Quality by Design in nanotechnology applied to cosmetics: A systematic review from conception to production

The cosmetic industry is experiencing a shift from traditional beautification to multifunctional products that combine aesthetics with scientifically validated skin health benefits. Among these advancements, nanotechnology enables improved penetration, stability and targeted delivery of active ingredients, but introduces new challenges for quality, safety and regulatory compliance. Within the European Union, these products fall under the scope of European Regulation (EC) No. 1223/2009 of the European Parliament and of the Council, which sets specific requirements for cosmetics containing nanomaterials. 1 The increased complexity and potential safety concerns of these products highlight the relevance of applying Quality by Design (QbD) principles to ensure robust formulation development, process control and regulatory alignment. However, in the healthcare products sector, QbD was officially proposed only for drug development. 2 Therefore, this systematic review, of 52 original articles selected based on predefined inclusion and exclusion criteria, focusing on studies addressing QbD principles, nanotechnology, and cosmetic applications while excluding reviews, toxicology, analytical-only, or marketing-oriented studies, aimed to analyse the current and potential application of the QbD approach in nanotechnology-based cosmetics and cosmeceuticals. Potential Critical Quality Attributes (CQA), Critical Material Attributes (CMA) and Critical Process Parameters (CPP) are identified across the product lifecycle. A certain emphasis is given to the role of Design of Experiments (DoE) in optimizing multifactorial interactions and to the underexplored integration of advanced process control strategies, such as Process Analytical Technology (PAT), Continuous Manufacturing (CM) and Real-Time Release Testing (RTRT), into nanocosmetic development. The analysis reveals that Particle size was the most identified CQA, found in 94.2% of the articles (n=49), followed by Polydispersity Index (PDI) in 76.9% (n=40) and Zeta potential in 75% (n=39) of the analysed sample of articles. Regarding CMAs, surfactant concentration and/or type was the most prevalent, reported in 46.1% (n=24), while for CPPs, the most frequent was sonication time, identified in 15.4% (n=8) of the articles. The results analysis further concluded that while QbD adoption in this field is still developing, its systematic application, combined with emerging manufacturing technologies, can connect the gap between laboratory-scale innovation and industrial-scale production, ultimately enabling safer, more effective and consumer-driven nanocosmetic products.