Fresh or frozen - understanding the supply chain needs of your cell and gene therapy
By Andrea Zobel
In recent years, cell therapies and other Advanced Therapy Medicinal Products (ATMPs) have begun to come into their own as highly promising treatments for a wide range of serious, chronic and rare diseases. ATMPs have the potential to transform the lives of patients suffering a range of conditions, from cancers to blood and immunological disorders.
With a record number of new cell and gene therapies (CGTs) approved in 2021(1), a surge in commercializations is anticipated. Commercializing a cell therapy is a complex process compared with other treatments, especially when it comes to supply chain needs. An in-depth understanding of all of the possible end-to-end workflows is vital.
During a recent roundtable hosted by The Medicine Maker, Andrea Zobel, Senior Director, Personalized Supply Chain at World Courier, explored the complexities of bringing cell therapies to the market. She was joined on the panel by fellow industry experts, Bill Shingleton Department Director, Applications and Biology at Cytiva, Michael Terhoeven, Head of Supply Chain at Miltenyi Biomedicine and Phil Morton, Chief Technology Officer, Albumedix. In this article, we summarize the supply chain challenges discussed by the panel facing ATMP developers.
Why do we still have issues commercializing CGTs?
Andrea: There are a few transport obstacles that need to be overcome to ensure successful commercialization of cell therapies. Firstly, they are time critical - fresh cells have a shelf life of between 12 and 96 hours before they begin to degrade. This limits the window in which patient samples can be transported to the manufacturing site (in the case of autologous therapies), and the timeframe for delivery of the finished dose to the patient - adding pressure when shipping to patients living overseas or in remote locations.
It would be beneficial to extend the shelf life of cell cultures, freezing cells below 150ºC using cryogenic storage techniques is one option to address the shelf-life issue for fresh cells, allowing them to be kept almost indefinitely. However, emerging markets and remote locations, in particular, may not have the specialist facilities required to maintain cryogenic storage and transport - for example, hospitals may not be able to handle liquid nitrogen used in freezing. This limits transport to the few countries with the necessary infrastructure.
Michael: Another critical challenge, in fresh and cryogenic, is having to synchronize across the different parties in the supply chain of the cell material and product: the apheresis centers, the logistics providers, the manufacturing, again logistics and finally the treatment centers as well as all the different functional actors within these parties. The synchronization needs to cover time and schedule aspects, cold chain, chain of identity and chain of custody dimensions. All interfaces need to be clearly defined, well managed and controlled.
How can these issues be addressed?
Phil: If you can really improve the stability of the cells post-thawing or in a fresh state, then these issues could be addressed, extending the shelf life of fresh batches and helping to alleviate the issues associated with cryostorage.
An important aspect is to look at the raw materials used in the formulation of the cells and how they are packaged up in that formulation. Albumin - of the right quality - can play an important role in the stabilization of fresh cells and can help prevent freeze damage for frozen cultures. With the right albumin, it may be possible to extend the shelf life of thawed cryopreserved cells from 12 hours to 72 hours, and potentially beyond, while fresh cells can potentially stay viable for 96 hours.
Bill: Innovations, such as liquid nitrogen-free control rate freezers and liquid nitrogen-free shipping devices can overcome issues relating to the lack of infrastructure for cold-chain transport. These liquid nitrogen-free control rate freezers are bench-based devices that can be taken directly into a cleanroom, which of course you can't do with liquid nitrogen. This simplifies the process of moving a product from the manufacturing suite to the treatment center.
Andrea: We receive a number of requests from clients for solutions that can allow doses to be delivered to and stored at treatment centers for a long time in advance of administration - not just for a couple of hours, but for days or a week or two. This is because the patient may not be ready to receive the treatment. We have the capability to achieve this and potentially to allow even longer storage in-clinic - what is holding this back is the regulatory environment in many markets, rather than technology.
Could decentralization of the manufacturing and storage of CGTs provide a solution?
Michael: If a product has a 36-hour shelf life, I don't think it is possible to manufacture for patients across the globe from a central location, making regional manufacturing a requirement for the time being. Even with a 36-hour window to deliver within a region - Europe, for example - there could be issues. Bad traffic conditions, for example, could cause delays that could push the product past its shelf-life limit.Andrea: Innovations, such as those discussed by Phil and Bill, are helping to mitigate the impact of these unforeseen problems. However, the successful delivery of a cell therapy comes down to the quality of the logistics. Logistics has to follow the science to find the best solution for the needs of the therapy. We have to prepare the logistics and the equipment and all the facilities to meet the product’s needs.
In conclusion, how do you see these issues evolving in the future?
Phil: If we have the innovation around the formulation of the cells themselves, we will be able to reach a position where we can have true flexibility on whether or not we're looking at fresh or frozen transportation. This will enable us to define a fuller strategy for the logistical aspect of ATMP commercialization that is centered around what is best for all patients wherever they are in the world, rather than our ambitions being restricted by geography. That is where I'm hoping the future will go.
Bill: We will move much more towards frozen, particularly for treatments where we need to store large batches of cells. Cryopreservation gives us the flexibility to do that. While the infrastructural challenges associated with freezing are not going to go away, rising demand for ATMPs will mean that more and more treatment centers are going to be equipped with the technology to handle frozen therapies. As an industry, we have to support where we can in these areas.
Michael: When allogeneic is an option, we can look at centralized manufacturing and storage solutions and most likely, frozen set ups. But when it is not an option, for instance with CAR-T and other cell therapies, there might be a bigger need for point of care or fresh logistics. We will have to follow science and see.
Andrea: The cell therapy space is growing in both size and complexity. Innovations in formulation and storage may well make it possible to extend the non-frozen shelf lives of some therapies to enable them to be transported easily worldwide from a single location, or even to allow higher-temperature frozen transport. However, this is unlikely to be the case for all products - some will still need cryopreservation to enable long-term storage and long-distance transit.
With this in mind, I think we are going to have to see cryogenic infrastructure extended globally to ensure therapies are delivered effectively to the patients that need them, whatever the products’ storage needs. Logistics experts are leading the way here, investing in the equipment and capability to transport sensitive treatments worldwide, and identifying creative transit solutions to reach all patients wherever they are being treated.