Tackling the complex nature of the cell and gene therapy supply chain
By AmerisourceBergen
For example, all the products based on patient own material (personalized medication) must maintain the chain of custody, chain of identity and good manufacturing practice (GMP) controls as they move to and from the manufacturing site. This is to secure the chain from apheresis until infusion back to the patient is closed. On the other hand, allogeneic and gene therapy products may be stored in depots before delivery to the patient or clinic.
Panelists at the second session of Cencora’s ThinkLive Cell and Gene Therapy Summit 2024 – “Beyond borders: Breaking barriers to enhance patient access in cell and gene therapy” – explored this complex topic in depth. During the session, Navigating the supply chain maze: Overcoming challenges and optimizing logistics for CGTs, panel moderator Andrea Zobel, PhD, Senior Director, Personalized Supply Chain, Cencora World Courier, asked participants to share their expertise and experience with managing the logistics of CGTs across the supply chain. Panelists included Mark Edwards, Senior Director, Supply Chain Management, Sangamo Therapeutics; Erik Agterhuis, Biotech Supply Chain Leader, Life Cell Science Supply Chain Management; and Hans-Peter Scherzer, Project Manager, Customer Success, Cencora World Courier.
From innovation to supply chain logistics
Health authorities demand tight control over temperature controlled logistics for drug products, beginning at clinical development. EU guidelines, for example, state that “where the ATMP requires controlled temperature conditions during transport and/or storage prior to administration, the sponsor should ensure there is a temperature monitor/log data and/or confirmation that required conditions have been met”i. Additionally, the Food and Drug Administration states that an investigational new drug should include a description of how the product will be shippedii.
Developers of cell and gene therapies are expected to consider the supply chain logistics around temperature, packaging, lane validation, and shelf life as an integral part of CMC. However, as the panelists shared, this is not always the case.
Mark noted that scientists tend to be focused on finding a process that gives them the best results, but these aren’t always feasible for the patient or the business. “It’s important that we make an effort early on to lean into those discussions so we can provide input and guidance on what’s realistic,” he said. An example was a proposal to take blood products from hospital sites across the US to a central location in a few hours, which required amending cryopreservation processes to meet requirements.
Erik pointed out that typically shipment and validated packaging is outsourced, and when questions arise – around temperature requirements, type of packaging, lane validation, etc. – the R&D department doesn’t always have the answers. “It’s still a learning process and when they move into clinical phase two, or even phase three and commercial, they are having to learn quickly, so there should be more alignment earlier in development,” he said.
Issues with logistics depend on the maturity of the company, Hans-Peter noted. This is apparent, for example, when a large pharmaceutical company acquires a start-up with promising studies, but which perhaps didn’t understand health authority requirements for shipment and customs clearance, he said. Once the product gets to commercialization, the acquiring company may be forced to consider the possibility of carrying out new stability studies and transport validation.
“In 2017 with the first CAR T therapy, Kymriah, the process was new to the authorities,” Hans-Peter notediii. “They weren’t used to dealing with liquid nitrogen equipment in a commercial phase. At this point it was more of a discussion and alignment between what we can offer to the health authorities and what they accept from our side. So, it was easier to adapt the mindset of the health authorities than with more mature products.”
Erik concurred, saying the Advanced Therapy Medicinal Product (ATMP) guidelines in Europe were new in 2018iv. Additionally, there were some logistical challenges at the time with Iceland’s volcanic eruption, which required careful lane mapping and backups, and a lot of back-and-forth communication as well as having a business continuity plan to address logistics challenges.
For its part, Sangamo adapts its lane processes for CGT products. “When you look at cell and gene therapy compared to normal pharmaceuticals, you have a few vials that are very expensive but, more importantly, are vital to the patient, so there's a huge moral burden to make sure that shipment is absolutely safe,” Mark said.
With that in mind, the company does a test shipment for each clinical site to check that the lane is robust and that addresses and contact details are correct, allowing them to fix any problems. “We make sure that the site has a chance to receive cryogenically frozen water and test how they will receive it, get it out of the shipper or how they will thaw it, so that everything is resolved ahead of the actual shipment. And then we micromanage that very carefully. We watch the shipment in relatively real time and have alerts set up. And we work very closely with the site to remove the risk as much as we can.”
Erik added that it is important to check with customs on the import/export process by testing with logistics partners with a mock shipment across the full supply chain. “It’s a big learning curve for everyone in the supply chain, but as customs and the airlines become more accustomed to these products and as the volume grows, it’s important to streamline processes with standardization and automation.”
From clinic to commercialization
Panelists also discussed whether commercial teams were taking learnings from clinical teams. As Erik noted, it depends on the size of the company and the inter-functional lines of communication.
“It’s more successful when you tie the two together closely to get everything correct in terms of dose sizes that the patient needs, the way the product is handled and received at the site,” Mark said. “But that can be more challenging for smaller companies that don’t have a commercial team internally.”
Hans-Peter noted that the commercial side needs to be proactive in terms of understanding the needs of the clinical team. “They should be getting involved in the clinical trial stage to define the right steps early on so the stability studies include the necessary temperature details for transportation. Often smaller companies are scared to share information with external providers, but it’s important to consider what it will cost from a risk perspective to not involve those external providers to ensure those pain points or risks that can occur in commercialization are covered early on.”
“In the past, transporting a product from A to B at a particular temperature wasn’t critical,” Hans-Peter said. “But having a time-sensitive product, all those logistics – transportation, distribution, etc. – must have a different focus. Now, as logistics providers, we are more in the center of the manufacturing process as well because we are a critical component of the entire chain.”
“Mostly we are using standard pharmaceutical processes, equipment, locations and sites for our cell and gene therapies, but beefed up with some micromanagement,” he said. “There is a lot of potential to make this process more robust, whether through standardization of laws and regulations so what you have in Europe is consistent with what’s happening in Asia and the United States, or having improved processes at airports so living tissue isn’t exposed to potentially damaging X-rays. It’s about having processes to receive and handle these products. That will likely mean a heavier reliance on technology to achieve the best outcome.”
Real-time temperature monitoring and knowing where a product is, in case there is a need to react quickly is key, Hans-Peter said, adding that one of the most exciting tools for him is the digital twin.
“This lets you create a duplicate of your real world where you can simulate different scenarios and see the outcome, and then also carry out predictive, real-time analysis,” he said. This gives companies insight into potential crises and how to react on short notice – for example, flight delays or airport closures, he added.
Given the fragile nature of cell and gene therapies, the focus should be on exception management, Erik added. “We know that 99.5% of shipments go well; it’s the 0.5% that we need to deal with and have the plans in place to mitigate those exceptions.”
While technological innovation is invaluable, it’s equally important to have an expert team to ensure all these processes get executed, Hans Peter emphasized. “You need to make sure they have the capabilities to react on their own and make decisions to quickly correct issues.”
Harmonize and digitalize
There are, however, several factors that create barriers and pain points for the CGT supply chain. Among these are lack of clear harmonization and alignment of the requirements, Mark noted.
“As cell and gene therapies grow, we need the airports, the customs agencies and other authorities to understand the nuances of these products -- what they are and how they need to be handled,” he said. “Of course, we need to be compliant and make sure everything's safe, but we don't think it's going to work effectively if we have to subject these materials to the standard process we use for other products. They need some special consideration to meet the needs of patients, which includes prompt and safe delivery.”
Standardization throughout the supply chain is key, Erik noted. “While that’s easy to say, it’s harder to achieve; however, we are seeing initiatives, such as the JACIE accreditation from the EBMT (European Society for Blood and Marrow Transplantation).” The purpose of JACIE accreditation is to promote high quality patient care in collection, processing and transplantation centers worldwidev. “If we don’t change, if we don’t work together – starting with regulatory processes within each country – we will be set up for failure and patients will suffer because it will take too long for products to get to them.”
Discussion in recent years has turned to digitalization of the logistics sector in general, Hans-Peter noted, adding that Europe is behind where it should be in terms of connectivity between different transport modes.
“The main problem is due to the fact that the different authorities don't standardize topics, so smaller or mid-sized companies are scared to invest money in what might be the wrong technology,” he said. “We need more guidance from the regulators in alignment with the logistics experts of the different sectors.”
Greater logistical efficiency will also be key to making cell and gene therapies more affordable for developing countries, Eric stated. “We need to push for greater standardization and automation of processes to reduce the cost of the product.”
Ultimately, the goal should be to provide patients globally with access to these life-saving products. To reach this goal regulations adapted to the nature of new therapies, advanced technologies for advanced therapies and a higher level of digitalization and standardization is needed, Andrea concluded.
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