Design and Manufacture of a Modular Continuous Unit Dose Pharmaceutical Lyophilizer

Abstract

Pharmaceutical lyophilization (freeze-drying) enables long term storage and simplified transportation for aqueous vaccines and protein formulations. Modern industrial pharmaceutical freeze-driers rely on large batch and open loop formulation processing, limiting supply chains and resulting in variable quality products. This work describes the design and manufacture of a modular continuous lyophilization machine for pharmaceutical production. Additionally, the scaling and design methodology outlined in this work enables the development of both smaller systems for laboratory testing and larger machines to fit the needs and requirements of individual facilities. This machine introduces three new technologies to the pharmaceutical freeze-drying process. The first innovation is a continuous flow lyophilization topology which separates the lyophilization steps spatially rather than temporally. This layout allows product to travel through the system in smaller batches for increased product uniformity and quality control. The second innovation is a weight-based sensor for monitoring residual water content. This sensor enables in-situ monitoring of product during sublimation, and it resolves mass measurements as small as 5mg. The third innovation is the implementation of a thermal shock method of inducing controlled nucleation. The convective cooling and spatial non-uniformity within the machine allow vials to experience a 40°C temperature drop in less than 30 seconds. This nucleation front starts on the vial walls, rather than at the top surface of the solution in the vial, potentially increasing the water sublimation rate during drying compared to current nucleation methods. The machine designed and built for this work integrates into modern factory processes and can be scaled from the lab bench to a production line. The manufactured prototype demonstrates improvements on the production rate, flexibility, and quality of existing machines.