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52 Pharmaceutical Technology ® The Real Message Behind Commercial mRNA Products April eBook 2023 PharmTech.com Stabilit y stabilize mRNA against pH-mediated degradation would, furthermore, likely be hazardous chemicals. The key to successful LNP production, therefore, is minimization of the time required for the LNP manu- facturing process. That, Cobaugh emphasizes, requires extensive understanding of the process from a quali- ty-by-design basis combined with thorough process val- idation. "It is absolutely essential to have a deep aware- ness of what levers can be pulled from both process and engineering perspectives to minimize the time for all aspects of the formulation process," he states. Rapid fill/finish important too With respect to fill/finish of mRNA therapeutics and vaccines, the strategy is generally no different than that of any other biological API, according to Mochayedi. The goal, agrees Cobaugh, is to fill the product—whether drug substance in sterile single-use plastic bags and containers or formulated drug product into sterile glass vials—and then freeze them as rapidly as possible but in a controlled manner. In this case, the challenges are largely engineering and equipment-related. Maintaining the cold chain For storage and shipment of mRNA, the requirement to maintain the cold chain to ensure its stability and integ- rity all the way to the patient is of utmost importance, Mochayedi says. "Central storage is usually performed at very low temperatures (-80 °C). Similarly, formula- tions containing nucleotides require shipment at low temperatures, which is typically achieved using dry-ice packaging," he notes. In some cases, mRNA drug prod- ucts may require the addition of a cryoprotectant to pro- tect the particles. The adjustment of excipients to protect the nanoparticles may also enable some formulations to be shipped at approximately 4 °C. Looking to lyophilization The production of m RNA-LNP formulations t hat are stable at warmer temperatures is a key focus of developers of candidate therapeutics and vaccines. One approach noted by Cobaugh involves the devel- opment of higher-quality DNA templates that are free of breaks (commonly referred to as nicks) that result in the shorter, more unstable mRNA sequences. Mo- chayedi points to new types of modified nucleotides and new capping technologies to physically altered forms of mRNA, such as circular RNA. "These new approaches may overcome some of the stability is- sues and enable a broader application of mRNA as a technology platform," he believes. Lyophilization of mRNA products as an alternative to freezing is the other main area of investigation. "Theoretically, there is no reason why freeze-dried mRNA products cannot be stored at room temperature as long as water is kept out of the storage containers," Cobaugh says. He notes that there has been prelim- inary success in this area and he is hopeful that lyo- philization will be applicable for mRNA products in the not-too-distant future. Mochayedi agrees, noting that significant investiga- tions into formulation optimizations to overcome the ultra-low temperature requirements of mRNA drug products during shipment and storage are underway across the industry, with lyophilization of formulated mRNA-LNPs as an extremely promising alternative for liquid-based products. "The complete drying of formu- lations afforded by freeze-drying would unlock the pos- sibility of much more easily providing mRNA therapeu- tics in countries with higher temperatures," he remarks. Editor's Note: This article was originally published in Pharmaceutical Technology's December 2022 issue. ■ Agilent ..................................................................................................... 31 BioVectra ................................................................................................. 53 Catalent ..................................................................................................... 7 Charles River ........................................................................................... 27 Curia .......................................................................................................... 3 Emergent ................................................................................................. 23 etherna .................................................................................................... 35 Recipharm ................................................................................................. 5 Thermo Fisher Scientific ........................................................................ 15 TriLink ....................................................................................................... 19 Ad Index COMPANY PAGE COMPANY PAGE