(119d) Model-Based Risk Mitigation Strategy for Late Stage Development of a Drug Substance Manufacturing Process

This work presents a strategy to identify options for the development of drug substance manufacturing processes through late stage while maximizing the use integration of computer based modeling and simulation technology and targeted laboratory experimentation. Our proposal considers the molecule specific product-associated risks and the process operational-associated risks as they systematically relate to and interact with each other across the entire GMP sequence.  An input to this strategy is a new unit operation model classification system designed to provide estimates of modeler effort when a risk is studied and addressed.  The classification system is employed to complete a process-wide risk , and a model-based development strategy is designed to mitigate (or eliminate) the multiple process risks.  The output of this strategy is a set of proposed options for executing late stage development and serves as planning tool which provides quantitative predictions of the effort required for each proposed option. and the impact (measured as process risk reduction achieved) for each of the development options is predicted  The various model-based development options are ultimately designed to produce the commercial-scale operating conditions and ranges as well as the necessary information package to write the CTD and successfully transfer the process to commercial manufacturing.