Quality-by-design in the scale-up of lipid-based nanocarrier formulations: a review

Lipid-based nanocarriers have emerged as versatile delivery systems for drugs, vaccines, and cosmetic formulations. However, their large-scale production is often hindered by challenges related to reproducibility, stability, and regulatory compliance, highlighting the need for systematic, science-based development strategies. The quality-by-design (QbD) approach provides a structured framework for developing robust, reproducible, and high-quality formulations through the definition of quality target product profiles, identification of critical quality attributes, material attributes, process parameters, and the application of tools such as design of experiments, design space, and process analytical technology (PAT). This review summarises the current state of the art in the application of QbD to the scale-up of lipid-based nanocarrier formulations, including lipid nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, liposomes, cubosomes and oil-in-water nanoemulsions. Recent studies demonstrate that the QbD can improve formulation reproducibility and identify key factors influencing successful scale-up. Nevertheless, significant limitations remain, as most reports focus on laboratory-scale optimisation, while scale-up is frequently addressed empirically and with incomplete reporting of process parameters. Studies describing scale-up strategies without the implementation of QbD are also discussed to provide a broader perspective. Future progress will require industrially relevant studies that fully integrate artificial intelligence and machine learning with QbD and PAT principles throughout the entire manufacturing process, enabling the safe, reproducible and scalable production of lipid-based nanocarrier formulations.