While using cell therapies that have a short shelf-life due to a “fresh” final product (meaning the product is not designed for long-term storage) is perfectly acceptable for proof of concept of the cell therapy, as development into late-stage and then commercial production becomes the goal, different constraints arise. This is where cryopreservation of final product becomes an option and, in some cases, even a necessity.
In hospital settings and small academic settings where early phase cell therapy development often takes place, it's quite feasible to manufacture a product, carry it down the hall, and infuse it into a patient, and it makes both economic and logistical sense to do so. However, once a cell therapy developer considers the possibility of a late-stage clinical or commercial product with potentially thousands of doses a year that need to be shipped to hospitals all over a continent or the world, it becomes much more logical to have a cryopreserved final product.
As part of staying within a short window for shelf-life, a fresh cell therapy product will need to be extracted from and then infused into patients on certain days of the week or even certain hours—which could mean extra expenses in labor and facilities to accommodate that schedule. For example, if a cell therapy developer completes the manufacturing of a patient-specific therapy at 5:00 pm or even 10:00 pm, it now needs to ship right away in order to reach the patient within the window. That requires pick-up and delivery at off-peak hours, which adds the extra cost of a specialized courier service. In comparison, manufacture of a cryopreserved product can be completed at any point during a seven-day work week, and can be stored until it can be shipped at a time that is most convenient for the patient, receiving hospital, and so on, at much lower cost.
The logistics can be greatly simplified and standardized when cryopreservation is part of the process. That's a key point because standardization of administration is, on the commercial scale, going to be necessary to minimize cost of goods.
Some risks of introducing cryopreservation of final product into a cell therapy process:
- The cost of the development work to integrate cryopreservation into the process may be significant;
- The addition of multiple additional unit operations to the cell therapy manufacturing process, each adding their own direct cost and accompanying risks;
- Additional unit operations (i.e. thawing) are put in the hands of the clinical sites, requiring investment in training and possibly equipment at those sites.
To help ensure that the benefits outweigh the costs, it is crucial to consider the introduction of cryopreservation of final product as early in clinical development as possible, mitigating the comparability risk. If a developer integrates cryopreservation prior to Phase I, there is no comparability risk. The same change between Phase I and II carries some comparability risk—the developer will still need to prove to regulators that the cryopreserved product is equivalent, but the burden of proof is lower in these early stages. If a developer waits to make the change until after Phase II, once efficacy has already been proven and the time has come for a pivotal trial, the burden of proof is much higher. After Phase III, proving comparability generally becomes significantly more difficult due to increased comparability risk and cost to run the necessary comparability studies.
Because of these hurdles and the intense time and cost that can be associated with not executing the cryopreservation process change seamlessly, it may be valuable for cell therapy developers to partner with a manufacturing development specialist that has a long history and deep expertise in cell therapy. The “cold truth” is that cryopreservation is not a process change that can be taken lightly—the stakes are simply too high.
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