Cryogenic handling and storage of cell and gene therapies

Temperature control is perhaps the most essential operational factor for a successful cell and gene therapy (CGT) trial. Yet, it is also expensive and challenging. CGTs often need to be held at temperatures as low as -185°C, which requires a specialized cold-chain infrastructure, equipment and operational considerations. In fact, it is estimated that temperature-controlled logistics account for nearly 18 percent of all biopharma logistics spending, according to the 2020 Biopharma Cold Chain Sourcebook published by Pharmaceutical Commerce. Here, we review the many considerations for the storage, transport, and handling of cryogenic materials used in CGT clinical trials. 

Cooling methods

Storing and transporting CGT materials at cryogenic temperatures is complex and requires specialized equipment, leaving limited options. For instance, cryocoolers are refrigerators that are specially designed to go down to cryogenic temperatures. However these are frequently smaller in size, and the risk for fluctuations in power or in thermocycling means that they are not the most stable options for transporting CGTs.

Instead, many turn to nitrogen for cooling. Nitrogen vapor freezers, as one option, pipe liquid nitrogen (LN2) into the lower portion of the unit, allowing the vapor — which the LN2 releases — to cool the upper racks. The drawback to this is that, if the unit is not designed properly, it can lead to temperature gradients at different levels within the freezer, which can be detrimental to samples. Another approach, submerging CGT materials in LN2, provides more uniform temperatures, but can be dangerous to work with, as human contact with LN2 can lead to injuries including severe frostbite. As such, LN2 is classified as a hazardous material that has many restrictions for shipping.

The top choice, particularly for transport, is the use of special LN2 dewars, called dry shippers. These involve using a porous material to absorb LN2, which then surrounds and cools the temperature-sensitive materials being transported. In addition to being safer to work with, these have the added benefit of not being considered hazardous materials in shipping — if prepared correctly, there is no free LN2 within the vessel. To be prepared for the immediate transport of CGTs, when required, it is important for a logistics company to have an ample supply of dry shippers on hand at any time.

Maintaining integrity during transport

The amount of time that a dry shipper can maintain temperature without being recharged can vary due to many factors, such as volume and quality. As a result, they can be rated for a holding time of anywhere from a few hours to more than two weeks. Age can also alter holding times, since elements of the dry shipper — including vacuum seals and the LN2 absorbent lining — can deteriorate over time. Knowing hold time limitations and accounting for these is critical, particularly since there can be lengthy delays in transport, such as going through international customs. Including a buffer for this additional time is often a good practice to make sure that the temperatures stay in the ideal range, even with delays.

Additionally, the hold time of a dry shipper can depend on how it is handled. These vessels are designed to be transported upright. But, if handled incorrectly — for example, transported on its side — the time a dry shipper can maintain cryogenic temperatures may drop drastically. Having properly trained staff, particularly that of an experienced biopharma services company such as Yourway, is key to ensuring materials are handled with the appropriate consideration. Additionally, smart sensors are able to monitor the temperature or even orientation of a dry shipper, and alert relevant parties if these go outside of optimal ranges.

Due to all of the above factors, validation of equipment — in other words, testing to make sure it can uniformly maintain the desired temperatures — is important to the safe transport of CGTs. Validation also allows the assessment of equipment’s performance under varied conditions, so it is easier to predict outcomes no matter what happens during transport. 

Support at the clinical trial site

Once a cryopreserved CGT arrives at the clinical site, it still requires a great deal of support. If it is not going to be used right away, it must be placed in appropriate long-term cryogenic storage. If it is going to be used, it needs to be dethawed properly, a procedure that is often very complicated to ensure the living cells in the CGT will survive to be a viable treatment. Either way, trial sponsors should make sure the destination site is properly equipped to take the required action.

Another consideration is whether the site has the right qualifications to administer a CGT to trial participants. The specific requirements can vary depending on the CGT, but can include elements such as equipment and specialized staff expertise. Some CGTs require intensive inpatient care and monitoring after administration, so sites must be equipped to handle those concerns as well. This can complicate logistics for transport, as qualified clinical sites are often concentrated in large academic hubs, such as in the Northeast and Midwest of the United States, thereby requiring greater transport times if a CGT is manufactured in other parts of the country.

Finding the right partner

Protecting precious CGTs is a complex endeavor, with many details and logistics to consider. Working with a biopharma services company that is experienced in cryogenic transportation, such as Yourway, makes sure that these irreplaceable therapies get to where they need to be, ready to save lives.

To learn more about CGT logistics, read Yourway’s whitepaper.