A short guide to cell therapy manufacturing, part 1
More cell therapies are entering clinical trials with big hopes for approval in the near future. But the manufacturing of these cells is — and perhaps always will be — a boutique enterprise, with many factors requiring careful consideration. This first article in a two-part series looks at starting small, defining processes and scalability.
If your only exposure to cell manufacturing until now has been the meagre information offered up on the websites of unregulated stem cell clinics, you might believe that the manufacture of stem cells, whether for cosmetic peels, vision repair or the treatment of ALS follows to a standard, simple routine. Remove the cells (usually from the blood or fat), cleanse, replace. Et voilà, you’re cured.
If only it were so easy. Though it gets very little attention compared to major scientific advances or clinical trial launches, cell manufacturing is critically important to the successful translation of stem cell therapies from the lab to the clinic. It’s far more complex than “one-shoe-fits-all”, involving the right cells, a suitable process to elicit the desired effect from the cells, and placing them into the patient in a way that is safe and effective. These steps can vary considerably, depending on what you’re looking to treat. For researchers, understanding the essential steps to determine optimal manufacturing processes, future scalability and risk reduction can make all the difference.
In Canada, a search for expertise in cell therapy clinical trials inevitably leads to Ottawa. It is here, at The Ottawa Hospital where studies have demonstrated remission — and even reversal — is possible for certain forms of autoimmune diseases such as aggressive multiple sclerosis, stiff person syndrome, and scleroderma. These all use autologous hematopoietic (blood) stem cell transplants as a basis for treatment. Because the cells are “minimally manipulated” and the process is similar to one used to treat leukemia for decades, manufacturing is less complicated and involves less regulatory oversight.
But Ottawa is also the home of several phase 1 and 2 trials — for septic shock, cardiac repair, pulmonary hypertension and multiple sclerosis — in which a more intensive manufacturing process is required because the cells are genetically engineered or changed in other ways. Building out the facilities and developing the correct procedures to manage this process requires careful attention and a lot of knowledge.
Dr. David Courtman, an OIRM investigator based at The Ottawa Hospital, has been around the cell manufacturing block more than a few times over his 25+ year career. His early experiences with Seattle-based ZymoGenetics gave him a solid foundation in the business end of manufacturing. Currently, he runs one of Canada’s leading GMP (Good Manufacturing Practice) facilities, where stem cells and gene-engineered cells are being processed for clinical trials.
“The most important consideration is that there is no one single approach,” says Courtman. “Every type of translational program, if we’re talking about cell therapy, may be distinctly different.”
Most translational manufacturing needs also start out small, says Courtman, who was recently appointed Regulatory and Manufacturing Advisor with OIRM. “If you had a product that you know is going to be overwhelmingly successful and you’re going to make a kazillion dollars from it in the end, you’re going to get investment up front. You’ll get $50 million or so to develop a bioreactor that’s completely closed and can be distributed around the world so that everyone can make this cell therapy product.”
This, however, is rarely — if ever — the case. The advantage of starting out small is that it affords the opportunity to plan, to do things safely, and to be nimble in order to find the sweet spot that balances cost with forward growth. According to Courtman, it requires a careful consideration of three important factors:
- Process
- Scalability
- Risk
Process
“Cell therapy products are really only defined by their process,” says Courtman. This is in contrast to drug manufacturing, which is based on a finite formula, resulting in a chemically-defined product that can be replicated in any facility across the globe with nearly 100 percent accuracy.
“When we get to advanced tissue engineering products, or cell therapy products, there’s no endpoint sterilization on the products and there’s no endpoint definition to say what those products are,” explains Courtman.
“The process is what defines the end product because the product can never fully be characterized. So the better you are at defining your process, the better you are at getting a standardized product and meeting regulatory approval and moving from a Phase 1 to Phase 2 to Phase 3 to product launch because you have to have a well-defined process for that.”
“You have to understand everything very well — you need evidence-based manufacturing,” he says.
“In other words, everything you do in your manufacturing, you need to have evidence that it is safe and that it’s producing what you expect. If you have that, you are in a much better space in terms of moving ahead in translation.”
Moving ahead in early phase clinical trials may also require moving towards GMP compliance and changes in processing along the way. In his own work, Courtman has designed facilities that allow him to be very flexible and safe, but not necessarily in full GMP-compliance. “Health Canada and the FDA both recognize that it’s a sliding scale, as you move from Phase 1 to Phase 2 to Phase 3,” explains Courtman, “and you always have to be assessing your risk, and making it safer as you go ahead. You want to do this anyway, because as you move forward and start looking at the therapeutic index of your product, you want it to be as high as you can get, and you want to remove any adverse events as a result of processing.”
Scalability
If a cell therapy succeeds in early phase trials and progresses to phase 3 and clinical approval, scalability — the ability to produce sufficient quantities of the cell product for everyone who needs it — will become a central issue in the manufacturing pipeline. While most needs within the smaller phase 1 and 2 studies can be met within the clean rooms of the sponsoring hospital or university, multi-centre trials with large numbers of participants, and clinical buy-in after approval will require a different model of production.
Two business models exist in cell manufacturing: scale up or scale out. Scale up is centralized, in which the cell product is manufactured in one or two facilities and then shipped to the locations where it is needed. But this model becomes problematic when the cell product is more specialized, or patient-specific, and needs rapid turnaround for optimal efficacy. The added time for shipping can be the make-or-break factor in such cases.
Scale out provides a model in which the cell product can be manufactured on site in smaller batches. The efficiency and size of bioreactors today makes it possible for most hospitals to equip a clean room that is dedicated to the manufacture of a single cell product. But as more cell therapies reach clinical approval, space for these clean rooms may be problematic and there is the larger concern over ensuring a cell product is the same in Toronto as it is in Atlanta or Lisbon or Beijing. Finally, scale out places more costs in terms of labour and equipment in the hands of the individual hospital. Even considering amortization of the costs of making verus purchasing therapies over the long term, such up-front investments can be prohibitive in some jurisdictions.
“There are problems on both ends,” says Courtman, “but the reality is, no one understands this from a business point of view. There’s no successful model out there yet. The business case is huge and very complex.”
Adding to this is the fact that cell therapies are not intended for long-term use. There may be many patients out there to treat, but cell therapy manufacturers are not seeking repeat customers the same way drug companies are.
“If you look at the model of drugs, where you create a drug, patent it and then a patient takes one every day for the rest of his life, there is lots of money to be made,” says Courtman. “But cell therapy products cannot operate on that type of revenue-generating model. Firstly, you cannot dose patients every day for the rest of their lives with a cell therapy product. And secondly, you probably have a limited number of doses you have to give them.”
These are among the reasons why cell therapies are more expensive than conventional treatments, but Courtman is optimistic costs will continue to come down as manufacturing processes are improved.
But, while it’s tempting to equate scalability with cost efficiency and to therefore consider production costs early in the game, Courtman says this is a mistake.
“Until you have a therapy, cost doesn’t matter. Heart transplants were hugely expensive at first but are now routine and relatively inexpensive. The point is, once you have a therapy, there will be massive numbers of people coming in to say, ‘Here’s how we can do it better,’ and it’s going to be done cheaper, better, and probably as effective. If you try to move to cost-effective before you have efficacy, you have no idea what you’re doing. You have to prove efficacy in humans first, then you can start worrying about cost-effectiveness and making it better.”
Part 2 will look at risk and regulation.
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