Developing a pharmaceutical fluid bed granulation & drying process via design of experiments based on a multivariate model

Abstract

This manuscript presents a lean industrial workflow to establish an operating design space for a commercial scale fluid bed granulation and drying process. The workflow involves confirming the operating design space by demonstrating that the drug product critical quality attributes are met at the most extreme processing conditions within the granulation design space. This eliminates the need to execute a large experimental design, since any processing condition bound by the adequately demonstrated extreme conditions should also be acceptable, assuming linearity and continuity. A PLS (partial least squares) model was used to illustrate the multivariate relationship among the important process outputs and inputs (material properties and operating control variable settings). Since the moisture content of the fluidized bed influences granulation, the design space was evaluated based on the moisture accumulation and removal rates (output of the PLS models). The PLS model identified the specific experiments needed to confirm the operating design space. These specific experiments were executed, and the design space was confirmed experimentally. The PLS-model guided experimentation resulted in a lean experimental study while delivering a robust drug product manufacturing process.