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PharmTech.com Innovations in mRNA eBook April 2024 Pharmaceutical Technology ® 11 Manufacturing tic potency," he explains. In addition, he comments that aggregation of LNPs during the reconstitution process af ter lyophi lization is anot her cha l lenge for lyophilized mRNA products. Pironti recommends using long freeze-drying cy- cles to prevent any damage to the LNPs within the for mu lat ion t hat cou ld under m i ne per for ma nce and stabilit y. Ethris has, Dohmen says, optimized it s produc t desig n a nd lyoph i l i zat ion process to account for these factors and improve the potency of the resulting product as well as a reconstitution process that prevents aggregation from occurring. Using mild conditions One approach for overcoming lyophilization chal- lenges t h at i s not appropr iate, wa r n s P i ront i, i s modification of the mRNA structure, as that would change the nature of the treatment and potentially undermine the efficacy of the finished therapy, she states. T he most i mpor t a nt st rateg y is to en su re t he chosen lyophilization process is as mild as possible, which requires accurate study of each freeze-drying phase to gain in-depth process knowledge and under- standing. "While an accelerated method might save time, the risk of damage to the formulated mRNA product is much greater," Pironti concludes. New formulation approaches In addition to mild conditions, formulation devel- opment i s essent ia l to est abl i sh i ng a n ef fec t ive lyophilization process for mRNA products. For in- stance, Pironti points out that the ionic strength of the chosen buffer can have a significant impact on the resulting cake post-lyophilization, potentially leading to better stability and easier reconstitution. She also notes that the concentration of the mRNA formulation pre-lyophilization can also affect the overa l l f reeze-dr ying process, whi le use of an ap- propriate surfactant may address challenges with respect to LNP aggregation. Increasing user friendliness Lyophilization does more than increase the stabil- it y of mRNA-LNP products for simpler storage and distribution. It also, obser ves Dohmen, is the next step toward user-friendly dr ug products that phy- sicians and patients can use without any concerns about stabi l it y a nd potent ia l agg regates. "As we design f uture m RNA medicines, especia lly those for ch ron ic condit ions t hat w i l l be adm in istered on a reg ular basis, optimizing for stabilit y in the hands of physicians and patients and reducing the potential for an immune reaction is of utmost im- portance," he states. CDMOs have a role to play Lyophilization technology in general has advanced in recent years, with improvements in automation, such as automated loading and unloading, which according to Pironti has significantly reduced the time required for manufacture and filling of mRNA products. Automated un loading is impor tant for these materials, because even post-lyophilization, mRNA formulations remain sensitive to tempera- ture. "By automating and accelerating unloading, Formulating for delivery to the lungs For its inhaled messenger RNA–lipid nanoparticles (mRNA-LNP) mRNA-LNP candidate, ETH47, for the treatment and prophylaxis of respiratory viral infections such as influenza and COVID-19, which is being investigated in a Phase I trial in the United Kingdom, Ethris faced additional challenges to optimizing the final formulation. "Delivery to the respiratory tract via an inhaled route of administration presents added challenges because it involves nebulization of the product, which induces additional stress to the formulation and can lead to LNP aggregation," Christian Dohmen, executive director, technology development & CMC with Ethris, explains. The company developed two strategies to reduce product deterioration and optimize the potency of lyophilized mRNA products, according to Dohmen. The first was to use a lipidoid rather than a traditional cationic lipid as the basis for LNP generation to obtain more tightly packed particles and package twice the amount of mRNA with the same amount of lipids. Lipidoid LNPs are, in addition, more stable than traditional LNPs, such as those used in commercial COVID-19 vaccines, Dohmen says. The second strategy was to further increase the stability of its final product formulation by adding a proprietary stabilizing excipient. The combination of these two solutions results in lyophilized mRNA products that exhibit "exceptional" stability of six months at room temperature, according to Dohmen. In addition, the drug product based on ETH47 can be nebulized for inhaled delivery to the respiratory tract without aggregation of the product. Dohmen also emphasizes that the advances it has applied to enable robust lyophilization and increased mRNA product stability during storage can be used to improve mRNA beyond only those designed for inhaled delivery. "This technology has broad application for the optimization of many different types of mRNA vaccines and therapeutics," he stresses.