Dry powder inhaled formulations of small molecule drugs are a mainstay of treatment for respiratory diseases such as asthma and COPD, and it’s a field where we have extensive experience here at Lonza. In the past few years, we’ve also done a lot of work on the spray-drying of protein therapeutics , and have successfully created dry powders for inhalation from these complex biologics. But what about RNA molecules? These became familiar during the Covid pandemic, with both the Moderna and Pfizer vaccines being mRNA-based. Might it be possible to make inhaled versions of these, too?
A spray-dried formulation that could be administered via pulmonary or nasal dry powder inhaler (DPI) would offer multiple advantages. The mRNA Covid vaccines required ultra-low temperature storage and distribution, which posed logistical challenges, but a DPI alternative could be stable at room temperature. A nasal formulation would be far less invasive than traditional vaccine delivery via injection, and could achieve a mucosal immune response. Virus transmission might be reduced by generating mucosal immunity at the site of viral entry.
Lipid challenges
The mRNA is formulated as lipid nanoparticles, with the RNA protected by a full encapsulation in a lipid matrix. But this poses a challenge for creating the particles required for nasal delivery – the lipid coating is liable to melt at high temperature, and the mRNA is also temperature-sensitive. Yet spray drying requires high temperatures.
The lipid is key to the ability of the mRNA to enter cells, and it’s vital that after spray drying the mRNA is still completely encapsulated by the lipid mix. It may seem counterintuitive to spray dry something that is so sensitive to temperature. But with our previous experience spray drying delicate proteins, we believed it could be possible.
So how can lipid nanoparticles be spray dried without damaging them? Evaporative cooling is the “magic" that makes it possible. While the temperature of the dryer outlet might be 50°C and the inlet gas 100°C, in reality the actual temperature experienced by the droplets that solidify into particles rarely goes above 40°C. We even experimented by further reducing the outlet temperature, and found we could still make a dry stable powder from the mRNA solution, rather than leaving an expensive puddle of API in the bottom of the spray dryer.
Maintaining the re-dispersibility of the powder is a challenge, and we have put a lot of effort in here. As well as keeping the mRNA intact and encapsulated, the lipid nanoparticles must remain about the same size, albeit embedded within a matrix of a sugar-based excipient in larger spray-dried particles. The size of these particles must be carefully controlled to ensure they are neither too big nor too small for effective inhaled or mucosal delivery. Optimising the LNP/matrix ratio is also important; the higher the loading, the more likely it is that the LNPs will agglomerate permanently, negatively affecting their activity. The composition of the LNP appears to matter, too.
There is a complex interplay between the formulation of the mRNA LNPs and the spray-dried particles. The structural integrity of an LNP depends on the spatial arrangement of its lipids. The formulation must be carefully designed to ensure the various lipids in the composition remain stable at the spray dryer’s outlet temperature, preventing the mRNA cargo from leaking out. But if the LNPs are too fluid, they will aggregate as they dry.
Test runs
We will always look to work with very small quantities at the outset, checking how it behaves in different situations before committing to the full process. For example, if the mRNA LNPs can’t survive the inlet nozzle that turns the solution into droplets, that is a problem we have to solve. This type of pre-feasibility stress testing is, obviously, not a replacement for doing test spray drying runs, but it is an important way to ensure precious, expensive material is not wasted on futile experiments.
For pulmonary or intranasal delivery, powders do not need to be sterile, merely manufactured under low bioburden conditions. With an eye toward future sterile applications of this technology, Lonza’s R&D team is now working on aseptic spray drying prototypes, which might be cost-competitive with lyophilization, and scalable to large manufacturing processes.
It sounds surprising that it is possible to spray dry such complex and fragile molecules. But we believe spray-dried formulations like this can offer significant benefits to patients. It could enable portable, shelf-stable mRNA-based products to be created, which would simplify product supply chains and storage. And, of course, inhaled medicines and vaccines are far less invasive for patients. The concept has so many advantages that we believe the effort we are putting into spray-drying mRNA LNPs is incredibly worthwhile.
