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

Use of a multi-vial mathematical model to design freeze-drying cycles for pharmaceuticals at known risk of failure

[EN] Freeze-drying is a dehydration method suitable for the stabilization of heat-labile pharmaceutical products, such as vaccines. Due to the vial-to-vial variability of heat and mass transfer during the process, the value of the critical process parameters (e.g., product temperature, sublimation rate) may be different between vials and batches often present significant product quality heterogeneity. The aim of this work was the development of a dynamic, multi-vial mathematical model making it possible to predict risk of failure of the process, defined as the percentage of vials potentially rejected by quality inspection. This tool could assist the design of freeze-drying cycle.This work was sponsored by GlaxoSmithKline Biologicals SA which was involved in all stages of the study conduct and analysisScutellà, B.; Trelea, IC.; Bourlés, E.; Fonseca, F.; Passot, S. (2018). Use of a multi-vial mathematical model to design freeze-drying cycles for pharmaceuticals at known risk of failure. En IDS 2018. 21st International Drying Symposium Proceedings. Editorial Universitat Politècnica de València. 315-322. https://doi.org/10.4995/IDS2018.2018.7421OCS31532

Pathways and variability of the off-equatorial undercurrents in the Atlantic Ocean

The cold upwelling waters of the eastern tropical oceans not only interact with the atmospheric circulation via changing the sea surface temperatures but also influence the biological activity via affecting the nutrient and oxygen contents of the upwelling waters. While the sources of the equatorial upwelling associated with the Equatorial Undercurrent (EUC) have been studied extensively, the relevance of the northern and southern off-equatorial undercurrents (NEUC, SEUC) for the off-equatorial upwelling regions has remained unclear. In this study we use output from a high-resolution, 1/12° model (FLAME) to investigate the mean pathways and variability of the off-equatorial undercurrents (OEUCs) in the Atlantic. In particular, a calculation of Lagrangian trajectories helps to gain insight into the source waters of the OEUCs and their connection to the upwelling regions in the eastern tropical Atlantic. In the model solution the sources of both OEUCs belong almost exclusively to the Southern Hemisphere. The pathways of the source waters are found to be governed by strong recirculations between the different eastward and westward zonal currents because of intense eddy motions associated with the tropical instability wave activity. Whereas the SEUC is predominantly fed through the recirculation in the ocean interior, the NEUC is also fed by a weak inflow from the western boundary current. Investigation of the fate of the NEUC shows only a weak direct supply to the upwelling in the Guinea Dome and along the African coast but a significant contribution to the equatorial upwelling

Pension's Resource-Time Trade-off: The Role of Inequalities in the Design of Retirement Schemes

Public pension schemes serve as mechanisms for inter-temporal income smoothing and within-cohort redistribution. This paper examines the influence of income and lifespan inequalities on the structure of a democratically chosen tier-pension scheme. We use a probabilistic voting model where agents vote on the size and the degree of redistribution (i.e. the Beveridgean factor) of the pension scheme and can supplement it with voluntary contributions. Our analysis reveals that when all agents can supplement the public scheme with private contributions, their voting behavior depends solely on the share of total income redistributed through the pension system, referred to as the redistributive power of the pension. Income inequality positively correlates with the equilibrium redistributive power, while lifespan inequality exhibits the opposite effect, leading to a resource-time trade-off; particularly when both inequality measures are correlated. In scenarios where low earners are hand-to-mouth and unable to make voluntary contributions, the effects on pension size (through mandatory contributions) and degree of redistribution become disentangled. Income inequality diminishes pension size while augmenting redistribution, whereas lifespan inequality increases pension size while reducing redistribution. We provide empirical evidence from OECD countries supporting these theoretical findings and calibrate the model on French data to quantify the effects

How to manage scale-up using the design space approach

How to manage scale-up using the design space approach. 2016 PDA Conference, Pharmaceutical Freeze Drying Technolog

Finite elements model of heat transfer predicts the edge vial effect in different freeze-drying configurations

Finite elements model of heat transfer predicts the edge vial effect in different freeze-drying configurations. 2016 CPPR Conference Freeze-Drying of Pharmaceuticals and Biological