The Challenge Of Getting Cell Therapies To Patients
By Ed Hess, Editor, BioProcess Online
The “Last Mile” has been associated with the telecommunication industry for a long time. It’s not a mile in distance as much as it is a metaphor. It represents that point in the chain where the product is finally delivered to the consumer. The last mile tends to be more complicated than all the miles that preceded it. It’s where all the variables and bottlenecks occur. Mastering this last mile is difficult and expensive.
The cell therapy space is currently facing its own version of the last mile as its products and patients grow in numbers. The words “difficult” and “expensive” would certainly apply to this last mile as well. However, the real watchword is “complexity.” While it’s nice to think there are simple answers to complex problems. Typically, complex problems require complex solutions. And, according to Ohad Karnieli, co-founder and CTO of Karnieli Ltd., cell therapy companies need to start addressing the issues that arise in the last mile.
Ed Hess: Related to cell therapy products, how do you define the “Last Mile?”
Ohad Karnieli: I see the last mile starting at the moment the cells are harvested. Culturing the cells and growing them and formulating them are governed by processes that are well defined. People know how to do these things, at least in lab scale. They understand the processes and the challenges. But, now that you have the cells in hand, what comes next? One option is cryopreserving the cells. By freezing the cells, you now have a way to get them to the patient. But, effective cryopreservation presents some issues. Another option is to ship the cells in a fresh state. A lot of the current cell therapies in oncology are very exciting, but the cells cannot be frozen in some of these applications as they might lose their activity and viability. This creates a very small window of time in which you have to get the therapy to the patient. That last mile is from the minute you harvest the cells until you get them into the patient’s body. That’s really where the complexity lies.
EH: What makes the last mile particularly challenging?
OK: There are really several things going on here. The first issue is cryopreservation and the affect that the freezing and shipping process will have on the cells. These are living things and their therapeutical activity is based on their physical state and health. They react differently to air pressure changes, temperature changes, vibrations, and a multitude of changes that occur during the shipping process. Within companies that produce these therapies, there is a real lack of understanding around this. Every company and every product needs to be tested to understand how these environmental conditions affect the therapy and its efficacy. In general, all of these same issues arise when you’re talking about shipping fresh cells as well. They may not be frozen, but those cells are going to be subjected to a range of environmental changes and handling conditions. For each product, a company needs to test and account for these.
It’s fair to say that cryopreservation is widely studied and fairly understood. But, even in that case, some research suggests we don’t have a full understanding on the process and its effect on cells. There are studies, such as one published by Dr. Jacques Galipeau, that suggests that cryopreserved MSCs (mesenchymal stromal cells) have a lower efficacy then MSCs that weren’t cryopreserved. You can see that between fresh cells and cryopreserved cells, the science is not complete. That’s why every company needs to test every product extensively to define the limits and tolerances.
EH: In the life cycle of drug discovery, when should this “last mile” testing begin?
OK: You have to start addressing these questions once the therapy enters clinical trials. If your trial is in phase one and running in a hospital environment where the entire process is contained and controlled, then you might not have to think about these issues at that time. As soon as you move out of this controlled environment [or if your trial does not take place in one hospital], you’re going to be confronted with these last mile problems. If your therapy needs to be delivered to different clinical settings and for different patients, then you should really start thinking about these issues as early in the process as possible. Before you can even consider injecting patients in a phase one study, you’d better have good answers for how you’re going to stabilize a therapy and actually deliver it to patients.
The regulatory pathway will force you to look at these last mile issues, but it’s just not soon enough in the process. You’ll have your shipment validation, for instance, as part of your regulatory file. Most companies start thinking about these issues at that point. This is typically around phase three, which is too late. Somewhere in the backs of their minds, companies know these issues exist. But, they’re just too focused on the product to stop and consider the complexity of logistics and handling related to their product. They don’t address these issues until they are forced to do so. It’s too complex to just postpone until this late in the process.
EH: How do you ensure proper handling at the clinical site as part of successful last mile execution?
OK: The truth is that the companies that produce these therapies don’t have a lot of visibility into how they are administered during clinical trials. In theory, for instance, thawing cells is very easy. You put a vial in a water bath and shake it gently until it thaws. For a 1 mL vial, that takes a minute. But, then you start using a 6 mL vial and that’s more thawing time. There are applications where 20 mL vial are being used. That’s going to take 20 minutes to thaw. Can you see a physician being responsible for this thawing process in all of these cases? No way. There will be other clinical personnel handling these products. And, if you don’t handle these products properly and with care and patience, you’ll kill the cells.
There are just so many variables that need to be considered. There are hospitals that thaw at the bedside. You might have a hospital that requires its pharmacy to handle thawing, but that pharmacy is three blocks away. These are two very different scenarios in which the product will be thawed and delivered to the patient. These are two very real scenarios. How do you handle each one? What personnel need to be involved? Who is trained to handle these products?
That’s why I say that, in theory, thawing cells is an easy step in the process. It is easy until you have to account for hospitals with slightly different scenarios. But, this is reality and each scenario needs to be accommodated. It gets very complicated very quickly. The more you dig into these question, you start to realize how big the gaps are.
About Ohad Karnieli
Ohad Karnieli earned his Ph.D. in biotechnology and genetic engineering from the Sackler School of medicine at Tel Aviv University. Dr. Karnieli is the co-founder and CTO of Karnieli Ltd., a leading cell therapy innovation solution provider and molecular diagnostic lab. Karnieli serves in many industry and scientific committees and is the chair of the Process and Product committee of the International Society of Cell Therapy.