Although the entire freeze-drying process is an energy intensive, time-consuming, and economically expensive process, the primary drying step is the longest and most critical step.
Consequently, there is growing interest in the pharmaceutical and biopharmaceutical industries to optimize the primary drying step with regard to both product quality and processing time. Optimization of the primary drying step requires significant knowledge of the process parameters, the formulation attributes, and the interrelationship between the process and the formulation.
There are several formulation properties and process parameters that play an important role during the optimization of the primary drying step. Characterization of the formulation in its frozen state provides critical formulation properties:
Glass transition temperature of maximally freeze-concentrated solution
Collapse temperature of an amorphous formulation
Eutectic melting temperature of a crystalline formulation
Degree of crystallinity of the formulation
Freeze-drying process design and optimization could be initiated once the optimum formulation is defined. Notably, understanding the freezing step is also essential to design and optimize the primary drying step.
The heat and mass transfer through a freeze-drying vial during primary drying have been successfully modeled in the past, and these models show reasonable agreement with current experimental measurements in different studies. The interaction of the primary drying input variables such as process parameters and material attributes which affect the quality of the product can be represented on a design space, which is a crucial part of the Quality-by-Design (QbD) paradigm.
The equipment capability limit forms one of the bounding elements of the design space, and the limitation occurs due to sonic flow in the duct, limited condenser refrigeration capacity or heating capacity. The other is formed by the critical product temperature beyond which the product quality is no longer acceptable.