Messenger RNA (mRNA) carries genetic instructions from DNA to a cell’s protein-making machinery, dictating protein production. mRNA manufacturers scale up production and advance the technology, translating scientific discoveries into medical applications.
Leading Companies in mRNA Production
The landscape of mRNA manufacturing includes both pharmaceutical companies that develop and produce their own mRNA products and contract manufacturing organizations (CMOs) that specialize in producing mRNA for other entities. Moderna and BioNTech are widely recognized for their pioneering efforts and significant production capacities, especially during the COVID-19 pandemic with their respective vaccines. CureVac is another prominent biotechnology company engineering mRNA for various candidates, including influenza vaccines which are in phase 2 trials.
Beyond these well-known developers, several CMOs play a substantial role in the mRNA production ecosystem. Lonza Group offers services including process development, analytical support, and large-scale manufacturing. Catalent has invested to enhance its mRNA capabilities, focusing on lipid nanoparticle (LNP) delivery systems, crucial for mRNA stability and delivery. Thermo Fisher Scientific provides services across the mRNA production pipeline, from custom synthesis to scalable manufacturing processes. Other contributors in the contract manufacturing domain include Curia, Merck, Aldevron, and ST Pharm.
The mRNA Manufacturing Journey
The manufacturing of mRNA is a multi-step process that begins with a DNA template. The target gene sequence is identified, optimized, and inserted into a plasmid DNA (pDNA) to serve as the template for mRNA synthesis. This pDNA is amplified in host bacteria, typically E. coli, within single-use fermenters to produce sufficient quantities, followed by purification and linearization using restriction enzymes.
The next step is in vitro transcription (IVT), where mRNA is synthesized from the linearized DNA template. This enzymatic reaction uses RNA polymerase and nucleoside triphosphates (NTPs) to create the mRNA molecule.
After transcription, the newly synthesized mRNA undergoes purification to remove impurities. This purification involves chromatography and filtration techniques to achieve high purity.
Following purification, the mRNA is capped to protect it from degradation and enhance its translation within cells. The purified mRNA is then encapsulated, commonly into lipid nanoparticles (LNPs), which serve as a protective delivery vehicle, safeguarding the mRNA from degradation and facilitating its entry into target cells. The final stages involve formulation, sterile filtration, and aseptic filling into vials, followed by quality control checks and storage at ultra-low temperatures to ensure product stability.
Beyond Vaccines: Diverse Applications
While mRNA technology gained widespread recognition through its use in vaccines, its potential applications extend into other therapeutic areas. In cancer treatment, mRNA is explored for personalized immunotherapies, stimulating the immune system to target cancer cells via tumor-specific antigens. mRNA therapies are also being investigated for genetic disorders, offering a safer alternative to traditional gene therapy by providing transient protein expression without the risk of integrating genetic material into the host genome.
For conditions like cystic fibrosis, mRNA can instruct cells to produce functional proteins that are otherwise missing or dysfunctional. mRNA technology shows promise in regenerative medicine, promoting tissue repair and regeneration in conditions such as heart disease by encoding proteins that stimulate tissue growth. The versatility of mRNA also extends to gene editing, where it can deliver gene-editing tools, and to protein replacement therapies for a wide range of diseases where patients lack specific functional proteins.
Innovations Driving mRNA Production
Manufacturers are continuously pursuing advancements to enhance the efficiency, scalability, and stability of mRNA production. Optimizing IVT reaction conditions improves mRNA yield and quality. Advancements in IVT enzymes also lead to higher transcription efficiency and yield. Novel purification techniques streamline the downstream process. Membrane chromatography, for instance, offers a faster, more scalable alternative to traditional methods, reducing processing time while maintaining high purity.
Continuous manufacturing processes, where raw materials are continuously fed and products are continuously removed, are being explored to increase efficiency, reduce labor, and accelerate production. This integrated approach can link various stages, from IVT to LNP encapsulation, potentially leading to automated production facilities. These innovations aim to address challenges like cost reduction, improved mRNA stability, and faster development and manufacturing timelines.