Integrating Quality by Design and Design of Experiments for Scalable Nanoparticle Therapeutics: A Comprehensive Review

Abstract

Nanoparticle-based drug delivery systems have tremendous advantages over the conventional dosage forms in terms of enhancing bioavailability, controlled release and tissue-specific targeting. However, despite great success at laboratory scale, the translation and commercialization of nanomedicines is still limited, mainly due to the inherent complexity of nanosystems, variability of the manufacturing processes and lack of globally unified regulatory frameworks. Integrating quality by design (QbD) with design of experiments (DoE) offers a scientific process for filling these gaps with more comprehensive formulation and understanding of processes. This review outlines QbD driven methodologies employed in the development of nanoparticles with a focus on the systematic determination of the quality target product profile (QTPP), critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs). The usefulness of DoEin screening and optimization methodology and multifactorial variables of formulation types is reviewed as a tool to derive robust design spaces and promote and provide predictive activity of nanoparticles such as particle size, polydispersity, drug loading, release kinetics, stability, etc. Updated knowledge about globally approved nanotechnology-based products is in the light of the rising clinical and regulatory acceptance of nanomedicine through various agencies. Additionally, the review summarizes key issues involving industrial implementation; from analytical limitations and barriers to the realization of the process on industrial scale, to stability issues and long-term safety evaluation; and emerging strategies including real-time monitoring, automation and advanced process control. By integrating QbD with DoE, industries can develop reproducible, efficient and scalable production processes for manufacturing nanoparticles.