Real-time Estimation of Bound Water Concentration during Lyophilization with Temperature-based State Observers

TL;DR

This paper introduces a novel temperature-based state observer for real-time estimation of bound water during lyophilization, enhancing product quality control without needing direct moisture measurement.

Contribution

It presents a new mechanistic observer that accurately estimates residual moisture in real time during secondary drying, using only temperature data.

Findings

The observer accurately tracks bound water concentration across various conditions.

Simulation and experimental results validate the method's effectiveness.

The approach can be extended to other desorption processes.

Abstract

Lyophilization (aka freeze drying) has been shown to provide long-term stability for many crucial biotherapeutics, e.g., mRNA vaccines for COVID-19, allowing for higher storage temperature. The final stage of lyophilization, namely secondary drying, entails bound water removal via desorption, in which accurate prediction of bound water concentration is vital to ensuring the quality of the lyophilized product. This article proposes a novel technique for real-time estimation of the residual moisture during secondary drying in lyophilization. A state observer is employed, which combines temperature measurement and mechanistic understanding of heat transfer and desorption kinetics, without requiring any online concentration measurement. Results from both simulations and experimental data show that the observer can accurately estimate the concentration of bound water in real time for all possible concentration levels, operating conditions, and measurement noise. This framework can also be applied for monitoring and control of the residual moisture in other desorption-related processes.