Integrating quality by design principles into spray drying technology for dry powder inhaler formulation: A comprehensive review

The dry powder inhaler (DPI), a device that sprays drug particles in a carrier-free form and demands concomitant management of particle aerodynamics, solid-state stability, device compatibility, and formulation composition, is one of the most technically demanding devices in the pharmaceutical drug delivery field and achieves reproducible lung deposition across diverse patient groups. Though several reviews have discussed the quality by design (QbD) principles of DPI development and optimization of the spray-drying process individually, none has combined the Péclet-number framework of particle morphology engineering, the construction of design space probabilistically using Monte Carlo, PAT-enabled real-time release testing, and the entire ICH Q812 regulatory continuum within a single, mechanistically based workflow focused on drug-delivery outcomes. This review fills the gap by critically synthesizing the literature on process engineering, formulation science, and regulatory science. The main quantitative results of the literature synthesis are that leucine at 10-30% w/w increases the fraction of fine particles by 15-40% compared to controls without leucine. Feed viscosity of 30–50 mPa·s is necessary to ensure acceptable atomization and droplet uniformity. The Péclet-number bifurcation (Pe < 1 yields dense spheres; Pe > 1 yields hollow or folded particles with mass median aerodynamic diameter of 1–3 µm (from geometric diameters of 3–10 µm) provides the mechanistic foundation for rational morphology engineering. The QbD-driven development programs reduce development cycle time by 20–40%, enhance design-space robustness, and facilitate real-time release testing of moisture content and particle size, replacing conventional end-product testing. The review presents a mechanistically based, integrated workflow that embraces Peclet-number particle-morphology engineering, probabilistic Monte Carlo design-space synthesis, and PAT-enabled real-time release-testing control strategies for both small-molecule and biologic DPI formulations. By connecting spray-drying process parameters to aerosol performance metrics, biopharmaceutical critical quality attributes, and clinical outcomes in asthma and chronic obstructive pulmonary disease, this review bridges the process engineering–drug delivery gap that prior reviews have not collectively addressed.