In-line monitoring of the freeze-drying process by means of heat flux sensors

The final qualities of a pharmaceutical product can be adversely affected by a suboptimized freeze-drying process. Multiple variables and operating conditions come into play, thus making the overall process difficult to control. In this study, we show how heat flux sensors can guide the in-line monitoring of freezing and primary drying of placebo formulations, leading to significant insights that contribute to our understanding of the phenomena involved. It was found that heat flux sensors can be used as a practical and robust tool to monitor a lyophilization cycle by defining the processing time and investigating different process scenarios. Concerning the freezing step, the heat flux sensors proved to be an effective way to detect both nucleation and end of crystal growth. Additionally, the sensors' signal highlighted the end of cooling and freezing steps and thus helped to eliminate uncertainty about the time required to reach thermal equilibrium across the batch. An ultimate potential of the devices was addressed to build the design space for freezing and primary drying, laying the foundations for new research on this topic

Effect of freeze-dryer design on heat transfer variability investigated using a 3D mathematical model

International audienceIn the freeze-drying process, vials located at the border of the shelf usually present higher heat flow rates which in turn result in higher product temperatures than central vials. This phenomenon, named edge vial effect, can result in product quality variability within the same batch of vials and between batches at different scales. Our objective was to investigate the effect of various freeze-dryer design features on the heat transfer variability. A 3D mathematical model previously developed in COMSOL Multiphysics and experimentally validated was used to simulate heat transfer of a set of vials located at the edge and in the centre of the shelf. The design features considered were the loading configurations of the vials, the thermal characteristics of the rail, the walls and the shelves and some relevant dimensions of the drying chamber geometry. The presence of the rail in the loading configuration and the value of the shelf emissivity strongly impacted on the heat flow rates received by the vials. Conversely, the heat transfer was not significantly influenced by modifications of the thermal conductivity of the rail, the emissivity of the walls and by the geometry of the drying chamber. The developed model revealed to be a powerful tool to predict the heat transfer variability between edge and central vials for the cycle development and scale-up and to compare various freeze-dryer design features