A Review on QbD-Driven Optimization of Lipid Nanoparticles for Oral Drug Delivery: From Framework to Formulation.

Oral administration is the most preferred route for drug delivery due to its convenience, non-invasiveness, and patient compliance. However, it is challenged by gastrointestinal barriers, enzymatic degradation, and first-pass metabolism, which reduce drug bioavailability. Lipid nanoparticles (LNPs), including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), offer a promising strategy to overcome these limitations by enhancing drug stability, permeability, and absorption. The Quality by Design (QbD) framework provides a systematic approach for LNP development to ensure consistent product quality. By promoting process understanding and control, QbD not only supports scientific formulation development but also enhances industrial scalability by reducing the experimental workload, shortening the development time, and lowering the production costs. This review highlights key QbD elements such as the quality target product profile (QTPP), critical quality attributes (CQAs), critical material attributes (CMAs), critical process parameters (CPPs), and design of experiments (DoE) and their roles in guiding formulation and process optimization. The effects of various CMAs and CPPs on the CQAs such as particle size, polydispersity index, encapsulation efficiency, zeta potential, and drug release are discussed. Furthermore, the in vitro, in vivo, and ex vivo performances of optimized LNPs were explored in detail. Overall, QbD offers a robust platform for the rational design and scalable production of high-quality lipid-based drug delivery systems for oral administration.