we learn from both that clinical trial process, but then also from the transition to commercialization for future products? And I think that’s really what we’re doing at bluebird – it’s really taking those learnings and figuring out where we can optimize both at the interoperation level but also in terms of a larger manufacturing system.”

The panel shared some ‘aha moments’ they have had along the way towards market approval, and what they have learned about removing bottlenecks without altering the biology of the product.

Erickson first talked about an ‘aha moment’: “Whether our comparability strategy is acceptable is going to be a key question with regulators. And we have plans to discuss that with them in advance of filings. But what is really the key first – do we believe we’re making the same cell as we make some significant changes to meet demand? And do we have the evidence necessary to prove that to regulators? Realizing that, you could say, that was an aha moment.”

Greg Bonfiglio from Proteus, LLC shared his experiences going from a fairly high-touch linear manufacturing process to a closed process. “We now have a universal cell line that we will be producing under GMP conditions. We’ve already produced it and have product from it. We need to develop a bioreactor that gets us there, that can produce that line and the products from that line on economic basis. We’re struggling with those manufacturing issues, but they’re core to the success of our business and our long-term business plan.”

The panel discussed utilizing enabling technologies and moving different cell types into the scalable manufacturing model. Kotz said, “Throughout this conference, we have talked about how these are processes that are built off of pretty manual, high touch, academic systems. They’re incredibly robust, they work really well – but from a manufacturing perspective how do you collect data and information on your process and look at that in real time, and keep track on quality and do this sort of closed loop iteration where you’re constantly improving your process and you’re constantly improving the manufacturing? It’s a huge challenge.”

Bonfiglio said, “One of the things that we are looking at is how well can you adapt a new technology to a change in process without fundamentally changing the technology. And that requires some pretty sophisticated readouts. The initial challenge that we’re facing is the release criteria; can you effectively measure what the cells are?”

Erickson added, “The first thing that knocks a technology out right away is the scale. Does it handle the volumes that we need to deal with? The next thing is automation. We need some level of automation if we’re going to invest the money into a technology. It has to perform something better than what our operators are going to do.”

Looking further afield, the panel talked about the paradigm of point of care, and whether we’ll see a pivot point in the future when it comes to available technologies, the capabilities of the process and the science around the therapy itself.

Kotz first said, “I think in the field in general, there’s this buzz about point of care. And I think from our perspective it definitely depends on the indication and on the therapy itself. For bluebird in our products, the way that they’re manufactured I think one of the main challenges in that model is all the release testing that is required for disposition of the product. You can do the manufacturing at point of care and at remote sites in a distributed model, but how do you deal with the testing?”

Erickson added, “When we talk about the future distribution of hundreds of thousands of doses a year, point of care receipt and dispensing product is just as hard, if you think about how much responsibility you’re putting on staff at a clinical site. This idea of even automating what happens at the clinic and maintaining equipment for storage and dispensing of our drug is something that we’re already thinking about.”

The panel then addressed the role of disposables. How can disposables change established processes and what should be taken into consideration when it comes to for example supply, design and validation?

Erickson said, “One way we look at it, as we’re integrating multiple steps of a process, is to use the base consumable that is the more complex piece ‘as-is’ and then having custom transfer sets that are simpler to piece together. Any simplification we can do to that helps with the supply chain, we’ll look at that.”

Kotz said, “One of those challenges for the new emerging technologies is: how do you ensure that supply chain, how do you ensure that you know all the testing that’s required, has been done. And you’ve locked in a material set for your therapy.”

The panel closed the discussion with some words of wisdom for those just starting or already on the journey to commercial manufacturing. Kotz first shared his thoughts, “Before you go into clinical trials, having a process that’s flexible enough to deal with surprises that you’re going to see when you start handling patient samples; having that process flexibility to enable you to execute on those trials and hit those trial end points is really important. Another area, depending on how you do manufacturing, is to build a great manufacturing team.” He added, “Having that light at the end of the tunnel and knowing that you’re going to be helping those patients is something that helps keep the teams inspired.”

Erickson echoed Kotz’s thoughts, “I think developing a good manufacturing team is really important, and having the right give and take between scientists, engineers, and manufacturing leadership and operator as you develop the process, is really important.”

From the investment criteria side, Bonfiglio commented on the importance of a well thought-through manufacturing strategy, and what is required if you’re pitching your venture, “You need to be able to show you have good technology that hits those kind of response rates, and you need to be able to show that you’ve thought about, in a very rational and reasonable way, manufacturing. Technology is diligence item number one. Manufacturing is diligence item number two, three and four.”

He continued, “The model has changed and we’re seeing these big rounds of financing in part because you’re expected to be able to have a plan where you can build your own manufacturing capacity, or at least identify folks who you can work with it will provide a reliable supply for you. So – manufacturing is a big issue.”

Watch the full panel discussion here.

Greg Bonfiglio is the Founder & Managing Partner of Proteus, LLC – an investment and advisory firm focused solely on Regenerative Medicine. Mr. Bonfiglio has over 35 years’ experience working with technology companies and serves on the Board of Healios KK, one of the largest publicly traded RM companies in Japan. He is the Chairman of the Board of the Centre for Commercialization of Regenerative Medicine (RM Translation Center in Toronto, Canada). Mr. Bonfiglio is on the Board of BioBridge Global (RM Translation Center in San Antonio, Texas) and on the ISSCR Finance Committee.

Isaac Erickson joined DiscGenics to manage the regulatory efforts in Japan leading to the successful acceptance of a Clinical Trial Notification (CTN). He also developed and directs the logistics network in support of both domestic and foreign clinical trials. In addition, Isaac is leading the process engineering group in assessing and implementing technology for successful transfer to DiscGenics’ new manufacturing site. Prior to DiscGenics, Isaac cultivated extensive experience in using sodium hyaluronate hydrogels for tissue engineering and stem cell delivery at both the University of Pennsylvania and at BioTime.

Ken Kotz oversees the selection and evaluation of technology programs with the goal of improving the production of cellular therapies across bluebird’s portfolio of products. Before joining bluebird, Ken worked as a principle engineer at Draper where he played a key role in technology and product development for cell and gene therapy manufacturing equipment. Prior to Draper, Ken held a faculty position at the Massachusetts General Hospital (MGH) and Harvard Medical School where he led a group of engineers creating technologies for point-of-care clinical diagnostics leading to a spinout, General Fluidics, to bring these tools to market.