Lyophilization is emerging as an effective way to prolong the shelf-life of biologics and to ease their refrigeration requirements, but its process development often requires multiple experiments. However, a Quality-by-Design approach can reduce the workload and streamline the process while improving outcomes.

Scientists at the Institute for Separation and Process Technology at Clausthal University of Technology in Germany recently showed that taking a digital-twin approach when designing the freeze-drying methodology for biologics increased productivity by up to 300%. It also reduced costs by 74% and lowered the global warming potential by 64% compared to trial-and-error design.

A recent paper detailed the effects of digital twin technology when lyophilizing sucrose, but the team’s earlier work focused specifically on biologics. These productivity, cost, and global warming benefits apply to both but, as, Jochen Strube, PhD, senior author of the paper and director of the Institute, tells GEN, “Biologics doses are quite small in relation to vial volume fill-up. Biologics tests will be run if the manufacturer calls for them.”

PAT enhances accuracy

Incorporating Process Analytical Technology (PAT) and modeling, the paper noted, enabled the digital twin “to accurately predict the product’s temperature and drying endpoint, showing smaller errors than the experiment.”

For example, because nucleation time typically isn’t controlled, variability in terms of ice crystal size and distribution is significant among batches. Therefore, they first ran tests to better control nucleation times and to optimize annealing methods.

By incorporating varying process conditions, the potential risks and their consequences could be modeled and used to inform the digital twin, thus enabling it to respond to fluctuations in real-time. Consequently, the resulting digital twin is gaining the ability to operate under “proven acceptable ranges rather than fixed set points, revealing the optimization potential of conventional processes,” Strube and colleagues report.

For drying optimization, they identified four key parameters: the critical temperature of the formulation, the vial heat transfer coefficient (showing behavioral differences between vials at the edge and at the center of the drying process), maximum allowing sublimation flux, and dry layer resistance.

“For model-based optimization, the target temperature was set 3°C below…the critical temperature.” But, they cautioned, if only the center heat transfer coefficient is known, the target temperature should be set 5–6°C lower “to prevent the collapse of the hotter vials,” they advise.

This digital-twin-based lyophilization optimization process took 14 days (versus several weeks otherwise) and involved 540 mL of product. For a new formulation using the same vial, the process would take only five days. Despite this notable speed gain, Strube says, “Scalability is a main benefit.”

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