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Promising novel cell and gene therapeutics have brought cold processing and cryogenic operations to the forefront. But these stressful environments can be a supply chain hurdle. The right material selections and regulatory compliance are not guarantees of success; suppliers must also provide timely delivery of the needed inputs.

In a recent presentation at the BioProcess International Forum, Ross Acucena, life sciences application director at Entegris, explored how to diminish the uncertainties and complexities encountered with expanded applications of single-use technology (SUT) in cold temperature and cryogenic operations. Risk equals the issue severity times the probability times the detection; decreasing probability has a big impact.

To listen to the presentation, visit info.entegris.com/single-use-system-design-for-cryogenic-and-cold-temperature-operations-webinar.

The cold chain ecosystem transports intermediaries for further processing and drug substances for clinical administration. Product must be protected through a fill, freeze, thaw, and dispense paradigm to ensure temperature control and safe arrival in the rough and tumble logistics environment.

Material selections are critical elements of manufacturing controls required at early clinical stages to ensure compliance with new guidances for cell and gene therapies. An FDA guidance for early-stage manufacturing and early clinical trials and the EudraLex 4 EU guidance that applies all the way through commercial manufacturing are starting to be applied to rapidly bring new drugs to market.

In early-stage manufacturing, regulators point to closed system processing using SUT and ready-made reagents as one way to help close the process and protect patients.

Single-use bag assemblies need low-temperature robustness, sterile connections, and flexible geometry while the companion freeze shells require low storage density and freezer compatibility. Entegris’ fluoropolymer Aramus™ 2D bag assemblies remain flexible even at liquid nitrogen temperatures of –196°C, making them an excellent SUT choice.

In a real-world distribution test, 500 mL–10 L Aramus bags filled with a surrogate solution were packaged in freeze shells and IATA-compliant thermo-safe shippers with dry ice to maintain them at below –60°C for greater than 144 hours. They were then shipped 2,800 miles (4,500 km) roundtrip by truck and air. The bags passed the challenge despite sustaining some heavy damage to the outer containers and after dealing with an additional set of simulation tests complying with ASTM D4169.

For free-fall drop tests (ASTM D5276), bags were frozen to –85°C, and initially dropped from 40.6 cm (16 inches), and then the height was incrementally increased to 91.4 cm (36 inches). While one-third of the single-layer polyolefin and multilayer polyethylene EVA bags failed, Aramus bags passed 100%.

Liquid nitrogen compatibility also was evaluated since some therapeutics require ultralow temperatures. Smaller-volume Aramus bags, up to 500 mL, underwent three freeze-thaw cycles from room temperature to –80°C, then –196°C. The bags froze at consistent rates and remained intact even when dropped immediately following removal from the liquid nitrogen.

Cold processing requires chemical compatibility as well. A common cryoprotectant, DMSO, is an effective solvent and can impact single-use materials. The Aramus bags withstood exposure to 100% DMSO, as shown by mechanical property tests, allowing use of the bags to provide process advantages in other interesting workflows, such as high-density cell banking.

Most importantly, in a quality risk paradigm the closer the relationship between suppliers and customers, the better the outcome. Transparency is crucial along with established change controls and measures to mitigate risk without influencing timelines. Notably, to support robust systems and processes, SUT must be available when needed. To keep up with the pace of growth, Entegris is ramping up capacity in its Bloomington manufacturing facility.

Entegris is committed to its customers’ success. Their vast knowledge base assists in establishing repeatable safe and highly effective processes for the successful qualification of SUT in complex workflows, especially cold processing and cryogenic operations. These attributes have been critical to manage the optimization, qualification, and scale-up of Aramus 2D assemblies utilized in the bulk drug distribution workflow of approved COVID therapies.

View the webinar www.entegris.com/cryogenicdesign.

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