20 years of flash nanoprecipitation – from controlled precipitation to global medicine

In the twenty years since the development of Flash NanoPrecipitation (FNP) technology, an antisolvent precipitation technique that uses rapid turbulent mixing to drive self-assembly of polymeric or lipid nanoparticles, the platform has been used for a wide variety of drug delivery applications in research and industry – most notably as the enabling technology for the global manufacture of the Pfizer-BioNTech COMIRNATY® mRNA lipid nanoparticle vaccine against SARS-CoV-2. Importantly, this makes FNP the only publicly-known manufacturing technology for global commercial-scale lipid nanoparticle formulation. This situation makes the technique remarkable and noteworthy and worth discussing broadly, which this article aims to do. It also sets FNP mixing as the benchmark technology against which other LNP manufacturing processes should be compared. Here we review the principles underpinning this continuous antisolvent precipitation technique, its scalability and use with downstream unit operations, and its utility in nanomedicine research. We discuss the current intellectual property landscape surrounding FNP technology and give examples of its industrial implementation for SARS-CoV-2 and low-cost antimalarial formulations. We end with a survey on recent improvements and extensions to the platform that enable the encapsulation of new classes of molecules and greater flexibility in manufacturing as FNP moves into its third decade.