Scaling up nanoformulation manufacturing: A multi–case study linking target product profiles, critical quality attributes, and quality by design

Abstract

Nanoformulation platforms have transformed drug delivery; however, reliable scale-up from laboratory to manufacturing remains the principal barrier to clinical translation. This review integrates target product profile (TPP)–driven requirements with critical quality attributes (CQAs), platform-specific unit operations, and Quality by Design (QbD) principles to analyze scalable manufacturing of five major nanoformulation classes—lipid/liposome, polymeric/micellar, nanoemulsion, nanocrystal, and albumin/biopolymer systems—which collectively represent over 80 % of clinically approved nanomedicines. Quantitative analysis across these platforms demonstrates that controlled micromixing and solvent displacement routinely yield lipid and polymeric nanoparticles in the 50–200 nm range, while energy density–constrained high-pressure homogenization governs droplet size distributions in nanoemulsions, and stress intensity and stabilizer adsorption dictate nanocrystal quality. Protein-based carriers are shown to be particularly sensitive to raw-material variability and crosslinking kinetics. Five industrial case studies (Doxil®/CAELYX®, Onpattro®, Comirnaty®, Abraxane®, and AmBisome®) illustrate how orthogonal analytics (e.g., DLS and AF4–MALS), closed single-use architectures, and digitally enabled QbD–PAT frameworks link critical process parameters (CPPs) to robust control strategies across development and commercial manufacture. Overall, the review highlights standardization, quantitative comparability, and data-driven control as central enablers of scalable and regulatory-ready nanomedicine manufacturing.