In this ‘Ask the Experts’ feature, a panel of key thought leaders share their perspectives on current obstacles and future developments facing the cold chain and logistics. For example, how have protocols surrounding distribution changed over recent years with regards to cell and gene therapy (CGT) products? What factors need to be considered when shipping these temperature-sensitive therapies? Discover more about this from our panelists, Emilio Frattaruolo (CSafe Global, OH, USA), Daniel Gibson (Anthony Nolan, London, UK), Benoit Moreaux (Bone Therapeutics, Charleroi, Belgium) and Glyn Stacey (International Stem Cell Banking Initiative, UK).
Cold chain and logistics questions:
- How have protocols surrounding cold chain distribution changed over recent years with regards to cell and gene therapy products?
- How do cold chain distribution processes differ depending on the type of product?
- What factors need to be considered when shipping these temperature-sensitive therapies?
- What major logistical challenges are present when considering commercialization of these products? How could these challenges be overcome?
- As CGT therapies become more prevalent and the patient group wider, the current cost of high touch supply chains will become an issue. How can high performance passive shippers help?
- In your opinion, how could cold chain distribution evolve to accommodate ‘just-in-time’ delivery of products irrespective of location?
- What advancements would you like to see in the cold chain over the next 10 years?
How have protocols surrounding cold chain distribution changed over recent years with regards to CGT products?
Emilio Frattaruolo (EF): CGT products represent a unique challenge when considering the traditional cold chain. Traditional cold chain distribution allows for well-defined supply chain mapping but with the introduction of autologous products the path each shipment takes can vary wildly. As such, CGT manufacturers have leaned on solution providers to develop extremely high-performance and long-duration parcel shippers to ensure their payloads remain viable even if supply chain disruptions occur.
Daniel Gibson (DG): The requirements to maintain a stable temperature during transit have always been there, however the desire to prove they maintain the specified conditions has really increased in recent years, partially because of the regulations but also as a result of slightly more complex logistics, which requires more surveillance. Thankfully, the available tools and expertise have improved to meet this need.
There are more options available now, take cryogenic shipping vessels for example. Smaller shipping containers that have the equivalent hold time are now available, meaning that in some cases shipment is now more cost effective. Advances in data logging mean that customers can also access ‘in transit’ data either via an online portal or by direct, instantaneous download from the logger itself providing critical data outputs regarding shipping condition, such as temperature trace, GPS locations and if needed, whether the shipper has been tilted beyond the manufacturers recommendations. This enables customers to make rapid decisions around patient safety or assess potential ramifications upon downstream processing for advanced therapy medicinal products.
Glyn Stacey (GS): Given the dramatic scientific developments in advanced medicines, development of technological advances in the cold chain have been relatively limited. Cryopreservation, storage and shipment options remain much along the lines of those used decades ago, as published in Regenerative Medicine . However, significant improvements have arrived for monitoring and recording shipment and storage, and equipment to facilitate continuity of temperature in the cold chain and reproducible thawing of cell-based medicines. Also, for cryopreservation in general there have been some developments in DMSO-free cryoprotectants that are also emerging, but their full added benefits remain to be explored . In addition, sourcing cryoprotectants manufactured and documented under established international standards, and supplied with appropriate disclosure of components for risk assessment and troubleshooting, remains a challenge.
How do cold chain distribution processes differ depending on the type of product?
EF: Generally speaking, the allogenic distribution process is closer to what we consider the traditional supply chain, which travels outbound from the manufacturing site to a distributor or clinical setting. Conversely, the autologous distribution process presents unique challenges as it requires an inbound as well as an outbound supply chain. This is what is commonly referred to as a ‘vein-to-vein’ model in that cells are captured from the patient, which are then transferred to a manufacturing facility to be developed into the therapy and then sent back to the patient to be infused.
DG: The chief differences occur between ‘fresh’ transport (usually either refrigerated at 2–8°C or ambient at 15–25°C) and cryogenic transport (-196°C). Anthony Nolan manages the logistics of these on a daily basis and have amassed significant expertise to ensure the product temperatures are maintained for the duration of the transport. The cord blood program ships cord blood for transplant in cryogenic condition, whereas often adult peripheral blood stem cells are transported at a control refrigerated range. The ‘fresh’ products are often moved via a carry-on service. We use this method to ensure we have a custodian observing the product between critical parts of the journey such as at borders and security checks. Standard courier services are also possible using well validated containers. Cryogenic products are typically shipped as cargo in the hold of a plane. The pandemic has demonstrated that cryogenic products have somewhat of an advantage as passenger flights are regularly being cancelled, whereas cargo flights have been less affected. However, cryogenic shipment is not for everyone depending upon the effects of the freeze thaw and impact on potency of the therapy.
Benoit Moreaux (BM): In the first clinical studies for Bone Therapeutics’ allogeneic, off-the-shelf cell therapy platform, ALLOB, the candidate was administered as a fresh product. Now a cryopreservation protocol has been developed and ALLOB is cryopreserved and maintained in LN2 (liquid nitrogen). A supply process has been developed with a logistic partner to ship the product for our Phase IIB clinical studies in seven EU countries.
GS: Typically for cell preparations there are three temperature ranges that are to be considered, which are imposed by biological factors that may be resolved as: 1) sub-normothermic just below normal growth temperatures; 2) hypothermic (cool but not frozen); and 3) ultralow where cell preparations are typically frozen . An important question to explore at the outset is whether the product could be successfully cryopreserved as there are crucial benefits for completion of more lengthy safety testing procedures and coordinating patient conditioning with product delivery.
What factors need to be considered when shipping these temperature-sensitive therapies?
EF: As with any temperature-sensitive therapy, the shipper must consider the storage and distribution temperature allowances, and shipment durations. Along with these considerations, the unique supply chain of certain CGTs may require intermediary steps such as re-icing or in-transit checks, multiple modes of transportation (aircraft/truck/car/handheld) and extended hold times due to flight delays or cancellations. To adequately protect the materials being moved, the shippers must map their supply chain and perform a failure mode and effects analysis to identify potential failure points and risks, and generate plans to mitigate them.
DG: To minimize issues with movement of products (both fresh and frozen) you must have in place realistic time frames for delivery, a thorough understanding of the legislation in different countries and how it will affect the transport of cells especially across borders. It is important not to underestimate the power of good open communication between the people involved at the various stages of the chain, knowing ‘who to call’ if something goes wrong may be the difference between success and failure. Additionally, having an excellent solution for tracking the shipment, and if possible, its condition, will always pay for itself in the long run.
Good risk assessment and contingency planning strategies should also be a primary consideration, being prepared for the unexpected can literally mean the difference between getting to the patient on time or not.
BM: The key factors are the traceability, avoiding losing our investigational medicinal products and the temperature monitoring. The dry shippers are equipped with a GPS system and a continuous temperature monitoring.
GS: The complexity and diversity of cell therapy products means that developing a science-based understanding of their stability characteristics can be a real challenge . Cells of different morphologies, membrane properties etc. may require different preservation and storage. Special consideration may also be required for mixed populations of cells with significantly different properties that can impact on stability and recovery of representative cell preparations. These variables may be difficult to assess or predict and careful validation of cold chain processes is vital for different products on a case-by-case basis.
What major logistical challenges are present when considering commercialization of these products? How could these challenges be overcome?
EF: The move from R&D and clinical trials to commercialization will always present a challenge regardless of the product type. That said, commercializing a CGT product requires additional considerations. For autologous therapies, which may require an inbound supply chain, many manufacturers are setting up dedicated operations centers that utilize visibility platforms to track each shipment as they progress to ensure that any disruptions are identified and recovery plans are implemented as needed to ensure the payload remains viable. To ensure this level of visibility, CSafe has designed our CGT shippers to accommodate whichever visibility device the shipper selects.
DG: Transportation of fresh products is always going to be a challenge, especially with passive transport containers, as the hold time is minimal when compared with cryogenic transportation (<96 hours vs ~10 days) without intervention by specialized logistics teams, but even then problems do occur. Cryogenic transport vessels can also often hold greater numbers of products per container, making bulk transport more feasible at the point of scale up. Frozen product also removes potential barriers around collection and processing of donor cells prior to transport to the destination as a cryogenic product is ‘ready to go’ – this has potential benefits in terms of risk to supply chain as well as reduced turnaround times prior to dispatch. Thus, it’s important to understand what stages of the process can be paused and the product stabilized for transport, whether it’s at the point of obtaining the initial cells (autologous or allogeneic), once cells have been isolated, or once they have been modified. Cryopreservation, as a method of stabilizing the products and removing the usual time restraints, enables us to divorce the patient treatment pathway from the manufacturing stage, which itself can be divorced from the donor work up pathway, which means the logistics and orchestration do not need to be so tightly choreographed to ensure on–time delivery.
Cost is also a major consideration, therefore approaches that partition the chain into smaller modules such as pre-processing of starting material at a site closer to collection, may ease burden on scheduling for example. Especially if this pre-processing can increase the shelf-life of the material, thus reducing risk and decreasing cost.
BM: The major challenge is that most hospitals are not equipped with LN2 infrastructure to store the advanced therapy medicinal product (ATMP) on site. In the future, either the hospitals should invest in LN2 infrastructure or the ATMP company should develop a cell-based therapy that can be stored at -80°C.
GS: Practicality of cold chain sustainability depending on local infrastructure such as availability of reliable low temperature storage, and ready access to coolants such as liquid nitrogen and solid carbon dioxide, is key and may be challenging for international cold chains. For unfrozen products the half-life may be very short, possibly just a few hours and thus highly efficient shipment logistics are crucial.
As CGT therapies become more prevalent and the patient group wider, the current cost of high touch supply chains will become an issue. How can high performance passive shippers help?
EF: High performance passive shippers offer a unique advantage when looking to reduce costs associated with high-touch supply chains. As these passive systems provide tight temperature control over long durations, manufacturers can move from white-glove services and into more cost-effective carrier modes. Additionally, as these shippers allow for longer durations before needing re-icing the cost of such operations can be eliminated, which not only reduces costs but also removes the risks associated with unpacking and repacking the systems.
DG: High performance passive shippers would enable the use of more standard shipping methods rather than the requirement for specialist logistics, which will for sure in turn reduce costs. This would need to be coupled with a suitable tracking and conditions monitoring solution to provide the same level of surveillance and control to intercept when there is a problem noted.
BM: The only way to reduce the logistic cost, which can be a few thousand euros per shipment, is to have the possibility to store the ATMP at the hospital in an LN2 system or to develop the possibility to store the ATMP at -80°C, but this can impact the shelf-life of the product.
GS: Shippers that can assure continuity of optimal storage temperature are clearly important for relatively unstable advanced therapy products and particularly so for unfrozen cell-based products.
In your opinion, how could cold chain distribution evolve to accommodate ‘just-in-time’ delivery of products irrespective of location?
EF: Just-in-time delivery of products will require a truly global network of facilities and partners that are able to provide preconditioned passive shippers globally. This network will allow manufacturers to deploy preconditioned shippers directly to collection sites and onto their final destination. With CSafe’s global network of service centers and our deep relationships with manufacturers, airlines and forwarders, we are well positioned to make ‘just-in-time’ delivery a reality.
DG: Just–in–time delivery will always be high stress, irrespective of the quality of the solution. At Anthony Nolan we have been delivering just–in–time delivery of transplant material for the last 45 years. In the stem cell donation world, once the cells have been collected the clock starts ticking and we have 72 hours to get the products to the patient for infusion. This may not sound too difficult when we consider a donor in London for a patient in Manchester, but the logistics, scheduling and hands–on monitoring requirements to cross borders and include long–haul flights become far more complicated.
BM: Hospitals which do not have a low temperature storage facility, could invest in LN2 infrastructure to always have the medical product available on site. In parallel, an increasing number of logistic companies have invested in hubs to store the ATMP in different countries and organize a shipment within 24 h after notification.
GS: Decentralized (i.e., local) manufacturing is an option for ‘just-in-time delivery’, but comes with additional challenges in assuring comparability of the product from different manufacturing sites, and this is a special challenge with cell-based medicines .
What advancements would you like to see in the cold chain over the next 10 years?
EF: Over the next 10 years I’d like to see manufacturers managing or dictating further down the supply chain to ensure the controls that are in place between the manufacturer and distributor level are also seen down to the last mile. This would mean more visibility by regulatory bodies down to the pharmacy and clinical level, which would greatly benefit patients and reduce spoilage/wastage of potentially life-saving therapies.
DG: Many of the solutions take time to prime for the condition you want to maintain. Whether it’s a refrigerated temperature that requires passive cooling elements or a cryoshipper that needs priming with liquid nitrogen first, this all takes time. Rapid, ready–to–use shipping solutions would help provide an agility. Liquid nitrogen is fantastic at holding a stable condition, however, it runs out and it’s not like liquid nitrogen is so readily available it can be easily topped up in the event of a disruption to the delivery. More portable, longer lasting battery–powered solutions could always be plugged in in the event of a disruption. These solutions, could with some development, be suitable for all temperature ranges and the vessel could be set to match the environment requirements needed. Electronic control systems would enable greater flexibility in this area; and who knows, given its 10 years and blue–sky thinking, perhaps it can be mounted to a drone for seamless door–to–door delivery.
BM: The major change should be the possibility to store the ATMP products at the hospital site.
GS: A key and fundamental step will be improving our understanding of product stability and this is particularly urgent for cell-based medicines. Also, it will be important to develop improved storage systems that facilitate cleaning of long-term cryostorage vessels, such as for archive and master stock of cell banks and vectors (i.e., starting materials). Finally, increasing the range of cryopreservation options so that logistics of delivery can be made available to more products will be vital but requires investment in research and education of more product developers in cryopreservation science.
Meet the experts
Emilio Frattaruolo | Vice President of Innovation, Passive Systems at CSafe Global (OH, USA)
Emilio Frattaruolo is responsible for the long-term global strategy of CSafe’s Passive Product portfolio and Client Services offerings.
Mr Frattaruolo brings a unique industry perspective formed over a decade spent providing engineering and operational leadership to both pharmaceutical manufacturers and cold chain solutions providers. Having functioned as an external consultant, internal subject matter expert and leader to organizations such as Sanofi Pasteur, Bristol-Myers Squibb and Biogen, he has a deep understanding of manufacturing, packaging and the clinical and commercial cold chain distribution process for critical life-changing therapies.
Frattaruolo holds a BS Degree in packaging science from the Rochester Institute of Technology (NY, USA) and is an IoPP Certified Packaging Professional.
Daniel Gibson | Director, Cell and Gene Therapy Services at Anthony Nolan (London, UK)
Daniel has worked to deliver innovative cell and gene therapies for patients derived from cord blood for over a decade. In this time, he has amassed the expertise in cell sourcing, cell processing and the associated logistics to help build and deliver scalable solutions to meet the growing industry needs.
Benoit Moreaux | Chief Scientific and Technological Officer at Bone Therapeutics (Charleroi, Belgium)
Benoit Moreaux brings 20 years of industry expertise in strategic operations planning and execution, as well as global quality assurance. Most recently, Benoit Moreaux was Chief Scientific Officer and Managing Director of Nikkiso Belgium, where he oversaw the Company’s scientific and technical operations, and drove business growth through innovation and product launch. Prior to Nikkiso, he held senior positions at Baxter and Johnson & Johnson, where he was responsible for drug and medical device development towards global product launch. Benoit is a Doctor of Veterinary Medicine and holds a PhD in Veterinary Sciences from the University of Liège (Belgium). As Chief Scientific and Technology Officer, Benoit Moreaux leads the preclinical activities as well as the clinical and commercial manufacturing operations.
Glyn Stacey | Director at the International Stem Cell Banking Initiative (UK)
Glyn Stacey is Director for the International Stem Cell Banking Initiative based in the UK and, together with the ISCBI Board and Steering Group, organizes regular international meetings which bring together experts in the field of pluripotent stem cells to discuss best practice in their use for basic research, cell therapy development and other applications. Glyn also holds a position as part of the Chinese Academy of Sciences President’s International Fellowship Initiative at the Academy’s Institute of Zoology (IOZ-CAS; Beijing, China); in this role, he advises the National Stem Cell Resource Center and the Institute for Stem Cells and Regeneration in their work on development of pluripotent stem cell-based medicines. Glyn is also the CEO of the biosciences consultancy SSCBio Ltd (UK), which provides advice and support internationally to a broad range of government institutes and private not-for-profit organizations.
 Stacey GN, Connon CJ, Coopman K et al. Preservation and stability of cell therapy products: recommendations from an expert workshop. Regen. Med. 12(5), 553–564 (2017).
 Awan M, Buriak I, Fleck R et al. Dimethyl sulphoxide: a central player since the dawn of cryobiology, is efficacy balanced by toxicity? Regen. Med. 15(3), 1463–1491 (2020).
 Williams DJ, Archer R, Archibald P et al. Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop. Regen. Med. 11(5), 483–492 (2016).
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of RegMedNet or Future Science Group.
This feature was produced in association with CSafe Global.