Contract development and manufacturing organizations (CDMOs) provide pharmaceutical companies critical support throughout drug development. They help to shorten timelines, enhance quality and ensure regulatory compliance. However, not all CDMOs offer the same level of service. The right CDMO can significantly impact the success of an mRNA vaccine or therapeutic program.
For mRNA drug makers, any disruption in the supply chain can lead to costly setbacks that threaten to delay production, creating bottlenecks and long lead times for clinical trials and patient treatments. A CDMO’s integrated bundled services, including plasmids, mRNA manufacturing and LNP formulation, deliver efficiencies that can help smaller, emerging companies gain a competitive advantage with cost savings and reduced risk. Leg Exerciser Machine
The mRNA manufacturing process requires specialized, GMP-grade materials. Many suppliers of raw mRNA material loosely use the term “GMP grade” to imply their products meet consensus standards, but this claim is often inaccurate. It is important to ensure mRNA platform material meets strict requirements that include: By working with a CDMO early in development, developers can ensure they have cGMP-compliant single-use equipment on hand for manufacturing at the appropriate scale and support from a team of experienced scientists to develop and validate their processes. Streamlining these activities with the same CDMO throughout development and clinical trial manufacturing can reduce costs by eliminating transfer fees. Additionally, early testing of platform materials in water runs can de-risk the overall process by identifying potential issues and enabling documentation to be redlined and finalized well ahead of manufacturing runs. This accelerates technology transfer and allows projects to be moved forward. Additional efficiencies can be realized by working with a full-service CDMO that provides cGMP storage at different temperature levels, packaging, worldwide transportation and logistics support, compliance management and analytical services.
GMP manufacturing projects are complex, making standardizing processes and creating flexible manufacturing systems difficult. As a result, multiple vendors are often required for each step in an mRNA manufacturing process. This can lead to duplicative work, delays and bureaucratic headaches. As a result, developers need to choose a partner that offers a full-service solution. This can help them streamline the entire process, enabling them to market faster and contain study, development and manufacturing costs. In addition, it’s critical to start with a supplier that can provide GMP-grade raw materials that meet stringent quality criteria. This is crucial because, as one vaccine developer discovered, the decision to use a lower-quality restriction enzyme for an mRNA synthesis step cost them hundreds of millions of dollars in lost revenue and delayed their clinical trial program by 18 months. In addition, a CDMO that can support the entire process, from cell line to formulation and fill-finish, can enable developers to speed up production timelines. The ability to run mRNA synthesis and downstream processing using the same equipment reduces production times. It reduces reliance on disposables and reagents, which can be time-consuming to source, deliver and maintain. The cGMP suites are outfitted with modular equipment that can be scaled to the needs of each product campaign.
A key challenge with mRNA production is that the process needs to be run at extremely low temperatures. This requires dedicated specialized storage and a robust supply chain. When an mRNA vaccine or therapeutic experiences a disruption in raw material availability, it can cause significant setbacks for developers and delay product delivery to patients. To mitigate this challenge, mRNA CDMOs must offer full-service solutions that allow for the rapid and cost-effective synthesis of plasmid DNA, linearization using a validated restriction endonuclease and ultrafiltration/diafiltration processes to provide high-quality GMP-grade mRNA. CDMOs can provide ab initio mRNA sequence design and synthesis, plasmid preparation and GMP-grade mRNA production services. In addition, mRNA CDMOs need the flexibility to scale up processes to rapidly meet demand and production capacity. This could be achieved through continuous processing to reduce operating costs and enhance throughput. Continuous processing also facilitates the use of advanced analytical technologies such as chromatography and constant characterization. In a time of increased resourcing and regulatory scrutiny, CDMOs that offer bundled solutions can help smaller, emerging pharmaceutical companies with limited capital to streamline their operations. In particular, small mRNA vaccine and therapeutic developers can benefit from a CDMO’s ability to provide plasmid, mRNA and lipid nanoparticle (LNP) formulation and fill-finish services at one site, eliminating the need to invest in expensive infrastructure and to coordinate multiple suppliers.
As the first mRNA vaccines enter clinical trials, it’s vital to have a GMP-compliant process, fit-for-purpose production equipment and analytical methods that demonstrate safety and quality. Unlike established vaccine platforms, which benefit from a pre-established supply chain and scalable strategies readily adapted to GMP manufacturing, the mRNA platform requires a unique set of new components and processes. This has required a highly conservative approach to scale up design, manufacturing and quality controls to be successful at the outset. As a result, the development of an mRNA-based process has been challenging. A major hurdle has been the availability of high-quality raw materials. Several suppliers have claimed to offer “GMP grade” raw materials. Still, these claims often lack clear definitions for endotoxin control, critical for IVT reaction components and large-volume buffers used in purification. Many mRNA processing steps are completed manually and must be scaled to an industrial scale. These steps include nuclease digestion and precipitation, which have significant downstream processing costs. Moving these steps to continuous processing (e.g., tangential flow filtration (TFF) and aqueous two-phase systems [ATPS]) could significantly improve processing efficiency and cost.
Additionally, encapsulating mRNA into lipid nanoparticles is a key step to accelerating the timelines for drug product release for clinical trial supply. This challenging process has yet to be standardized, and sourcing the correct raw materials is a critical requirement for a successful end-to-end GMP mRNA production pathway.