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PharmTech.com Innovations in mRNA eBook April 2024 Pharmaceutical Technology ® 13 CORONA BOREALIS - STOCK.ADOBE.COM The Making of mRNA Chris Spivey A tidal wave of questions floats the need for more upstream automation. S udden demand for large-scale manufacturing of messenger RNA (mRNA) drug substances during the COVID-19 pandemic has few par- allels in the history of pharmaceuticals. Some might posit penicillin production during World War II as an analog, or perhaps early insulin availability. Pan- demics and epidemics such as smallpox, typhus, cholera, influenza, HIV/AIDS, or the bubonic plague, all relied more on infection control for resolution than on manu- facturing capacity. New therapeutic uses for mRNA are now ramping up good manufacturing practice (GMP) demand, especially for clinical trial supply. Moderna collaborated with CARsgen Therapeutics to combine an mRNA therapeutic cancer vaccine with a solid tumor chimeric antigen receptor (CAR)-T cell ther- apy, aiming to treat multiple cancers (1). Pfizer part- nered with Beam therapeutics to co-develop mRNA and base editing approaches (2), while BioNTech and DualityBio have a partnership to develop differenti- ated antibody-drug conjugates, for solid tumors (3). In terms of upstream manufacturing for novel mRNA drug products, this technical complexity forms a tidal wave of question marks. Costs decrease while complexity rises A paper published in Molecular Pharmaceutics (4) exam- ined reducing complexity by evaluating what common process could be standardized through extrapolations of clinical trial complexity, based on four Phase I/II dose-ranging studies. While not the amounts of product required during the COVID-19 pandemic, clinical trial doses quickly mounted up in terms of both volume and manufacturing challenges related to techniques pur- sued, but also formulation delivery requirements. The authors state, "from the four studies, the aver- age mRNA usage was 5500 μg and for the 75 trials in 2021, 412 500 μg of RNA would need to be formulated, purified, sterile filtered, and fill-finished. At concen- trations of 100 to 200 μg of mRNA per mL, this would amount to 2063 to 4125 mL of drug product" (4). As an interesting foray into possible future manufacturing, the authors went on to contrast traditional mRNA with a self-amplifying method. Often, this is cited as potentially a 100 to 1 decrease in required finished product due to higher potency performances, but this study chose a picturesque perspective, saying, "as- suming the entire population consists of 7.7 billion