(111d) Linking Unit Operations During Design Space Development and Definition

A greater importance has been placed on having a systemic and comprehensive approach to pharmaceutical development and lifecycle management as outlined by quality by design principles. Greater emphasis has been placed on defining the manufacturing design space. A drug substance process design space can be defined using a statistical based design of experiments (DOE) approach to establish input parameter ranges that provide assurance of consistent performance and meet product quality specifications. Traditionally, a separate set of designed experiments has been used for each unit operation to establish a robust operating space. Unfortunately, the performance of one step may depend on the quality attributes of the preceding process stream thus the linkage of process steps when conducting process characterization and defining the process design space is critical. In this presentation, we evaluate and compare two methods to link multiple unit operations during process characterization: forward linking and partition designs. Results of these methods applied to a biopharmaceutical process are presented and the benefits and challenges of each method are discussed.