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The clinical potential of mRNA was revealed with COVID-19 vaccines, but that was just the beginning. “Today, this Nobel prize–winning technology is being leveraged for many therapeutic applications, and there are over 330 ongoing clinical studies involving mRNA,” states Telmo Graça, PhD, Process and Technology Lead—mRNA at Lonza.

However, manufacturing mRNA to cGMP standards at scale is challenging. “When the transition to cGMP mRNA manufacturing occurs the number of tasks required to build an end-to-end workflow is often underestimated, even by biopharma companies that are used to operating in state-of-the-art cGMP facilities,” Graça comments.

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The interconnected landscape of activities and competences required to ensure a successful mRNA cGMP Manufacturing Campaign.

Increasing mRNA Yield

To move an mRNA molecule toward cGMP manufacturing, the workflow typically starts with template design followed by in vitro transcription (IVT). “To build a bridge between innovation and manufacturing, you should be asking your development team or CDMO questions such as: ‘How robust is your IVT screening process?” and “To what extent is your process optimized for variances in mRNA constructs?’ ” Graça advises.

Ilaria Pettinati, PhD, Group Lead Process Development—mRNA at Lonza, adds, “With IVT, for example, when we perform Design of Experiments (DoE) for different IVT combinations or assess different sources of T7 RNA polymerases, we see our mRNA yields increase by two- to threefold. This shows the power that optimization and continuously assessing raw materials can deliver.”

Choosing the Right Capping Strategy

Before transferring an mRNA production process from R&D to a larger scale, it is important to define the quality target product profile, and then ensure that such product characteristics are met in each unit operation. This strategy helps to develop a platform process where units of operation can be combined or exchanged while being scalable and cGMP compatible.

Pettinati explains, “One of the most important decisions to make when transferring an mRNA production process to cGMP manufacturing is to define the capping strategy. Currently, co-transcriptional and post-transcriptional (enzymatic) capping are available. Both provide efficient capping of the mRNA 5’ end, but the selected option will influence yield, stability of the transcript during IVT reaction, as well as the design of the downstream process.”

Optimizing Processes

The next stage requires development of appropriate upstream and downstream processes suitable for cost-effective manufacturing of mRNA with the required Critical Quality Attributes.

“Process development and scale-up decisions can have knock-on effects when one is manufacturing at scale. This is where engaging with a development partner that has expertise in the production of mRNA as both a drug substance and a drug product can help de-risk the project,” Graça says.

Downstream processing should be optimized for the shortest possible timelines with a minimum number of steps to guarantee mRNA quality and minimize loss of material—thereby lowering the costs of raw materials. Scalability and cleanability of equipment (if required) from process development to cGMP manufacturing should also be assessed and simplified where practicable.

Pettinati explains, “Early decisions will impact process equipment dimensions and determine if the cGMP facility is fit for purpose. Optimizing IVT conditions, assessing different raw materials, and considering the effect of downstream process parameters can have a major impact on process time, mRNA yield, and purity, which could all make the difference between the success or failure of a cGMP manufacturing campaign.”

Leveraging Experience

Few companies can offer end-to-end mRNA manufacturing to cGMP standards on a large scale. Working with a manufacturing partner like Lonza, which has both the technical and regulatory expertise gained from producing a commercial COVID-19 vaccine, increases the chances of success. Lonza’s approach of early process engagement also accelerates the path to cGMP maturity and contributes to efficient, cost-effective manufacturing of mRNA vaccines and therapeutics.


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