Modeling of Primary Freeze Drying Phase of Lyophilization of Ebola Virus Disease Vaccine

Abstract

Lyophilization, or freeze-drying, is a commonly used technique to extend the shelf life and increase the stability of various pharmaceuticals by removing excess water from the product. The process can be energy and time-intensive, but it is often required for approval of widely used pharmaceuticals, including the Ebola Virus Disease vaccine. The process can be broken down into three phases: freezing, primary drying (sublimation), and secondary drying. The focus of this model was on the primary drying phase, which is the longest and most critical of the three stages. The success of the lyophilization process largely depends on the result of the primary drying phase, making it crucial to optimize key parameters that characterize this stage. Therefore, the main objectives of this study were to develop a model to form a better understanding of the sublimation reaction that occurs during primary drying and to optimize key process parameters to increase the efficiency of the process. COMSOL Multiphysics was used to develop a computational model of the lyophilization process to achieve these objectives. A 2-D axi-symmetric geometry was used to construct the vial in which the pharmaceutical product was placed during lyophilization. Three different COMSOL physics interfaces were chosen to model the primary drying phase for a duration of 20 hours for the Ebola virus disease vaccine. Whereas most prior models use a moving sublimation boundary, this model employed a non-equilibrium sublimation front formulation to simulate the behavior. From our sensitivity analysis, it was determined that permeability is a critical factor affecting sublimation. Increasing permeability not only increased the amount of sublimation but also allowed for sublimation to occur more evenly throughout the domain. This was due to the increased vapor flow throughout the domain, driving the pressure gradient powering sublimation. Other parameters, including the heat transfer coefficient, chamber pressure, and sublimation reaction constant, primarily affected sublimation at the boundary rather than throughout the entire domain. Increasing the heat transfer coefficient and sublimation reaction constant while decreasing the lyophilization chamber pressure increased sublimation at the vial edge. This model elucidated key insights into the sublimation process. Pressure buildup into the vial was specifically identified as the main limiting factor of sublimation, and this can be improved in future studies by adjusting various parameters including those analyzed in a sensitivity analysis. This key finding provides further insight into the physics and mechanism that drives the phase change and provides a foundation for further research and optimization. Furthermore, while this study focused on the Ebola Virus Disease vaccine, this computational model can be customized with the properties and process parameters for other vaccines of interest, making it a valuable tool for many pharmaceutical manufacturers