Use of computational fluid dynamics for improving freeze-dryers design and process understanding. Part 1: Modelling the lyophilisation chamber.

This manuscript shows how computational models, mainly based on Computational Fluid Dynamics (CFD), can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular, the freeze-dryer chamber and the duct connecting the chamber with the condenser, with the valves and vanes eventually present are analysed in this work. In Part 1, it will be shown how CFD can be employed to improve specific designs, to perform geometry optimization, to evaluate different design choices and how it is useful to evaluate the effect on product drying and batch variance. Such an approach allows an in-depth process understanding and assessment of the critical aspects of lyophilisation. This can be done by running either steady-state or transient simulations with imposed sublimation rates or with multi-scale approaches. This methodology will be demonstrated on freeze-drying equipment of different sizes, investigating the influence of the equipment geometry and shelf inter-distance. The effect of valve type (butterfly and mushroom) and shape on duct conductance and critical flow conditions will be instead investigated in Part 2.

Freeze-drying of enzymes in case of water-binding and non-water-binding substrates.

Enzymes typically have a critical instability, which dominates both formulation and process development. In this paper, the ability to preserve the enzyme activity during freeze-drying was investigated for both water-binding and non-water-binding substrates. For this purpose, acid phosphatase was used as model protein. In addition, a procedure for the fast development of a freeze-drying cycle is shown. For the secondary drying part, the effect of processing temperature and time on enzyme activity was investigated. The enzyme activity decreased continuously during secondary drying, with a dramatic drop associated with processing temperatures higher than 293 K. Besides product temperature, the residual moisture level and water mobility are also important. As the residual moisture level and water mobility depend on the product formulation, the stabilizing effect against the enzyme deactivation was studied for a number of formulations which contain different additives, that is, sucrose, lactose, mannitol, and poly-vinylpyrrolidone, with a dramatic activity loss associated with crystallizing excipients. This study also confirmed that not all water-binding substrates can successfully protect the enzyme against deactivation. In fact, water-binding substrates containing reducing sugars (lactose) showed the highest loss of activity.

On the use of a dual-scale model to improve understanding of a pharmaceutical freeze-drying process.

The evolution of product temperature and of residual ice content in the various vials of a batch during a freeze-drying process can be significantly affected by local conditions around each vial. In fact, vapor fluid dynamics in the drying chamber determines the local pressure that, taking into account the heat flow from the shelf and, eventually, radiation from chamber surfaces, is responsible for the sublimation rate and product temperature. These issues have to be taken into account when using mathematical simulation to predict the evolution of the product as a consequence of the operating conditions (recipe design), as well as during the scale-up of a recipe obtained in a small-scale equipment to a large-scale unit. In this framework, a dual-scale model can significantly improve the understanding for pharmaceuticals freeze-drying processes: it couples a three-dimensional model, describing the fluid dynamics in the chamber, and a second mathematical model, either mono- or bi-dimensional, describing the drying of the product in each vial. Thus, it can be profitably used to gain knowledge about process dynamics, and to improve the design of the equipment, as well as the performance of the control system of the process.