Controlled nucleation and heat flux measurements as innovative technologies for freeze-drying

Biologics, e. g. proteins, are prone to several degradation processes during manufacturing, e. g. deamidation, oxidation, hydrolysis, aggregation, and denaturation, which poses challenges for adequate shelf life time of the final product. Freeze-drying has become the method of choice to stabilize these products. Besides maintaining product quality, researchers focus on the optimization of freeze-drying cycles with respect to economic drying times. Consequently, the need for rigorous product monitoring and process analytical technology (PAT) tools during cycle development is high. Controlled ice nucleation (CN) and heat flux measurements raised great expectations for freeze-drying cycle optimization and control in the last years. The aim of this thesis was to evaluate, in case of controlled nucleation, its potential to improve product quality, process control, and efficiency, and in case of heat flux measurements, its potential as a new PAT tool. This thesis showed that CN did not directly improve product quality with respect to mAb stability or inter vial batch homogeneity of the final product. Solely, for special products, it was shown to shorten reconstitution times. Additionally, heat flux measurements were shown to be a valuable PAT tool, which monitors critical endpoints, e. g. freezing or primary drying. Furthermore, heat flux measurements provide critical process parameters.