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In just four years, mRNA vaccines have saved millions of lives worldwide. Celebrated for their rapid development and manufacturing, these vaccines have proven over 90% effective against COVID-19. Yet, the potential of mRNA technology extends far beyond vaccines. It holds the promise of creating therapeutic proteins to replace missing or defective ones and enabling precise advanced gene editing with CRISPR-associated proteins.
But the technology is not without its hurdles. A major challenge is the need for ultra-cold storage, as at ambient temperatures liquid formulations of mRNA encapsulated within lipid nanoparticles (LNPs) are prone to degradation caused by hydrolysis and oxidation.
While ultra-cold storage (-80°C to -20°C) slows degradation, it requires costly equipment, continuous monitoring during transportation, and trained personnel.
The result? The life-saving vaccines have so far been primarily accessible to people in high-income countries. Additionally, ultra-cold storage contributes a significant carbon footprint which raises further considerations about its deployment at scale.
To bring mRNA vaccines and future therapeutics to the world, we need alternative formulations that don’t require ultra-cold storage, and the means to prepare them at scale.
Dry powder mRNA formulations
Dry powder formulations of mRNA present a viable solution. By enabling room temperature stability, they simplify storage and transportation, removing a significant barrier to access.
However, current methods for making dry powder formulations of mRNA, such as freeze-drying and spray-drying, may damage the LNPs and ultimately the sensitive mRNA molecules due to ice crystal formation, shear forces, and thermal exposure. And efforts to optimise formulations by modifying the lipid composition, incorporating stabilising excipients, and adjusting buffer pH, have so far only achieved limited success.
Injection vs. inhalation of mRNA therapeutics
Dry powder formulations not only facilitate global access, they also open up an alternative drug delivery route through inhalation to the lungs which can unlock improved protection against respiratory infections.
While injected vaccines primarily offer systemic immunity, protecting against severe disease, they do not induce sufficient mucosal immunity in the respiratory tract. This means that vaccinated individuals can still shed active viruses and spread the infection. Inhaled vaccines, on the other hand, offer enhanced protection by creating both systemic and mucosal immunity.
Pulmonary delivery of mRNA-LNPs is also promising for the treatment of lung diseases such as asthma, idiopathic pulmonary fibrosis, lung cancer, and various pulmonary infections.
However, successful pulmonary delivery poses another challenge. Deep lung deposition and optimal absorption requires particles with precise properties, including mass median aerodynamic diameters (MMAD) between 1 μm and 5 μm.
A gentle, fast and controlled process for making mRNA formulations
To address these needs, we’ve developed a novel vacuum-spray drying process for producing room-temperature stable dry powder formulations of mRNA therapeutics. The process is characterised by reduced shear stress, minimised ice crystal growth, and rapid drying of microscopic droplets and particles.
Our technology can be implemented at small and large volumes to support benchtop applications like personalised cancer vaccines and manufacturing at scale for mass vaccinations, with projected throughputs for benchtop and production systems shown below.
A - contents of a 10-dose vial of low-density dry powder for room temperature-stable reconstitution, B - rapid dissolution in water, and C - 10 doses ready for injection.
New possibilities for transportation and drug delivery
At the clinic, the dry powders can be reconstituted for injection. This provides a practical and versatile solution to distribute prophylactic vaccines, and future mRNA therapeutics, particularly in resource-limited settings.
Reconstituted formulations can also be delivered by means traditional nebulisers, which create an easily inhalable mist. However, nebulisation shares some of the limitations of established dry powder manufacturing methods, such as shear stresses that damage sensitive mRNA-LNP formulations. Moreover, as complex and therefore relatively high-cost devices, nebulisers may not be the first choice for single-use applications like vaccination.
In addition to being able to generate dry powders that can be reconstituted at the clinic, our technology also allows precise control over particle size, shape, and porosity. This opens up the possibility of creating mRNA-LNP powder formulations fit for direct delivery to the lung using low-cost dry powder inhalers.
Ultimately, this could make it possible for patients to non-invasively self-administer mRNA drugs without the need to travel to the clinic, transforming global access to mRNA vaccines and future therapeutics.
At TTP, we are dedicated to advancing healthcare by pioneering innovative drug delivery solutions that tackle critical global challenges. Leveraging the expertise of our multidisciplinary team of biologists and engineers, we develop novel, scalable technologies that redefine therapeutic possibilities and meet the diverse needs of patients worldwide.
