Microparticulate drug delivery systems, e.g., micropellets (MPs), are used in a variety of pharmaceutical formulations such as suspensions, injectable systems, and capsules. MPs are currently manufactured mainly via batch, solvent-based processes, e.g., spray-drying and solvent evaporation-extraction. In this paper, we present a novel, solvent-free, continuous hot-melt extrusion-based approach with an inline cold pelletization step and the potential of unprecedented on-the-fly formulation changes, aiming at producing the smallest particles usable for injectable applications. A biodegradable, crystalline dispersion consisting of poly(DL-lactic acid) (PLA) filled with metformin as the model drug was chosen on purpose to elucidate the broad applicability of the process also to formulations with limited stretchability and complex pelletizability. Next to optical/statistical particle analyses and in-line high-speed camera investigations providing insights into the pelletization process, the injectability of the most promising micropellets was compared to that of one marketed formulation. Fast extrudate haul-off speeds and high numbers of pelletizer knives resulted in particles with a narrow and small particle size distribution with a d 50 below 270 µm and aspect ratios close to 1. To omit protruding drug particles to ensure sufficient extrudate stretchability and allow for the smallest MPs, it was found that the d 90 of the embedded drug must be significantly below the extrudate diameter. Upon adapting the syringe diameter, the produced micropellets revealed similar injectability parameters to the marketed formulation, showcasing the potential that the proposed setup has for the manufacturing of novel microparticulate formulations., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)