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A variety of strategies for producing high-quality nanoparticles have been reported in recent years. Batch-based bottom-up and top-down technologies are generally the most efficient methods, but present a number of challenges, particularly in terms of variability, safety, sustainability and large-scale production. In this study, a scalable, semi-continuous production line was built by connecting individual processing units, including a high shear mixing device, the Microfluidizer® technology and a cooling system. Each unit was equipped with an adequate temperature control to allow solvent-free production of solid lipid nanoparticles (consisting of Precirol® ATO 5 or Gelucire® 43/01) and nanostructured lipid carriers (additionally comprising Labrafac™ lipophile WL 1349). Subsequently, critical formulation parameters and critical process parameters (CPPs) of the individual processing units and their effects on particle size (i.e., critical quality attribute (CQA)) were investigated to identify appropriate input parameters for the subsequent Design of Experiment (DoE) studies conducted after linking the process units to a semi-continuous production line. For particle size monitoring, spatially resolved dynamic light scattering (SR-DLS) measurements were conducted and compared to standard DLS measurements to evaluate the applicability of SR-DLS as an inline monitoring tool. It was found that matrix composition, emulsifier concentration, pressure and number of cycles when processing through Microfluidizer® processor were the most influencing parameters. By optimizing these parameters, five-times higher throughputs could be achieved by the semi-continuous manufacturing line. In addition, the particle size measurements with SR-DLS confirmed the feasibility of implementing this technology for real-time particle size monitoring as an important safety factor in quality control., Competing Interests: Declaration of competing interest The authors confirm that they do not have any relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)