Predictability, Stability, and the Importance of In-House Expertise
Another important facet of establishing a cold chain process is in validating its predictability. Defining the critical parameters of the process, from the time and temperature to the concentration of cryoprotectant, as early as possible allows researchers to iterate without heavily impacting a product’s viability. “For allogeneic therapies in particular, the challenge is in producing as much as possible,” Lequertier told BioProcess Online. “Identifying equipment that can manage hundreds or even thousands of doses and cryopreserve them is a big challenge for the future.”
CAR-T cells are very stable when stored at low temperatures. The trickier step in the process comes with shipping the product to a clinical site, as this is when it must come in contact with cryoprotectants that can compromise its efficacy: “I would say the viability of the cells that come in contact with the cryoprotectant is a couple of hours, so the difficulty is really focused there.”
As with any transformational additions to a process, incorporating cryopreservation into cell therapy production comes with a significant up-front investment. Beyond cryogenic equipment is expertise in cryopreservation, as well as investment in safety measures, training, and other costs associated with implementing these technologies in a production paradigm. “You can have a lot of money in the cryogenic tanks, in manufacturing and management, in all those assets, and the support of the equipment suppliers, but what you really need is expertise in the cryopreservation process,” Lequertier says. “Because it’s included in the manufacturing process of your CAR-T, it needs to be properly controlled, validated, and monitored.”
Comparing a cell pre- and post-cryopreservation for changes is a difficult ask, according to Lequertier, but from what Celyad has been able to observe, its cold chain process has not impacted the viability of the CAR-T therapies it produces. Simplification and scale-up for the process remains the biggest challenge for cryopreservation in the cell therapy space, Lequertier says, but the need to optimize these technologies will only grow alongside the therapies themselves. “All of the players – manufacturers, suppliers, the clinical side – should continue to invest in this area.