A dynamic design space for primary drying during batch freeze-drying
´SÉVERINE ´THÉRÈSE F. C. MORTIER1,2, PIETER-JAN VAN BOCKSTAL2, INGMAR NOPENS1, THOMAS DE BEER2, KRIST V. GERNAEY3*
*Corresponding author
1. BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
2. Laboratory of Pharmaceutical Process Analytical Technology (LPPAT), Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
3. CAPEC-PROCESS Research Center, Department of Chemical and Biochemical Engineering, Technical University of Denmark, Building 229, 2800 Kgs. Lyngby, Denmark
Abstract
Biopharmaceutical products are emerging within the pharmaceutical industry. However, biopharmaceuticals are often unstable in aqueous solution. Freeze-drying (lyophilisation) is the preferred method to achieve a stable product with an increased shelf-life. During batch freeze-drying, there are only two adaptable process variables, i.e. the shelf temperature and the pressure in the drying chamber. The value of both should be optimized, preferably in a dynamic way, to minimise the primary drying time while respecting process and equipment constraints and ensuring end product quality. A mechanistic model is used to determine the optimal values for the adaptable variables, hereby accounting for the uncertainty in all involved model parameters. A dynamic Design Space was constructed with a risk of failure acceptance level of 0.01%, i.e. a ‘zero-failure’ situation. Even for a risk of failure of 0.01%, the computed settings resulted in a reduction of the drying time by over 50% compared to current practice.
INTRODUCTION
Among the approved biopharmaceutical drug products, approximately 50% are freeze-dried products (1). This indicates that freeze-drying or lyophilisation is the method of preference to stabilise biopharmaceuticals which are unstable in an aqueous solution. However, freeze-drying has some major drawbacks as it is an expensive, time- and energy-consuming process (2, 3). As common in the pharmaceutical sector, freeze-drying is a batch process, consisting of three major process steps: (a) a freezing step where vials filled with the aqueous drug formulation are placed on temperature-controlled shelves which are gradually cooled until approximately -45°C, leading to crystallization of most of the water into ice, (b) a primary drying step under vacuum conditions (approximately 10 Pa), during which the shelves provide the energy required for ice removal by sublimation, and (c) a secondary drying step, where the remaining unfrozen water is removed by desorption until a dry cake is obtained (Figure 1). To ensure end product quality, several Critical Quality Attributes (CQAs) are defined for freeze-dried products (4,5).
To guarantee optimal therapeutic a ...
