On the use of mathematical models to build the design space for the primary drying phase of a pharmaceutical lyophilization process.

The aim of this article is to show a procedure to build the design space for the primary drying of a pharmaceuticals lyophilization process. Mathematical simulation of the process is used to identify the operating conditions that allow preserving product quality and meeting operating constraints posed by the equipment. In fact, product temperature has to be maintained below a limit value throughout the operation, and the sublimation flux has to be lower than the maximum value allowed by the capacity of the condenser, besides avoiding choking flow in the duct connecting the drying chamber to the condenser. Few experimental runs are required to get the values of the parameters of the model: the dynamic parameters estimation algorithm, an advanced tool based on the pressure rise test, is used to this purpose. A simple procedure is proposed to take into account parameters uncertainty and, thus, it is possible to find the recipes that allow fulfilling the process constraints within the required uncertainty range. The same approach can be effective to take into account the heterogeneity of the batch when designing the freeze-drying recipe.