mRNA can deliver a range of therapeutic modalities. It can trigger a specific protein to act as a vaccine, replace a defective protein, or stimulate an anti-tumor response.
Each mRNA project requires unique formulation and storage considerations. Additionally, significant flammable materials are central to mRNA production, necessitating tailored containment and handling requirements.
Scalability
To achieve scalability, the mRNA manufacturing process must be optimized to increase yield, reduce production time, and minimize resource usage. This includes refining and streamlining each step of mRNA synthesis, purification, and formulation.
The scalability of mRNA manufacturing is crucial to its success as an accelerated platform for vaccines and gene therapies. It allows for rapid response to disease outbreaks and pandemics. It also enables the rapid development of new therapeutic approaches to address diseases with unmet needs. mRNA can deliver a range of functional proteins to cells, which can act as a vaccine, trigger an immune response, or replace a defective protein. Despite its early successes, however, mRNA technology has many challenges.
Large-scale mRNA production is challenging, and mRNA synthesis requires significant quantities of specialized raw materials. These include plasmid DNA (pDNA) with a T7, SP6, or T3 RNA polymerase promoter, a linearized mRNA sequence, a cofactor for the RNA polymerase, nucleotide triphosphates, and other reaction buffer components. Additionally, the mRNA needs to be purified from impurities and contaminants. This is challenging to achieve at the cGMP scale.
The mRNA production process requires large volumes of flammable material, requiring specific containment and handling measures that vary from project to project. This may necessitate a facility design that requires hazardous area classification and other design features, such as potential blast zones. This is a key issue that needs to be addressed by solutions providers. However, mRNA technology is well-suited for continuous processing at the microfluidic level and can use single-use technologies to streamline and de-risk the entire facility design process.
Cost-effectiveness
Achieving cost-effective production is an essential hurdle for the development of mRNA vaccines. Compared to monoclonal antibodies, mRNA manufacturing is more complex and requires more raw materials. The manufacturing process is also labor-intensive. It involves a lot of process optimization and screening for impurities to ensure the success of in vitro transcription (IVT). In addition, it requires specialized equipment for the purification and encapsulation of mRNA into LNPs.
As a result, the overall process costs are high. A key to lowering the cost of mRNA manufacturing is to reduce the number of process steps. For example, reducing the number of purification steps and implementing tangential flow filtration (TFF) could significantly lower processing costs. Replacing RNases with aqueous two-phase systems or precipitation could substantially reduce costs and require sterile filtration.
Despite the challenges, there is reason to be optimistic about mRNA’s potential as a vaccine platform.
Flexibility
Due to its relatively simple structure, mRNA can be manufactured continuously. This allows for high production rates and a modular supply chain. In addition, mRNA can be processed with various chemical modifiers to improve its stability and translation efficiency. This flexibility makes it ideal for both clinical trials and larger-scale patient doses.
Furthermore, the fact that mRNA is produced in a GMP facility eliminates time-consuming cloning and protein expression steps. This significantly reduces the total manufacturing time. It is also possible to switch to a new target in a short period with minimal process adaptations. This enables mRNA manufacturers to respond rapidly to pandemics and other public health emergencies.
Despite these advantages, the current mRNA manufacturing process could be more laborious and expensive. A new approach is needed to meet the demand for mRNA vaccines. It also provides a platform to enhance the quality of the final product and reduce costs by enabling automated controls and in-line analytics. In addition, the system will allow cost-effective purification strategies that do not require multiple chromatographic steps.
Safety
mRNA is a highly complex molecule that is sensitive to degradation. Its enzymatic synthesis and subsequent purification are critical processes. The mRNA must be free from double-stranded RNA, truncated mRNA, and residual DNA. The process requires special equipment designed to work with these large molecules. The mRNA must also be encapsulated into lipid nanoparticles (LNPs) to ensure stability. The resulting vaccines are typically administered orally and can target various diseases.
The relative simplicity of mRNA production makes it suitable for continuous processing, especially at the microfluidic scale. This enables efficient enzyme recycling and product recovery, and the use of expensive reagents can be minimized. New chromatographic operation modes, such as multimodal chromatography, could further reduce the number of purification steps.
The technology holds great promise for combating infectious diseases, including influenza and rabies. But mRNA vaccines still need to be validated in clinical trials, and more research is needed before they can be widely used. In addition, the current focus on cancer targets has limited the ability to compare mRNA vaccines against conventional vaccines.
