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.