Earlier this year, Lonza entered into a strategic collaboration with Germany-based biotech Ethris to develop room-temperature stable, spray-dried formulations of mRNA-based vaccine candidates designed for mucosal delivery.
Room-temperature stability aims to address the supply chain challenges associated with mRNA vaccines, including a dependence on ultra-low-temperature storage and complex delivery systems. Overcoming these challenges will simplify production, reduce costs, and support rapid, scalable vaccine development, according to Kim Shepard, Director of Advanced Drug Delivery at Lonza, as well as pave the way for needle-free nasal administration and mucosal immunity. We spoke to Shepard to find out more about the challenges and benefits of spray drying, and how it compares with other techniques.
What are the main technical challenges faced when developing a spray-drying process for mRNA-based therapies?
Producing spray-dried mRNA vaccines presents several challenges, primarily related to the stability of mRNA and the need for effective encapsulation in lipid nanoparticles (LNPs). As a result, the manufacturing process must be precisely controlled to produce consistent and high-quality vaccine particles.
For an mRNA-LNP dry powder for intranasal delivery, a unique set of quality attributes needs to be achieved for a successful product. The integrity and activity of the mRNA itself must be preserved, as well as its encapsulation efficiency within the LNPs. The size of the LNPs must also remain the same to enable effective transfection into cells. To achieve effective delivery to the respiratory tract, particle engineering is also crucial. For intranasal delivery, particles with a median size of ~20µm are targeted, while simultaneously reducing fine particles which could travel into the lung. A fine balance of formulation and process approaches must be considered to preserve the mRNA and LNPs while enabling sufficient drying and particle engineering to achieve a high-quality powder.
The goal for a spray-dried mRNA product is to achieve shelf stability at ambient or refrigerated temperatures, eliminating the need for frozen or ultra-cold storage. To support this, the chosen excipients must ensure appropriate shelf stability. Additionally, the formulation should be robust enough to withstand brief exposures to temperatures of 40 or 50°C, reflecting the practicalities of global vaccine distribution. Most formulations will require storage with desiccants or packaging in low-humidity environments to maintain their integrity.
How does spray drying compare to other formulation and delivery techniques for mRNA therapeutics?
Compared with other formulation techniques, spray drying offers significant advantages in terms of stability and delivery efficiency for mRNA therapeutics. While vehicles like LNPs or polymeric nanoparticles are effective for mRNA delivery, their liquid or frozen forms often demand complex manufacturing and costly ultra-low-temperature storage. Spray drying transforms these formulations into powders that are potentially stable at higher temperatures (refrigerated or even room temperature), thereby simplifying the supply chain.
Recent advancements in lyophilization processes have significantly improved the solid-phase stabilization of mRNA LNPs, and the process is particularly beneficial when the primary objective is to reconstitute and inject the mRNA LNPs. However, for delivery routes that require particle engineering, such as respiratory delivery, spray drying is the preferred method, even with the scalability challenges it presents.
While LNPs are efficient at protecting mRNA and facilitating cellular entry, the spray drying process itself must be carefully optimized to preserve the integrity and potency of both the mRNA and its delivery vehicle against thermal and shear stress. The resulting powder form also opens possibilities for needle-free administration routes, such as nasal delivery, though this requires further development in particle engineering.
What regulatory considerations are most pressing when working with spray-dried mRNA formulations?
A main regulatory consideration for spray-dried mRNA formulations is the ability to demonstrate that the manufacturing process reliably produces a product of consistent quality, without compromising the integrity or function of its critical components. Regulators take a close look at data to ensure that the inherent stresses of spray drying do not degrade the mRNA molecule or negatively alter the structure, size, and encapsulation efficiency of its delivery vehicle, such as LNPs. This necessitates extensive stability indicating, analytical characterization, robust process validation identifying critical parameters, and stringent control over the final powder's attributes, including particle size distribution and, crucially, residual moisture content, which directly impacts stability.
In addition to these considerations, the preservation of potency and the integrity of spray dried mRNA products post device delivery should be demonstrated. Furthermore, the safety, compatibility, and necessity of any excipients added to protect the formulation during drying must be thoroughly justified and their impact assessed.
While there is no specific regulatory guidance for inhaled RNA products, the scientific community for inhaled medicine continues to advocate for such guidance. In lieu of specific regulatory guidance, companies create their internal specifications based on development data generated for the drug product.
What are the unique manufacturing or scale-up considerations when compared to more conventional biologics?
Manufacturing spray-dried mRNA in LNPs involves distinct technical hurdles compared to conventional biologics such as peptides or proteins. Due to the nanostructured nature of the mRNA inside the LNP, there is an additional “layer” of quality attributes that need to be considered: both the mRNA activity and integrity, as well as the encapsulation efficiency and nanoparticle size of the LNPs, are critical. Both the mRNA and the LNPs can be sensitive to the shear and drying stresses encountered during the spray drying process, requiring specific excipient strategies for stabilization.
Additionally, in the upstream of the spray dryer, the LNP manufacturing process involves unique mixing and scale-up challenges to properly encapsulate the mRNA.
Do you see spray-drying becoming a broader platform capability across the mRNA field, or is it more suited to particular therapeutic categories, such as respiratory delivery?
Spray drying of mRNA can be particularly advantageous when particle engineering is required. Additionally, inhaled dry powders are not required to be sterile, in contrast with injectable products. For indications where sterility is a requirement, an aseptic spray drying process would need to be designed. As a result, this process is experiencing an uptick across the pharmaceutical industry due to increased demand for mRNA therapeutics. These advancements enable us to streamline the supply chain and enhance the stability and delivery efficiency of mRNA therapeutics.
Read our interview with Carsten Rudolph, Co-founder and Chief Executive Officer of Ethris, to learn more about this partnership.
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