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12 Pharmaceutical Technology ® Innovations in mRNA eBook April 2024 PharmTech.com Manufacturing it is possible to minimize the risk of formulations being exposed to temperatures that are impactf ul on final stability," Pironti says. T he advances in lyoph i lization tech nolog y are being leveraged by contract development and manu- facturing organizations (CDMOs), particularly those invested in acquiring relevant experience in t he production and handling of mRNA therapies and vaccines, Pironti adds. "CDMOs with this expertise have the knowledge and infrastructure to support pharmaceutical companies in accessing advances in lyophilization so they can harness it in a well-struc- tured way to support the efficient commercializa- tion of their mRNA products when they reach this stage," Pironti contends. The most successful CDMOs, according to Pironti, have deep knowledge of their mRNA manufacturing platforms, allowing the development of effective lyo cycles and identification of optimal formulations based on approaches t hat are wel l-k nown and a l- ready established. Pironti also stresses the importance of working with an expert CDMO with experience in mRNA pro- cess and formulation development and manufactur- ing and the infrastructure for both lyophilization and subsequent sterile fill/finish activities. "Part- nering with such CDMOs allows mRNA vaccine and therapy developers to benefit from existing knowl- edge about effective approaches, streamlining the development journey and eliminating the need to reinvent the wheel," she observes. Best tip for success: address lyophilization early in development T he development of opt i m a l lyoph i l i z at ion pro- cesses takes time for even the simplest molecules. For complex mRNA-LNP products, it can be longer still. The lyophilization process itself also takes time, a nd a s ment ioned above, longer, a nd m i lder ap- proaches are best for sensitive mRNA formulations. Consequently, Pironti suggests that if a pharma- ceutical company has a very short window in which to pass the mRNA candidate from early development into the clinic, it might be necessar y to avoid lyo- philization at the clinical manufacturing stage to accelerate the route to the clinic. However, Pironti believes that the earlier lyophilization is considered in the mRNA-LNP formulation development journey, the easier it will be to create an effective process that affords the maximum stability and simplified stor- age capabilities offer by lyophilization. Significant advance for the mRNA field Lyophilization is a great step toward further advanc- ing the mRNA field, according to Dohmen, and he is excited to to see lyophilized products reaching a nd adva nci ng t h rough cl i n ica l development to commercialization. "In the end, we need more us- er-friendly drugs, especially if mRNA technology is to find use beyond vaccines," he says. For Pironti, the stabilit y af forded by lyophiliza- tion has clear benefits for mRNA vaccines designed to tack le f ut ure pa ndem ics, pa r t icula rly when it comes to logistics. "A lyophilized product can sim- plif y logistics in a scenario where vast numbers of doses of vaccine need to be manufactured and dis- tributed across the globe, as there is no need for spe- cial cold-chain transport or storage," she comments. Scalability and cost of goods are two issues that still must be addressed, however, especially when thinking about vaccines where many doses are re- quired, according to Dohmen. "The abilit y of lyo- philization to improve access to mRNA vaccines in developing countries by removing the cold-storage requirements will only be realized if the vaccines are affordable as well," he explains. Finally, Payne notes that now that global mRNA vaccines have been commercialized, the stabilit y of mRNA products is going to be highly scrutinized going for ward. "As therapeutic candidates for per- sonalized treatments and vaccines for widely spread viral infections advance through the clinic along with mRNA products formulated for many dif fer- ent delivery routes, such as nebulized or aerosolized powders, regulatory agencies will be looking closely at their safety and efficacy, which are both directly impacted by stability. Robust, repeatable lyophiliza- tion processes will become increasingly important as a result," he concludes. Reference 1. Arcturus Therapeutics. Japan's Ministry of Health, Labour and Welfare Approves CSL and Arcturus Therapeutics' ARCT-154, t he First Self-Amplif y- ing mRNA Vaccine Approved for COVID in Adults. Press Release, Nov. 28, 2023. ■ The development of optimal lyophilization processes takes time for even the simplest molecules. For complex mRNA-LNP products, it can be longer still.