The New Cold Standard in Cellular Therapy

The New Cold Standard in Cellular Therapy

Less-than-desirable temperatures can have an adverse effect on your product. Image credit:

How are Cell Therapies “Challenging” the Cold Chain?
Clinical trials across the United States are testing novel cellular therapies designed to treat everything from heart disease to leukemia to immune system disorders. Several of these therapies, most notably CAR T-cell therapies, are nearing FDA approval, and the companies involved are gearing up for commercialization. The sheer number of therapies making their way through clinical testing highlights the need for robust, scalable methods in manufacturing, product delivery, and downstream processing. The cold chain is an often an overlooked part of this process.

Cell therapy manufacturing has come a long way in terms of automating some processes that would normally require labor intensive, highly skilled input. While high throughput cell isolation, modification, and expansion methods still require expert oversight, the mechanics of these processes are now frequently being automated and even integrated through the use of “all in one” systems, such as the popular CliniMACS Prodigy®.

But the journey of these “live” biologicals doesn’t end once the manufacturing process is complete—far from it. The logistics of product delivery are proving to be just as challenging as the mechanics of manufacturing. Cell therapy products are uniquely temperature-sensitive, and inadvertent temperature excursions can negatively impact their potency, safety, and efficacy. Consequently, there is a need for a new “gold standard” in cold chain solutions to make sure cell-based products maintain their efficacy all the way to the patient.

Pharmaceutical cold chain procedures make up a multi-billion dollar global industry. [1] As cell-based products start feeding into the pipeline of approved drugs, there is a greater need for monitored, tightly controlled temperature regulation. Pharmaceutical companies that are used to dealing with biologicals like vaccines and protein-based drugs are finding that answers such as dry ice shipping may not go far enough to protect what is essentially a “living” product. Technology for cold chain solutions needs to become more sophisticated, to include things like real-time temperature and humidity tracking, data logging, and chain-of-custody reporting.

Shipping and Transport
Across the globe, clinical trials are recognizing this challenge, and responding with innovative cold chain related technology. For example, current permutations of liquid nitrogen dry shipping dewars are designed to have longer hold times than previous versions. The dewars take advantage of a relatively new packaging technology that holds the liquid nitrogen in a matrix in suspension. This prevents leaking regardless of how the dewar is positioned during shipping. [2] As the liquid nitrogen changes phase from liquid to gas, cooling occurs, maintaining the contents of the shipping dewar at a constant -196° C. Temperature can be maintained for 10 days or more, making the packaging very useful for international shipping.

The new cryogenic dewar technology has other advantages. It’s being used by some clinical trial physicians as a kind of temporary freezer. Patient samples can be collected throughout the week, then shipped together to a testing center for further analysis. Since it’s virtually impossible for the dewar to leak, it’s no longer shipped under a HAZMAT designation, which cuts costs in labeling, training, and documentation. It also makes shipping more flexible, because shipments are not restricted to specifically trained airlines or couriers.
Shipping procedures are not the only issues facing the commercialization of cell-based pharmaceuticals. There are also regulatory considerations to take into account, and these considerations are being reflected in various cold chain technologies. New regulatory guidelines that govern the distribution of temperature-sensitive pharmaceuticals, and in particular cellular therapies, now often incorporate temperature monitoring, data logging, and track and trace technologies that provide chain-of-custody documentation.

Regulatory Standards
The Foundation for the Accreditation of Cellular Therapy (FACT) embodies a set of global standards developed specifically for the cell therapy industry. [3] The Foundation was co-founded by the International Society for Cellular Therapy (ISCT) and the American Society of Blood and Marrow Transplantation (ASBMT), for the purpose of establishing evidence-based requirements to help ensure the highest quality products and therapeutic care. The internationally recognized set of requirements for FACT accreditation governs cell collection and processing, banking, release, product delivery logistics, and patient administration.
FACT will begin accrediting programs for immune effector cells, such as CAR T-cells, in 2017, and it’s to be expected that most if not all companies and research institutes that handle these products will seek such accreditation, not only to protect efficacy, but also for the confidence such accreditation instills in the integrity of marketed cellular products. This in turn will accelerate the implementation of more sophisticated cold chain solutions, as well as delivery and point-of-care solutions, that incorporate automated data tracking and chain-of-custody.

Commercializing CAR T-Cell Therapies
There are literally hundreds of millions of dollars being invested in CAR T therapies, primarily because the outlook for treatment has been so good. Scientists are truly excited about what looks to be a complete paradigm shift in cancer treatment; and the potential for vastly improved cancer survival rates in the not-so-distant future. “CD-19 targeted” T-cell therapy is one of the first in this class of immune cell therapeutics expected to be approved in the near future. In light of this prospect, scientists are scrambling for ways to convert what is essentially a “boutique” therapy [4] into a fully commercialized treatment. CAR T-cells are not “off-the-shelf” products. Instead, they are personalized to each patient, and this complicates both manufacturing and delivery.

At this stage of the game, much of the work on commercializing CAR T-cell therapy has focused on manufacturing. A recently completed multicenter clinical study [5] demonstrated the feasibility of collecting apheresis products from multiple patients at different centers, and using them to manufacture clinical grade CAR T-cells at a centralized facility. The finished T-cell products were cryoshipped back to the original centers for administration to each patient. This type of flexibility bodes well for streamlining manufacturing of T-cell products that are personalized, but prepared using an identical process and identical reagents. Downstream processes, particularly cold chain related processes, need to be automated and standardized in the same manner.

On-Site Cold Chain Handling
The aforementioned study brings up another point at which the cold chain comes into play, namely on-site handling. Shipping and transport cold chain technologies are being standardized. On-site cold chain handling should also be standardized if we are to maintain product integrity at the point of care. Both during manufacturing and in the treatment clinic, therapeutic cells are transported to and from liquid nitrogen or -80°C storage, transferred between labs and facilities, or removed from storage for functional assays and quality control testing. Even if the cells in question are not themselves destined for patient infusion, the data that is generated from them is critical to informing clinical trial outcomes, and ultimately, to patient safety.

The cell therapy industry already has a number of solutions in place to protect the integrity of cell-based products during handling. MedCision’s BioTTM line of products offer both dry ice and liquid-nitrogen based workstation and transporting solutions designed to keep therapeutic products in a safe and stable temperature range during sorting and handling. Even short temperature excursions outside the optimal range can affect the health and functionality of cellular products, [6] so it’s important to always follow best practices for storage and handling. In the face of a rapidly changing medical landscape that includes live cell therapeutics, we need to insure that the cold chain is keeping pace with the rest of the cell therapy field.

[1] Pharmaceutical cold chain logistics is a $12.6-billion global industry. Pharmaceutical Commerce. April, 2016.
[2] Sawicki MW. How Cold Chain Logistics Work in Clinical Trials. Applied Clinical Trials. Nov 2015.
[3] Maus MV, and Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. Journal for ImmunoTherapy of Cancer. 5:36, April 2017.
[4] Lulla P., and Ramos CA. Expanding Accessibility to CD19- CAR T Cells: Commercializing a “Boutique” Therapy. Molecular Therapy. 2016.
[5] Locke FL. et al. Switch to Standard View Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Molecular Therapy. 25 (1): 285–295. 2017.
[6] Norkus, M. et al. The effect of temperature elevation on cryopreserved mesenchymal stem cells. Cryoletters. 34(4):349-359. 2013.

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