Implications of porous-flow in the design of freeze-thaw systems for biopharmaceuticals and rational scale-down methodology

Conference Dates

July 14-17, 2019


Porous-flow through an ice matrix is a ubiquitous phenomenon during both freezing and thawing of biopharmaceutical formulations. During the freezing process, when the ice dendrites are formed, the proteins and excipients are excluded from the ice front. A concentrated aqueous solution is entrapped by the ice dendrites, creating what is called a mushy layer. By the action of gravity or pressure forces, the concentrated solution may flow through the ice matrix, disrupting the homogeneity of the mixture at the macro-scale. The concentrated solution is transported away from the mushy layer, creating spots of more concentrated solution in some regions of the container. During the thawing process, the same phenomenon occurs and is responsible for the strong stratification of the biomixture observed in the final liquid solution. Macro-concentration in the ice matrix and final stratification of the liquid solution are adverse phenomena that may trigger protein aggregation. Therefore, well-designed scale-down methods should mimic these adverse conditions that happen at large scales.

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