Development of a fluid bed granulation design space using critical quality attribute weighted tolerance intervals.

The fluid bed granulation and drying unit operation were used as a case study for control systems implementation. This single processor was used to blend, granulate, dry, and cool the materials. The current study demonstrated control of each of the phases using a fully automated, hybrid control system that incorporated first-principle modeling, empirical design of experiments (DOE), and process analytical technology to assure the production of constant product quality. The system allowed data to be collected efficiently for the development of a rigorous design space that combined formulation factors, process factors, and their interactions to define a tolerance surface where risk of future product failure was significantly reduced. The DOE incorporated microcrystalline cellulose and lactose monohydrate, excipients with substantially different wetting properties, to elucidate the relationship between the critical process parameters of the unit operation and the material properties of the formulation components. The extended analysis of covariance model enabled these factors and their interaction terms to be described in a single model. The results indicate that the development of a tolerance interval-based weighted design space can enhance product understanding and thereby help to assure future product quality.