(466f) Implementation of Reaction Modeling and Process Analytical Technology in Design Space Development

A key aspect of Quality by Design (QbD) in pharmaceutical manufacturing is the development of a design space for multivariate processes.  In this case study, we explored the application of mechanistic modeling and process analytical technology (PAT) to define the design space of a reaction that generates the  pharmaceutical intermediate of a drug substance in development.

The reaction involves a nucleophilic aromatic substitution that affords the desired material along with two critical impurities.  The main parameters impacting the formation of the impurities are the excess base and the temperature of the reaction. A reaction model based on mechanistic studies was built using data captured by HPLC and then used to conduct simulations that generated the response surfaces corresponding to the conversion of the starting materials and the formation of the critical impurities. In addition, the reaction progress was analyzed with Raman spectroscopy and a chemometric model was built to allow real-time monitoring of the starting material conversion. Combining the knowledge of the reaction response across multiple parameters with Raman spectroscopy for real-time monitoring of the reaction progress allows for relaxation of processing constraints and resulting in the expansion of the design space.

In summary, this work shows the synergistic benefits of combining mechanistic modeling and PAT in a QbD approach to enhance the design space and robustness of a process.