Mechanistic Modeling of Continuous Lyophilization for Biopharmaceutical Manufacturing

Abstract Lyophilization (aka freeze drying) is a typical process in (bio)pharmaceutical manufacturing used for improving the stability of various drug products, including its recent applications to mRNA vaccines. While extensive efforts are dedicated to shifting the (bio)pharmaceutical industry toward continuous manufacturing, the majority of industrial‐scale lyophilization is still being operated in batch mode. This article presents the first mechanistic model for a complete continuous lyophilization process, which comprehensively incorporates and describes key transport phenomena in all three steps of lyophilization, namely freezing, primary drying, and secondary drying. The proposed model considers the state‐of‐the‐art lyophilization technology, in which vials are suspended and move continuously through the process. The validated model can accurately predict the evolution of critical process parameters, including the product temperature, ice/water fraction, sublimation front position, and concentration of bound water, for the entire process. Several applications related to model‐based process design and optimization of continuous lyophilization are also demonstrated. The final model is made available as an open‐source software package that can be leveraged for guiding the design and development of future continuous lyophilization processes.