Mechanistic Modeling of Continuous Lyophilization for Biopharmaceutical Manufacturing

TL;DR

This paper introduces the first comprehensive mechanistic model for continuous lyophilization in biopharmaceutical manufacturing, enabling better process understanding, prediction, and optimization of all three lyophilization stages.

Contribution

The study develops and validates a complete mechanistic model for continuous lyophilization, incorporating key transport phenomena across all process stages, and provides an open-source software tool for process design.

Findings

Model accurately predicts process parameters like temperature and ice fraction.

Validated model demonstrates potential for process optimization.

Open-source tool (ContLyo) facilitates future process development.

Abstract

Lyophilization (aka freeze drying) is a typical process in pharmaceutical manufacturing used for improving the stability of various drug products, including its recent applications to mRNA vaccines. While extensive efforts have been dedicated to shifting the pharmaceutical industry toward continuous manufacturing, the majority of industrial-scale lyophilization is still being operated in a 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 in MATLAB and Julia as an open-source software package called ContLyo, which can ultimately be leveraged for guiding the design and development of future continuous lyophilization processes.