Abstract
Biopharmaceuticals are often lyophilized to improve their storage stability. Controlling ice nucleation during the freezing step of the lyophilization process is desired to increase homogeneity of product properties across a drug product batch and shorten the primary drying time. The present communication summarizes the process optimization of the freezing process when using vacuum-induced surface freezing to control ice nucleation, in particular for amorphous samples. We characterized freeze-dried samples for solid state properties, and compared these to uncontrolled nucleated samples using bovine serum albumin (BSA) as a model protein. Freezing parameters were optimized to obtain complete nucleation, adequate cake resistance during the subsequent lyophilization cycle, and elegant cakes. We highlight the challenges associated with vacuum-induced surface freezing and propose optimized freezing parameters to control ice nucleation, enabling manufacturing of amorphous samples.
Highlights
Thermolabile drug products, such as biopharmaceuticals, are often stabilized by lyophilization.Water is gently removed from their liquid form to minimize degradation pathways [1,2,3]
Nucleation may occur at different temperatures in different containers of the same drug product batch. This implies differences in the pore size distributions for individual samples of the same drug product batch, since the ice crystal size is dependent on the nucleation temperature. For this reason, controlling the ice nucleation temperature is of great interest, as it leads to increased homogeneity of product attributes, such as the residual moisture across a batch [11]
The focus of this process development was the lyophilization of amorphous samples, such as formulations containing proteins
Summary
Thermolabile drug products, such as biopharmaceuticals, are often stabilized by lyophilization. The nucleation temperature defines the size of the ice crystals, which relates to the pore structure of the final freeze-dried product. This implies differences in the pore size distributions for individual samples of the same drug product batch, since the ice crystal size is dependent on the nucleation temperature For this reason, controlling the ice nucleation temperature is of great interest, as it leads to increased homogeneity of product attributes, such as the residual moisture across a batch [11]. Besides improved inter-vial homogeneity, ice nucleation may be controlled at the highest feasible nucleation temperature, which was demonstrated to shorten primary drying times due to the larger pore size and increased sublimation rate [8]. The study highlights the challenges associated with vacuum-induced surface freezing and proposes optimized freezing parameters to control ice nucleation
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