Small-Scale Tools to Assess the Impact of Interfacial and Shear Stress on Biologic Drug Products.

Proper risk analysis needs to be in place to understand the susceptibility of protein to unfold and aggregate in the presence of interfacial and/or shear stress. Certain techniques, such as agitation/shaking studies, have been traditionally used to understand the impact of these stresses on the protein physical stability. However, the stresses applied in these systems are convoluted, making it difficult to define the control strategy (i.e., adjustment in process parameters to reduce foaming/bubble formation, change pump type). We have developed two small-scale tools that allow for the isolation of interfacial and shear stress, respectively. These systems, in combination with computational fluid dynamics and numerical approximations, help simulate the normal operating ranges as well as the proven acceptable ranges for different unit operations such as tangential flow filtration (TFF), mixing, and filling.

Optimization of Primary Drying in Lyophilization During Early-Phase Drug Development Using a Definitive Screening Design With Formulation and Process Factors.

Development of optimal drug product (DP) lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the DP formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. To overcome these development difficulties, an 8 factor definitive screening design, including both formulation and process parameters, was executed on a fully human monoclonal antibody DP. The definitive screening design enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different DP formulations. This concept is demonstrated on a monoclonal antibody DP where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions.