A short guide to cell therapy manufacturing, part 2
Risk and regulation
In the development of cell therapy products, there are three main phases that drive the choices (and costs) involved in manufacturing: research, clinical trial and licensed (approved to sell for clinical use). Part one of this two-part series looked primarily at the key drivers in the research phase. This provides an overview of considerations for clinical trials and the production of a licensed product.
Let’s assume you’ve run the gauntlet of pre-clinical research and have a cell therapy product ready to test in humans in hopes of bringing a new treatment option to patients. Quite often, it’s presumed that the initiation of human clinical trials makes product manufacture in a GMP (Good Manufacturing Practice) facility a necessity. The rationale is that the compliance levels in a GMP facility will ensure utmost safety.
That’s not necessarily the best way to proceed, especially since clinical trials are designed to find the most effective and efficienct soltion. They need to be open to flexibility; at least that’s the opinion of Dr. David Courtman, OIRM Manufacturing and Regulatory Advisor based at The Ottawa Hospital, one of Canada’s leading centres for cell manufacturing for clinial trials. Indeed, Health Canada backs this up, acknowledging that clinical trials are part of drug development, a state that is not yet fixed in the same way an approved clinical drug or product needs to be.
“As we move ahead in early phase clinical trials, we may make significant changes to a cell therapy product,” explained Courtman. “So we have to start in facilities that allow us to be very flexible, and do things safely, but not necessarily according to full GMP compliance.”
The defining factor is risk. “It’s always a balancing act and regulators like Health Canada know this. What you’re balancing is therapeutic index against availability for the patient,” said Courtman.
Placing too much emphasis on maxiumum risk-reduction too early in the manufacturing process can result in escalating costs that may prohibit production entirely. Such a scenario is of no value to patients or the health care system in the long term.
Instead, Courtman said, “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, you always have to be assessing your risk, and making it safer as you go ahead.”
It’s a process of translation that demands continued scientific monitoring and exploration, in order to fully understand where the risks are and how they can best be mitigated.
“As you move up into larger trials, you have to be reviewing things much more,” said Courtman. But you want to do that anyway, because as you move forward and you 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.”
From the regulatory perspective, as part of a clinical trials application (CTA), Courtman explained that Health Canada wants to know:
Have you thought about the risks?
Have you asserted the right risks?
Have you ethically told the patient about the risks?
Are these acceptable risks going ahead?
“Most of the time if you do this correctly, they are on board.”
Typically, Health Canada will want to see evidence of three runs of production, demonstrating consistency of both product and procedure before they will green-light a clinical trial. However, there are variations on the scale of regulation.
“A cell therapy product, if it’s homologous use, is barely regulated. So if you take a cell out and put it back in the same person, to do the same thing and you haven’t really done much to it, you’re not going to have much issue in terms of regulation,” said Courtman.
This notion of “minimal manipulation” is the core of practice for clinics selling unproven therapies — therapies that have not been established as safe or effective through clinical trials or a peer-reviewed publication record and therefore have not been approved by Health Canada or similar regulatory body elsewhere in the world. However, since minimal manipulation is deemed to be of low risk, they can often skirt the stricter regulatory requirements. Such clinics have emerged in several cities across Canada and in other parts of the world and their proliferation has prompted authorities in Australia and California to propose or implement measures to restrict advertising or to reclassify minimally manipulated cells as drugs in an effort to curb the sale of unproven therapies.
On the other end of the spectrum, said Courtman, are cells that do fall under a drug classification, such as “those that are removed, genetically engineered and reinserted in back in a different location in the body in order to treat a disease.”
“And then there are even more complicated approaches, where you may have the genetic modification I just mentioned, to which you also add a material of some sort, so a combinatorial approach — a material and a drug in a cell together. That becomes very complicated from a regulatory and safety standpoint.”
From the manufacturing point of view, risk also varies depending on the quality of materials used and when the reagent (an active ingredient or biologic) is added. At a recent worshop on clinical translation co-organized by OIRM, Friederike Pfau, coordinator in the Laboratory of Experimental Organogenesis at the University of Laval explained that research-grade, non-GMP-compliant reagents are more commonly used in early product development for cost efficiencies.
These research-grade reagents, explained Pfau, are considered higher risk. “Once the process has been established, higher grade reagents that are specifically intended for use as a drug, biologic or medical device can be used. In some situations a suitable replacement cannot be found, and a long list of risk assessments need to be performed to ensure the reagent will not create any adverse effects in patients.”
At what point the reagent is introduced into the manufacturing process may also impact risk, Pfau continued. “In early stage manufacturing, a reagent may be washed or have cleared the system prior to the production of the final product, presenting little risk. Reagents introduced in later stages of manufacturing may still be present in the final product and will therefore require assurances that they present no risk to patients. With increased risk come more tests, but it means that once you’ve qualified your reagent, they can be added to the approved list for use in the [GMP] manufacturing process.”
GMP and approved products
Moving into the production of clinical-grade cell therapy products intended to be licensed for sale will at some point require manufacturing in a GMP certified facility. To be marketable, the product must also have passed phase III clinical trial. GMP certification provides documentation that the facility is following the license process.
For Pfau, “GMP is the ship that guides you around the iceberg of regulation.”
It’s a system for quality management that controls all aspects of production: air (cleanroom), cleanliness, equipment, personnel, procedures, and change (both planned and unplanned).
“Good documentation and record-keeping is the basis of GMP compliance,” Pfau expanded. “If it’s not documented, it didn’t get done. This is the view of regulators and inspectors.”
Today, much of the equipment available for manufacturing can be GMP compliant. Courtman selected the isolators he built into his facility because of their flexibility to the changes required in product development, but also because they record the process data and control the conditions such as cell temperature — elements that will one day be required for GMP compliance.
The precise timing of this move from research-based manufacturing to clinical manufacturing — — and indeed, the meaning of GMP itself — may depend on where you reside, said Courtman.
“Canada is different than the US and is different from Europe in terms of how it is inspected and regulated,” he said. “In Europe, even if you’re a hospital and only doing clinical trials, your clean rooms might get inspected and certified as a GMP. Technically, that’s not what GMP is. If it’s a non-licensed process, you can’t really do GMP, which is why I try to remove all the terms “GMP” from contracts because technically you’re not, in the North American sense, doing GMP. GMP was developed for licensed products only.”
This data and process record is vitally important in cell manufacturing, said Courtman. “If I make a drug, it’s a chemically defined product and I know exactly what it is. It doesn’t matter how I made it or where in the world I made it, what I’ve got here is 99.999% pure and that’s it.”
“In contrast, cell therapy products are really only defined by their process 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.”
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