Outsourcing
Extra steps for safety
An aseptic approach requires the use of specially trained personnel and equipment to create the necessary sterilised environment, and these extra stages introduce their own challenges to the integrity of the sterilisation process, as well as adding extra expense to the overall production cost.
Dalip Sethi, scientific affairs director at Terumo Blood and Cell Technologies, outlines some of the considerations: “The major challenges for complex drug substances, such as cell therapy, are maintenance of viability and sterility, ensuring cell number and volume consistency among bags or vials, and increasing efficiency. “Cell therapy products cannot be sterilised at the end of manufacturing; therefore, ensuring their sterility through aseptic processing is critical. The challenge can be overcome by utilising closed or functionally closed systems in an appropriate classified environment,” he adds. If an aseptic regime is required, there are some special issues that must be taken into account. According to Tom Heathman, vice president of commercial operations at Ori Biotech, there are different ways to overcome the obstacles depending on whether the cells within the product originated in the body of the patient set to receive it (autologous), or whether they were harvested from an external source (allogeneic). “For allogeneic cell therapy products, the manufacturing batch is typically filled into multiple bags or vials,” he explains. “Currently, there are very few technologies that can do this in a fully closed and automated way, which leads to risk of product contamination as products are manually filled in a grade A biological safety cabinet.” Technologies are currently in development that can close and automate these process steps, he adds, but the techniques are in their infancy and have not reached commercial scale yet.
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For autologous therapies, product sampling for release testing must occur for every product, and it is necessary to ensure there is traceability and the avoidance of cross-contamination. Once again, Heathman emphasises the importance of implementing closed systems and digital solutions to manage this workflow to help to mitigate these risks, particularly as the scale of production increases. “Given that cell and gene therapy products are living therapeutics, ensuring that products are held in a biologically compatible state throughout the fill/finish steps is critical in maintaining product viability and potency. Optimising these process steps to minimise hold times of products in the downstream process can help to mitigate these concerns,” Heathman adds.
Cell and gene therapy production is currently carried out by human hands, with very little automation featured in the process.
“Given that cell and gene therapy products are living therapeutics, ensuring that products are held in a biologically compatible state throughout the fill/finish steps is critical.”
Tom Heathman
Mitigating concerns, preserving safety According to Sethi, one of the measures taken to mitigate these concerns is the addition of a cryoprotectant, such as dimethyl sulfoxide (DMSO), during the final formulation, fill and finish process. “As the final step prior to reinfusing patients in the hospital, it is critical that the integrity of the final cell product remains intact,” he says. “The final cell product is cryopreserved post-fill and finish for transport to the clinic.” The addition of cryoprotectant is performed at cooled temperatures, such as 4–8ºC. The addition of pre-cooled cryoprotectants at low temperatures can help maintain post-thaw viability, which can be achieved using systems that allow and maintain user-specified temperatures, adds Sethi.
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