Freezing Time Prediction of Biologic Formulated Drug Substance Using the Plank Model

Abstract

The freezing of biologics has been widely studied from the physical chemistry point of view, for instance in terms of cryo-concentration, excipient crystallization, pH swing, potential protein denaturation, etc. In contrast, considerations on the processing aspects are very limited. For instance, the impact of freezer temperature, container size, freezer load, and freeze chilling capacity on the freezing rate in the most frequent case of freezing in a bottle have not been reported. In this study, the freezing time of either water or buffer solution was measured in various processing conditions. Experimental trials were conducted using containers ranging from 1 to 20 L in two types of freezers: a normal freezer (−30°C set point) and an ultra freezer (−70°C set point). These trials showed that both the container size and the freezer load influenced the freezing times. The current study demonstrated that the use of the well-established Plank model for freezing, coupled with freezer performance characterization, allows the description of the actual freezing kinetics in a very simple and accurate manner. The kinetics can then be modeled to accurately predict both the actual freezer temperature (possibly above the set point) and the freezing time based on freezer load.