Identification and Quantification of Heterogeneity in Freezing and Primary Drying Steps of Lyophilization

The ultimate goal of the freeze-drying process is to deliver a consistently stable, efficacious, easily reconstitutable, and non-immunogenic final product to the patient at an affordable cost. However, heterogeneity in the heat transfer to vials across the batch and in mass transfer resistance to sublimation were found to lead to variation in the factors affecting product quality both intra- and inter-batch. The overall objective of this research was to identify and quantify the sources of variation in the freeze-drying process, which alter the thermal history of the product and investigate their effects on the product quality attributes. Effects of processing parameters on the measurement of vial heat transfer coefficient (Kv), one of the major factors affecting the product temperature and drying time, were studied. This study found several nuances and pitfalls of Kv measurement. Calculation of Kv for developing a cycle for a new product should be based on measurements made at target shelf temperatures and chamber pressures, using the vial and fill volume of the new product. Experimentally obtained distribution in Kv across a batch of vials was combined with variations in three other input parameters – dry product layer resistance, fill volume and shelf temperature – in a first principles based, steady-state heat and mass transfer model to quantitatively predict the distribution in primary drying times in vials in the batch. A method was developed to experimentally measure the spatial variation in pressure in the drying chamber using a differential capacitance manometer and custom-made rig installed in a laboratory freeze-dryer. These measured pressure gradients were found to have an insignificant effect on drying time in comparison to the variations in the position-based Kv or ice nucleation temperature-dependent dry product layer resistance. Lastly, the effect of heterogeneity in the freezing and the primary drying steps of lyophilization on the reconstitution time for a lyophilized high concentration monoclonal antibody was investigated. Differences in product temperature and drying times affected the cake properties such as wetting, disintegration and hydration, altering reconstitution times