In-Line and Off-Line Optimization of Freeze-Drying Cycles for Pharmaceutical Products

Abstract

The problem of process design for the freeze-drying of pharmaceutical products is here addressed. A comparative analysis between the various optimization tools so far proposed is given. The above analysis aims to give some guidelines to lyophilization professionals in the choice of the best design strategy compatible with their objectives and the technology available. In particular, this study examines the strengths and weaknesses of design space and of the different model-based control techniques so far proposed with a view to a better understanding of factors that still limit the use of these techniques at the manufacturing scale. With this regard, the above methods are compared in terms of robustness and scalability of the cycle, number and type of input parameters, management of product and equipment constraints, as well as batch unevenness. The first part of the study is carried out by means of mathematical simulations, as this approach makes it possible to better investigate the controller performance eliminating the uncertainty due to the experiment reproducibility. This study shows that although design space can provide a detailed view of the impact of processing conditions on product quality, its use for the cycle development can hardly lead to a real process optimization. By contrast, this objective can be achieved if model-based control is used. Experiments obtained for mannitol and sucrose-based formulations confirmed this result.