Overview: Reducing CO2 emissions is not only essential for the planet, it also helps drive efficiency and remove redundant processes from supply chain, increasing the profitability and sustainability of business models. Cell therapy shipping and manufacturing processes are no exception and there is now concerted effort to make these processes more sustainable and to reap further cost savings.

One of the most carbon-intense elements of manufacturing cell therapies is cold-chain logistics. We have previously shown, that switching to a liquid nitrogen-free (LN2-free) cryopreservation process can reduce CO2 emissions by 87%, and the cooling costs by > 95%. In this application note, we consider the shipments within the cell therapy workflows from initial patient sample to final cell therapy arrival at the patient’s side. We determined that by streamlining the delivery processes through efficiency-led design and smart logistics, manufacturers can reduce the financial costs of transport and CO2 burden by > 55%. This is possible by combining the VIA Capsule™ shipper with smart sterilization techniques to reduce the required number of shipments for any given cell therapy manufacturing process.

The current shipping model: The cell therapy shipping process is a substantial cost and logistic burden for the overall manufacturing workflow. Dry shippers are the most commonly selected vessel, with a typical shipping process shown in Figure 1:

  1. The shipping vessel moves from the manufacturer’s warehouse to the hospital.
  2. A patient sample is collected and shipped to the centralized manufacturing facility.
  3. The vessel is sent to a shipper facility to be sterilized (after having transported a biological sample).
  4. The sterilized vessel returns to the manufacturing facility.
  5. The final cell therapy ships from the manufacturing facility to the patient’s hospital.
  6. The shipping vessel is sent for sterilization.
  7. The shipping vessel returns to the manufacturing facility until needed, or to the hospital to collect and transport another patient’s sample.

A typical shipping process

Fig 1. A typical shipping process; the three key locations are the manufacturing site, the shipper facility where sterilization and LN2 filling take place, and the hospital where the patient is located.

Exact process steps vary from case to case. However, a common step in all of these processes is sterilizing a LN2 shipper several times during the process. Typically, manufacturers sterilize a LN2 shipper and fill it with liquid nitrogen at an outsourced specialist courier, before shipping it to the clinic or the manufacturing site, and returning it empty to the specialized courier between shipments for additional sterilization and to add new LN2 coolant. Usually only the specialist courier can refill the LN2 shipper, requiring additional, and costly, empty shipments.

The cost of shipment, both financially and in terms of carbon footprint, directly relates to the number of movements the vessel takes — the weight of the cell therapy itself being minimal compared to the weight of the vessel and the vehicle transporting it. This means that the carbon emissions of transporting a vessel — whether for sterilization, topping up with coolant, or moving a therapy — will be the same. The financial burden is similar too — while the shipment might be less critical when not containing a therapy, each day a shipper is out-of-action for cleaning or adding coolant makes it unavailable for biological use.

VIA Capsule™ system aims to eliminate both these inefficiencies with innovative ultraviolet (UV) sterilization and using electricity instead of LN2 for instrument cooling.

VIA Capsule™ system, shown in Figure 2, is a smart shipping system that uses a Stirling engine to maintain a low temperature. This electric-only power source removes the need for a liquid coolant. The system can maintain ultralow temperatures for up to five days, and you can plug it into a regular power supply at any point to extend this autonomy. You can sterilize it using the built-in UV lights without having to warm the system. This maximizes efficiency and reduces redundant shipments in the process logistics.

The internal design of VIA Capsule system

Fig 2. The internal design of VIA Capsule™ system allows for rapid and automatic sterilization, with a single lid to enable recharging with electricity.

Why sterilization is required: Sterilization is essential for patient safety, and manufacturers apply it between each use of a shipping vessel. Sources of contamination include:

  • LN2 itself which can carry and disperse bacteria and fungus, hence its exclusion from clean rooms.1,2
  • Potential leaks from a biological sample that was incorrectly packaged or damaged.3,4,5
  • Particles from the air that can enter every time the lid is removed for access.

LN2 sterilization:
Traditional LN2 shipping vessels present a unique challenge for sterilization. As LN2 cannot be used during shipping in closed spaces, which includes most road vehicles and aircraft, a conventional LN2 shipper (shown in Figure 3) has a special molecular sieve surrounding the sample container. The sieve absorbs the LN2 in a process known as charging. LN2 can no longer spill when it’s absorbed even if the vessel is tilted, making it suitable for shipment.

However, cleaning a molecular sieve is a significant challenge. The nitrogen is in the sieve matrix, so manufacturers need to sterilize both the outside and the inside of the molecular sieve. Cleaning only the outer surface of the molecular sieve does not sterilize the interior. Because manufacturers need to sterilize and refill LN2 shippers after each shipment, they must return the empty dry shipper to a specialist manufacturing site, warm it up, and perform a deep clean before adding new LN2. The special properties of the molecular sieve that make it useful for shipping are a severe handicap when it comes to sterilization. The sieve stops LN2 from leaking out, but it also hinders access when it comes to applying cleaning products. Even if you use UV light to sterilize an LN2 shipper, the light will not penetrate the molecular sieve, making it ineffective.

Additionally, a specialist courier needs to charge the shipper, which makes the vessel usable for a limited period before needing to be refilled again. For both practical and traceability considerations, topping up is usually not possible in clinical and manufacturing sites.

Elements of LN2 shipper

Fig 3. Elements of LN2 shipper. LN2 is poured into the system, which then absorbs into the molecular sieve around the storage chamber.

UV light and its role in sterilizing and recharging VIA Capsule™ system: The innovative design of VIA Capsule™ system, which uses a thermal mass and not a liquid coolant to cool, allows for full accessibility of each internal area of the instrument. By using an innovative integrated UV-light based sterilization system, you can automatically sterilize the VIA Capsule™ system in a small amount of time, and without needing to warm the system. You can also activate the UV system to sterilize the instrument even at cryogenic temperatures.

UV light is emitted naturally as part of solar radiation, and it is usually segmented into three components: UVA from 315 nm to 380 nm wavelength; UVB from 280 nm to 315 nm; UVC from 100 nm to 280 nm. UVA is the primary cause of sun-induced skin aging, while UVB causes sunburn and is a major risk factor for skin cancer. UVC, the wavelengths used within the VIA Capsule™ sterilization system, is a strong germicide. While UVC rays can’t pass through glass or plastics, they can pass through air at ultralow temperatures and coolants like LN2. This makes it well-suited for sterilizing low-temperature shipping systems.6

Because VIA Capsule™ systems don’t use UV-blocking molecular sieves, the UV light can sterilize every part of the sample chamber. This means you don’t need to ship the vessel to a sterilization or specialized courier site for cleaning. Additionally, there’s no need to top-up the liquid coolant — you only need to plug VIA Capsule™ shippers into a regular electricity supply to recharge for the next shipment, or use it as temporary storage until the therapy or biological sample is required.

These innovative features reduce the number of shipments, saving time and logistics efforts, and reducing the carbon footprint of the overall cold-chain delivery process.

Effectiveness of UV sterilization:
UV light-based sterilization has the additional advantage of being effective at low temperatures. While manual cleaning requires a system to be warmed up before sterilization, UV light sterilization can occur while the system remains at ultralow temperatures, further reducing turnaround times. Figure 4 shows the effectiveness of a 20-minute UV sterilization cycle applied to VIA Capsule™ system.

Effectiveness of UV sterilization taking place at ultralow shipping temperatures

Fig 4. Effectiveness of UV sterilization taking place at ultralow shipping temperatures. Left: Agar plates with swabs taken before sterilization of a VIA Capsule™ system. Right: Similar agar plates with swaps from inside the VIA Capsule™ system after sterilization.

Estimating logistics simplification: By using smart logistics, VIA Capsule™ system eliminates redundant shipments and substantially simplifies logistics.

A schematic of a smart shipping process

Fig 5. A schematic of a smart shipping process, where the shipping vessel no longer needs to be returned to the shipper facility for cleaning and LN2 refill.

This smart logistic chain can consolidate seven steps into three:

  1. VIA Capsule™ system is delivered to the hospital.
  2. A patient sample is taken and shipped to a centralized manufacturing facility. VIA Capsule™ system is sterilized automatically with a UV cycle at the manufacturing site.
  3. The final cell therapy is shipped from the manufacturing site to the hospital. VIA Capsule™ shipper can then be used to deliver a new patient’s sample to the manufacturing site, or returned when no longer required.

The physical shipping of a product is the largest contributor to CO2 emissions in the cold chain delivery process. A 100-mile journey in a van emits approximately 25 kg of CO2, compared with only 1 or 3 kg of CO2 required to cool and maintain the low temperature of the of a LN2 dry shipper or a VIA Capsule™ shipper, respectively.7 Reducing the number of trips from seven to three reduces the carbon footprint of this process by 57% — 3/7 of the original.

To further reduce emissions, you can use the initial shipment for another product being manufactured concurrently. This reduces empty shipments and CO2 emissions by another third.

The above typical workflows are examples and can be tailored to individual products, as there can be multiple manufacturing and clinical sites within a cell therapy’s journey. Sometimes shipping is also required within a hospital, for example, between clinic and clean rooms. VIA Capsule™ system can support this and provide additional temporary storage as needed, eliminating the need for costly and carbon-intensive LN2-based transport and storage. This reduction in shipments also gives a two-fold improvement in capital costs; reducing extra shipments and letting each shipping instrument be used more effectively, reducing the total number of vessels required and the initial capital cost.

Summary and conclusions

Dry shippers must be transported empty many times in a typical delivery process, and the innovative design of smart shipping systems can enhance the current logistics chain. Using VIA Capsule™ system can reduce the carbon footprint of cold-chain shipment by > 55%, and help reduce operating and capital costs. Importantly, reducing the number of steps in the cold chain gets therapies into patients more quickly, thereby having a meaningful impact to healthcare in a more environmentally sustainable manner.

Literature references:

  1. Grout B.W.W., Morris G., 2009. Contaminated liquid nitrogen vapour as a risk factor in pathogen transfer. Theriogenology. 71(7):1079-82.
  2. Morris G.J., 2005. The origin, ultrastructure, and microbiology of the sediment accumulating in liquid nitrogen storage vessels. Cryobiology, 50(3):231-8.
  3. Tedder R., Zuckerman M., Brink N., Goldstone A., Fielding A., Blair S., et al., 1995. Hepatitis B transmission from contaminated cryopreservation tank. The Lancet, 346(8968):137-40.
  4. Fountain D., Ralston M., Higgins N., Gorlin J., Uhl L., Wheeler C., et al., 1997. Liquid nitrogen freezers: a potential source of microbial contamination of hematopoietic stem cell components. Transfusion, 37(6):585-91.
  5. Khuu, H., Cowley, H., David-Ocampo, V., Carter, C., Kasten-Sportes, C., Wayne, A., Solomon, S., Bishop, M., Childs, R. and Read, E., 2002. Catastrophic failures of freezing bags for cellular therapy products: description, cause, and consequences. Cytotherapy, 4(6), pp.539-549.
  6. Parmegiani, L., Accorsi, A., Cognigni, G., Bernardi, S., Troilo, E. and Filicori, M., 2010. Sterilization of liquid nitrogen with ultraviolet irradiation for safe vitrification of human oocytes or embryos. Fertility and Sterility, 94(4), pp.1525-1528.
  7. European Environment Agency. 2020. Average CO2 emissions from new cars and new vans increased again in 2019. [online] [Accessed 5 November 2021]