Reliable access to high-quality starting material is a primary challenge in cell therapy manufacturing. Freshly isolated leukopak starting materials depend on donor availability and are vulnerable to cell losses from scheduling changes and other unforeseen circumstances. Flexibility often is required for cell therapy manufacturing. Therefore, relying solely on freshly isolated starting material is impractical, particularly when cell therapy logistics involve global shipping and distribution.
Donor sourcing is among the most critical factors shaping cell and gene therapy (CGT) supply chains. In the best of times, sourcing donor material for the rapidly expanding cell therapy industry is a challenge. The sheer number of CGTs in development has put pressure on starting-material suppliers, which are struggling to keep up with demand. Cryopreserved leukopaks could be an important stopgap that significantly alleviates current sourcing concerns.
Many CGT developers and research facilities already consider cryopreserved leukopaks to be valuable, shelf-ready resources. Unfortunately, preconceptions regarding the impact of cryopreservation on cell quality discourage wider application. However, when prepared using optimized protocols and quality control, materials from cryopreserved leukopaks retain functionality and efficacy as well as â€” and sometimes more effectively than â€” freshly isolated materials, enabling critical research to continue.
Donor Sourcing During a Pandemic
The COVID-19 pandemic is diminishing donor travel and availability, making freshly isolated donor material difficult to obtain. Even the most dedicated donors are understandably anxious about travel and exposure to clinical settings. COVID-19 research also has become so critical that clinical trials for many therapeutics have halted temporarily despite acknowledged impacts on patients (1). Although necessary to protect public health, such deferrals delay drug filings. Meanwhile, research into other conditions must advance.
Protecting donors is paramount for starting-material suppliers. Through the foreseeable future, they will implement social-distancing measures in donor centers. But even after those centers increase production to prepandemic levels, scheduling and delivery of material will remain challenging because of modified hours and/or days of production. Certainly, the temporary slowdown of leukapheresis donations presents a conundrum to suppliers working with the healthcare industry to solve current health crises. However, companies hoping to ramp up CGT programs after restrictions lift can benefit from reevaluating preconceived notions about fresh and cryopreserved starting material to offset continuing logistical difficulties.
Starting-material suppliers are helping researchers to study the SARS-CoV-2 coronavirus by securing access to COVID-positive donations (2) and mitigating sourcing challenges using cryopreserved leukopaks from healthy donors.
Studies show that cell viability and function decrease over time when leukapheresis products are stored at room temperature or, to a lesser extent, at 4 Â°C (3).
Consequently, long-distance shipping of fresh CGT starting material correlates with a decline in viability and efficacy. Cryopreservationâ€™s effects often are overestimated because of outdated literature. The process requires thorough understanding of temperature, volume kinetics, and cell subset physiology, but when it is undertaken with optimized procedures and reagents, cooling preserves cell health and functionality in a near-perfect state until application. Thus, cryopreserved leukopaks are not only a practical necessity for long-distance shipping and long-term storage, but they also provide higher-quality products than fresh materials subjected to equivalent shipping and storage times (4).
Process control and quality oversight are used to mitigate the peril of variable efficacy, but cryopreserved materials offer a simple way to ensure consistency. Access to multiple cryopreserved samples from the same donor enables a researcher to assess identical donor criteria and expect highly similar cell counts and quality among related samples. Such advantages facilitate long-term research without introducing additional variability.
Donor-sourcing difficulties significantly hinder manufacture of CGT products. Cryopreserved leukapheresis starting materials could be an important part of the solution.
1 Coronavirus Pandemic Brings Hundreds of US Clinical Trials to a Halt. NPR, 11 April 2020; https://www.npr.org/sections/health-shots/2020/04/11/832210606/coronovirus-pandemic-brings-hundreds-of-u-s-clinical-trials-to-a-halt.
2 Support for Your COVID-19 Research. Charles River Laboratories, https://www.criver.com/products-services/support-your-covid-19-research?region=3601.
3 Gniadek T, et al. Optimal Storage Conditions for Apheresis Research (OSCAR): A Biomedical Excellence for Safer Transfusion (BEST) Collaborative Study. Transfusion 58(2) 2018: 461â€“469; https://doi.org/10.1111/trf.14429.
4 Clarke D, Smith D. Managing Starting Material Stability to Maximize Manufacturing Flexibility and Downstream Efficiency. Cell and Gene Ther. Insights 5(2) 2019: 303â€“313; https://doi.org/10.18609/cgti.2019.033.
Brad Taylor is director of global marketing, and Dominic Clarke is global head of cell therapy at HemaCare, 8500 Balboa Boulevard, Suite 130, Northridge, CA 91325; https://hemacare.com/contact.