Rational approaches and transfer strategies for the scale-up of freeze-drying cycles
The rational development and optimization of freeze drying cycles in the laboratory should be based on knowledge of the critical formulation properties, such as the collapse temperature. Once a recipe has been finalized that ensures acceptable quality of the final product, the transfer to manufacturing scale can be initiated. When scaling a freeze drying cycle from the laboratory to pilot or production scale, identical product temperature profiles over time must be established to assure the same quality defined in the lab. To achieve this, several important factors have to be taken into consideration. The most important parameters such as nucleation behaviour, differences in heat and mass transfer, freeze dryer design and performance and their impact on product quality will be surveyed. Additionally, methods to evaluate and compensate differences between freeze dryers are presented.
Freeze drying is a widely used process for stabilization of labile active pharmaceutical ingredients by removal of the solvent (typically water) at low temperatures (1). The relatively long process time and high energy consumption during constant cooling and heating of the shelves and the condenser make lyophilization a very cost-intensive drying technology (2). In the last years, pharmaceutical manufacturers have broadened their efforts to optimize freeze drying recipes and thereby shorten the process time (3). The more aggressive processes applied lead in turn to greater susceptibility of the product to potential process deviations, for example of chamber pressure or shelf temperature, and inhomogeneities within the batch.
The development of an appropriate freeze drying cycle is usually performed in laboratory scale freeze dryers (shelf area 0.1 to 0.5 m2) with only limited amounts of product and at most several hundred vials. Later in the development phase, the optimized recipe needs to be transferred to a production scale lyophilizer with 10 to 50 m2 shelf area and correspondingly a much larger number of vials. There a ...