The Impact of the Freezing Stage in Lyophilization: Effects of the Ice Nucleation Temperature on Process Design and Product Quality

The Impact of the Freezing Stage in Lyophilization: Effects of the Ice Nucleation Temperature on Process Design and Product Quality
Michael J. Pikal, Ph.D., Shailaja Rambhatla, and Roee Ramot, School of Pharmacy, University of Connecticut
Lyophilization is the most common method for manufacturing solid protein pharmaceuticals (1) and is central to the preservation of materials which must be dried very thoroughly (< 1% moisture) in order to ensure stability and require a gentle, sterile process for doing so. However, the multitude of variables inherent in a large batch of individual vials in a complex drying chamber configuration makes process control difficult at best; and a thorough understanding of the process and the materials science of different formulations is necessary to avoid product damage.
A solution's lyophilization occurs in three steps: first, the solution is cycled through a freezing step, in which most of the water separates into ice crystals throughout a matrix of glassy and/or crystalline solute. This step is of paramount importance (2) in determining the details of the remainder of the cycle, and it is here where two main problems come into play: First, the concentrations of all dissolved materials will increase dramatically as water freezes into ice, potentially imparting massive pH changes and/or significant increases in the rate of second order degradation processes which could degrade the product. Note that this also means most of the desiccation actually occurs at freezing, as the solute is dramatically concentrated (3). Second, the temperature at which the solution will form ice, Tn, is stochastic, as well as dependent on a number of process and formulation variables and thus induces heterogeneity in a vial batch (2), causing process control problems in the primary drying stage.
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