(754d) Model-Guided Quality by Design: A Case Study On a Pharmaceutical Final Intermediate

This case study outlines an application of Quality by Design (QbD) principles to the development of the final intermediate manufacturing process.  The final intermediate process consists of three steps: (1) deprotection, (2) alkylation and (3) recrystallization.  This study will focus on the alkylation step which affords two key impurities and requires control of three process parameters: temperature, solvent ratio and reagent equivalents to produce high quality material. 

 Through a multi-staged experimental plan, a statistical model was developed and refined to guide the selection and verification of the manufacturing design space. Early Design of Experiments (DoE) laboratory work established the dependence of the quality attributes on specific process parameters which were investigated further to develop an initial statistical model  This model was further refined through incorporation of additional laboratory and production-scale data to provide guidance for the determination of the optimal manufacturing design space. The 95% prediction intervals of the model were utilized as an initial guide for the design space.  The design space was verified in the laboratory and at pilot scale.  This presentation will discuss the implementation of QbD principles to maximize the manufacturing process robustness for the alkylation step through experimental design, statistical model development and design space verification.