Supply Chain: Considerations & Strategies for Manufacturing of Cell Therapies
The first step is the leukapheresis stage; blood is taken from a patient frozen, shipped to manufacturing sites and then reprogrammed by adding a viral vector to create the CAR-T cell. Cell therapies require living cells, which can cause stability issues in materials and final products.
Frequently the shelf life of cell therapies is very short. This presents a logistic challenge; precise timing and management of scheduling, manufacturing, and shipping are needed to ensure the product doesn’t become inert before it reaches the patient. Additionally, transporting cells from manufacturing facilities to hospitals requires a complex cold chain. It can take several weeks before the treatment is available, which can be critical for patients with serious health conditions. It also triggers manufacturing variability, as cells from the patients can link to very different behaviours of the cells in the manufacturing process.
Because autologous cell therapies are personalised products that are custom made to target individual cancers, manufacturers must ensure that the products are consistently tracked and identified. Additionally, because it is an “autologous process, the manufacturing is triggered by the cancer treatment decisions”. This requires that every step of the process is documented, no matter how complex the supply chain becomes. The consequences of a patient receiving the wrong therapy are severe and can even be fatal.
Most CAR-T manufacturers hold contracts with major logistics companies for tailored medical courier services, which are effective but expensive. However, in the past few years, dedicated I.T companies, such as Trakcel and Vineti, have begun offering software solutions for cell supply chain management. These companies aim to make delivering a scalable and regulatory compliant easier for both clinical trials and commercial settings.
Regulatory Compliance: Characterisation, Reliability and Safety
As this form of cell therapy is relatively new, one of the primary concerns for regulators and researchers is ensuring safety. Unfortunately, ensuring and proving cell therapy products are safe and effective is generally more complex than other treatment types.
T cells designed to attack cancer can send the immune system into overdrive by triggering an inflammation of proteins called cytokines into the bloodstream. This is known as Cytokine release syndrome, which can cause high fevers, make patients’ hearts race out of control and send blood pressure plummeting. These side effects are one reason Car-T therapies have only received approval for a narrow range of patients whose cancer hasn’t responded to conventional treatments. Additionally, CAR-T therapy is offered only at select cancer treatment centres with trained teams that follow rigorous safety protocols to control side effects.
Researchers are designing new forms of the treatment, changing how patients’ T cells are engineered to make the therapy less risky. For example, scientists are trying to install safety switches that can turn off CAR-T cells on command and design T cells that activate only under certain conditions. Another method is to add features that help the T cells target cancer cells more specifically but ignore healthy cells or reduce collateral damage from T cell–boosting drugs. Meanwhile, doctors are learning how to manage the side effects for patients better.
Scalability and Cost
For cell therapies that receive clinical approval, scalability becomes the primary concern. Unfortunately, the necessary infrastructure and labour result in prohibitive costs; Kymriah costs approximately $475,000 per patient. The solution to this will almost certainly include increased automation. Chaminda Salgado (Scientific Leader, GSK) argues that the key to lowering the cost of goods “is to minimize the testing burden by validating out as many tests as possible, before you reach the commercial phases.” and “Implementing disruptive technology to fully automate sample to result processes of burdensome methods such as flow cytometry and PCR”.
Automation would minimise the possibility of human error, improving the reliability of the process and decreasing turnaround time and increasing capacity. Some automated, closed systems are already on the market, such as Miltenyi Biotec’s CliniMACS “Prodigy” system, which offers an all-in-one solution for cell processing in a closed, GMP-compliant environment. Additionally, Fresenius Kabi’s “Lovo” cell processing system automates tasks such separation, washing, fluid exchange, platelet depletion, and fluid exchange. Although these systems are still relatively early in development, automation will almost certainly be a central topic as demand for CAR T-cell therapies.
Supply chains, regulatory approval and scalability are familiar challenges for the pharmaceutical industry. However, while cell therapies face added obstacles compared to other forms of therapeutics, solutions are actively being worked on, and the future looks bright. In 2012, only twelve clinical trials were investing CAR-T cell therapy products. In 2020 there were over 500. Since 2017 four CAR-T products have reached the market, and double digits are likely in the next few years.