(607f) Use of Mathematical Models to Scale up Lyophilization Process

Lyophilization is the process of removing water from a solvent system at low temperatures to enhance the shelf life of a water labile product. This the most used process in pharmaceutical industry in the area of parenteral drug development. Even though the process has existed for years, scale up of the process has been using empirical approach in a majority of cases. Here we make an attempt to summarize in a concise manner the method that we follow to successfully scale the lyophilization process from lab scale (~200 vials) to commercial scale (~10000 vials) using mathematical models

Systematic approach using mathematical modeling to scale up lyophilization process will be presented. We will compare experimental results with modeling outputs using real time projects as well as model compounds e.g. sucrose. We compare a mathematically intense computational fluid dynamic (CFD) model (commercially available) which solves coupled heat and mass transfer equation to a simple one dimensional steady state model (based on literature). The predictions from both these models are compared to experimental results at different scales. Based on these results we conclude that we successfully applied mathematical models to scale up the lyophilization process. Most often we do obtain similar results from a simple one dimensional model and CFD model with respect to primary drying time and temperature predictions. CFD model does provide slightly more accurate predictions. It should be noted that using CFD model we can obtain additional estimates on water content present in the lyophile and can also perform secondary drying calculations.

Inputs to the models

? Heat transfer coefficient of the vial (can be estimated by a combination of experiments and theoretical calculations)

? Mass transfer resistance (we currently use the Manometric Temperature Measurement data to calculate resistance offered by dry layer as a function of dry layer thickness)

? Material properties of the product that is freeze dried and also vial dimensions