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14 Pharmaceutical Technology ® Innovations in mRNA eBook April 2024 PharmTech.com Upstre am processing people, and each person receives two doses, a total of 15.4 billion doses or 4.5 million L of the vaccine is required. In perspective, 4.5 million L would fill two Olympic-sized swimming pools (2500 m3), whereas saRNA [self-amplifying RNA] vaccines, which we as- sume are 100-fold more potent, would only require 0.02 Olympic-sized swimming pools. Assuming that production costs, which account for materials, RNA, and LNP [lipid nanoparticles] production, scale lin- early, vaccinating the entire population with Pfizer/ BioNTech's mRNA vaccine would cost approximately 150 billion USD. In contrast, with saRNA, it would only cost approximately 1.5 billion USD" (4). GMP-grade products To help guarantee the safety, quality, and regulatory compliance of the final product, Dale Patterson, vice president and general manager, Thermo Fisher Sci- entific, says, "First, raw materials should be of high quality and meet established specifications. This in- cludes the use of pharmaceutical-grade chemicals, enzymes, and reagents that comply with relevant pharmacopeial standards. Suppliers should provide appropriate documentation, including certificates of analysis, transmissible spongiform encephalopathy agents (TSE) and Bovine Spongiform Encephalopa- thy (BSE) statements, etc. to demonstrate compliance with GMP requirements." Patterson also talks about transparency, traceability, and documentation being crucial for ensuring quality control and for meeting regulatory requirements. Containing costs "Implementing f lexible and modular manufacturing systems," says Patterson, "such as bead-based solid phase mRNA synthesis or biosynthesis of oligonucle- otides that can be easily scaled up or down to accom- modate varying production volumes is essential. This ensures efficient and cost-effective manufacturing while maintaining product quality and regulatory compliance," he avers. Melanie Cerullo, chief quality and regulatory of- ficer, ReciBioPharm, draws attention to infectious disease, where "you may need to scale up the manu- facturing process to very high levels as we saw with [COVID-19]. So, the challenge becomes how to make a lot of material most efficiently. We are currently working with [FDA] and MIT [the Massachusetts In- stitute of Technology] on a grant to develop a contin- uous mRNA-LNP manufacturing process to enable rapid scale up and manufacturing of large quantities of doses for this very reason." P a t t e r s on c ont i nue s , "a not he r s t r a t eg y i s t o le ver a ge autom at ion a nd proces s opt i m i z at ion tech nolog ies. T h i s i nc ludes t he u se of robot ics, machine learning, and artificial intelligence to au- tomate production tasks and improve process con- trol. Automation can reduce labor costs and min- imize the risk of human error, resulting in higher efficiency, consistency, and product qualit y." One ca n refer to a n ex plorat ion by F DA to pu rsue a n mRNA potential "platform pathway" for mRNA in the regulatory space. The concept gets complicated whether one is dealing with saRNA or circular RNA (circRNA), as handling and manufacturing aspects var y significantly. However, Cer ullo contends, "the most ef ficient way to make process improvements is to have good, standard workf lows for process development and manufacturing, evaluate and apply learnings from each time you r un the process (like a continuous improvement loop), and be mindful that some con- structs will behave differently and need individual- ized solutions." For its part, Pfizer found end-to-end automation for in vitro transcription reactions increases process t hroughput of m RNA vaccines and t herapeutics. Because of this, Pfizer is creating a spin-off team to further develop assays capable of automation. Karena Smith, senior associate scientist at Pfizer, said this "allows template-directed synthesis of mRNA mole- cule. Therefore, developing a method to understand how each component affects the process is incred- ibly valuable" (5). By using a high-performance liq- uid handler for automation, "Pfizer increased the reaction throughput eight-fold whilst achieving a ten-fold decrease in reaction scale." Smith contin- ued, saying, "the automated process saw less than a 10% difference in final concentration samples, and no differences in mRNA attributes when compared to a manual process." Better processes According to Cer ul lo, "most m RNA manufact ur- ing platforms for the drug substance are aqueous based and don't have organic solvent requirements … However, organic solvent is widely used for lipid New therapeutic uses for mRNA are now ramping up good manufacturing practice (GMP) demand, especially for clinical trial supply.