A New Perspective on Scale-down Strategies for Freezing of Biopharmaceutics by means of Computational Fluid Dynamics

Abstract Common approaches to scale-down freeze-thaw systems are based on matching time-temperature profiles at corresponding points, however little is known about the differences in anisotropy between the two scales. In this work Computational Fluid Dynamics (CFD) modeling was used to investigate these differences. The modelling of the convective flow of the liquid phase within ice porous structure and volume expansion caused by freezing enabled accurate prediction of the local temperature and composition, for evaluation of potential stresses on protein stability, such as cryoconcentration and time in the non-ideal environment. Overall, the small height of the scale-down containers enhances cryoconcentration. The time under stress was consistent in both scales, except when the walls of the container could deform. In general, the common approach of matching the time-temperature profile at the center of the containers was more effective as a worst-case scenario than a scale-down model. This work shows that instead of considering a single matching time-temperature location; one should aim for a more general perspective by measuring many locations. Container geometries and heat transfer rates should be designed to match stresses related to protein integrity for equivalent mass fractions between both scales, which can be achieved with the assistance of CFD models.