An Industrial Data-Calibrated Mechanistic Modelling Framework for Robust Operation and QbD Design-Space Analysis in Pharmaceutical Fluid-Bed Drying

Process digitalization through high-fidelity modelling is increasingly used to support Quality by Design (QbD) and Operational Excellence in pharmaceutical manufacturing. In this study, an industrial data-calibrated mechanistic modelling framework was developed for an industrial pharmaceutical batch fluid bed drying process, integrating a mechanistic model calibrated using real industrial data. The objective was not only to predict final moisture content, but also to characterise process dynamics and the effects of key process parameters, transforming the validated model into a decision-support tool for defining robust operating regions within a QbD framework.

The mechanistic core incorporated two-phase fluidisation hydrodynamics, granular moisture diffusion and convective heat transfer, while model parameters were calibrated using data from eight full-scale industrial batches and evaluated using four independent batches. The validated framework enabled virtual experimentation across inlet air temperature, airflow rate and drying time, together with Monte Carlo-based uncertainty propagation.

Validation against four independent batches showed agreement for final residual moisture within the experimentally represented range, with a root mean square error of approximately 0.3% on a wet basis. Simulation results revealed nonlinear interactions among critical process parameters and identified operating regions satisfying residual moisture criteria while maintaining favourable relative energy-performance conditions. Monte Carlo-based uncertainty propagation showed that central operating regions exhibited lower sensitivity to disturbances, whereas boundary conditions amplified variability in critical quality attributes.

Overall, the framework extends mechanistic process simulation towards probabilistic design-space construction and risk-informed decision support in pharmaceutical manufacturing.