Novel flexibility index formulations for the selection of the operating range within a design space

Abstract

The importance of the Design Space (DS) definition lies in the assurance of quality, a key goal of Quality by Design, and in the broadening from a single acceptable operating point, to a collection of feasible operating regions. Therefore, properly defining the limits of the design space is vital to provide manufacturing flexibility and quality assurance. In this work, we propose new MINLP reformulations to the extended flexibility analysis, where we distinguish between process and model parameters, to efficiently calculate a new flexibility index for process parameters. This index defines a hyperrectangular operating region within a design space of a pharmaceutical process in terms of the process parameters and accounts for the uncertainty in the model parameters, described by hyperrectangle and ellipsoidal sets. We illustrate the application of these novel techniques on several examples.