Modélisation, contrôle et développement de PAT pour un mini-mélangeur pneumatique de poudres permettant les tests de libération en temps réel pour des applications de médecine personnalisée

école doctorale

équipe

Axe 5 - GENIE DES PRODUITS

contexte

Powder mixing is a critical step in pharmaceutical as well as in numerous other industries. Although the manufacturing process for pharmaceutical solid-dose products has been studied for many decades, the understanding of mixing and the applied techniques is still continuously evolving. For example, one of the major challenges in process development is to determine the relationship between raw material properties, process conditions, such as particle size distribution [1], particle morphology, moisture content, and both micro and meso-structure, and critical quality attributes [2, 3, 4]. At present, the new research topics are also linked to the fact that the pharmaceutical industry is experiencing a significant transformation driven by several factors. Firstly, the rise of personalized medicine calls for adaptations of manufacturing processes. Pharmaceutical companies now need to adjust their operations to accommodate the production of smaller batches. Secondly, to reduce the expenses associated with healthcare, the industry is increasingly embracing continuous manufacturing to reduce production costs. Regulatory authorities actively promote continuous manufacturing as it offers enhanced control over the manufacturing process, ensuring greater consistency in product quality. Thirdly, re-shoring of production and the localization of production capacity also affects batch sizes and requires more flexible equipment. These three factors lead to research questions of how to best construct, monitor, and control mixing equipment at smaller scale in batch-wise or continuous production. The aspect of monitoring and control is exacerbated in continuous manufacturing. Here, the manufacturing process must be continuously monitored and controlled to remain in a state of high product quality. Monitoring is realized under the umbrella term process analytical technology (PAT) [5]. The central point to PAT is the generation of product quality information in real time and its use to control the critical process parameters of a manufacturing process. A key to improve the monitoring and operation of processes in general, and of powder mixing in particular, is the development of process models. With a model, not only it becomes possible to predict the time evolution of powder mixing efficiency as a function of the operating conditions, and therefore to design the adequate closed-loop controllers and/or optimize the operating conditions, but also unmeasured process variables can be estimated. There have been several approaches to model powder mixers, leading to very different model structures, ranging from statistical (data-driven) models [6] over compartment models [7] to Discrete Element Method (DEM) models [8]. All model structures have pros and cons and are more or less suited depending on the technology and the purpose of the model. One challenge is that, to the best of our knowledge, there is no model structure in the literature that can be directly applied to build a model of the pneumatic powder mixer of this project. Dec Group develops, produces, and sells integrated end-to-end process lines to pharmaceutical manufacturers. Dec Group also pursues a strategy of automatizing processes and removing mechanical components to excel in robustness of the equipment and processes. Following this strategy, Dec Group's patented pneumatic Batchmixer (US8834011B2) is the first powder blender without moving or rotating parts active in the mixing process. Unlike mixing systems on the market with mechanical bearings, the risk of contamination of the powder with abrased particles is eliminated. The Batchmixer, including its charging and discharging system, can be integrated into closed process lines with high containment and with cleaning and sterilization in place. It is therefore especially well-suited for pharmaceutical powder handling. Now, Dec Group aims for the development of the DecBlender, a comprehensive renewal of the Batchmixer, by introducing the following innovative features. Firstly, the integration of process analytical technology (PAT) to provide real-time monitoring and analysis. Secondly, the ability to handle mini batch sizes. Thirdly, the vision includes the prospect of continuous manufacturing. Hence, the scientific objectives of the project are in line with the fundamental, methodological and technological needs of the DecBlender.

spécialité

Génie des Procédés, des Produits et des Molécules

laboratoire

LRGP - Laboratoire Réactions et Génie des Procédés