Mechanistic Modeling and Analysis of Transport Phenomena for Continuous Lyophilization

2024-09-10

AI Summary

The pharmaceutical industry’s transition to continuous lyophilization is hindered by the absence of a comprehensive, first-principles-based mechanistic model spanning the entire process. Method: We developed the first multi-physics, first-principles model coupling freezing, primary drying, and secondary drying stages. It introduces a novel dynamic heat and mass transfer formulation for suspension-mounted moving vials, enabling quantitative description of ice/water phase change, sublimation front migration, product temperature evolution, and bound water removal. Multi-scale modeling and phase-change kinetics analysis are rigorously validated against high-fidelity experimental data. Contribution/Results: The open-source software toolkit ContLyo (MATLAB/Julia) enables process design and optimization. This work establishes a foundational mechanistic modeling framework for continuous manufacturing of next-generation biologics, including mRNA vaccines.

Technology Category

• Machine Learning: Life-Long and Continual Learning
• Cognitive Modeling & Cognitive Systems: Neural Spike Coding
• Constraint Satisfaction and Optimization: Mixed Discrete/Continuous Optimization

Application Category

• User Modeling, Personalization and Recommendation: User modeling and simulation for interactive and conversational systems
• Systems and Infrastructure for Web, Mobile and WoT: Applied ML and AI for Web-based mobile applications
• Security and Privacy: Data transparency and provenance

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.

Problem

• Develops a mechanistic model for continuous lyophilization processes.
• Predicts critical parameters like temperature and sublimation front position.
• Provides open-source software for designing continuous lyophilization systems.

Innovation

• Mechanistic model for continuous lyophilization process
• Incorporates key transport phenomena in all steps
• Open-source software package ContLyo for process optimization