(603g) Towards Continuous, Transferable and Sustainable mRNA Vaccine Manufacturing Processes

RNA-based products have the potential to become one of the most disruptive modalities in the pharmaceutical landscape. In addition to the clinical success of mRNA vaccines against SARS-CoV-2, the COVID-19 pandemic has highlighted the key role that RNA production can play in disease management. Unlike conventional biologicals, these new products can be manufactured using disease-agnostic platform processes. They further rely on a relatively simple and rapid production system. However, large-scale manufacturing remains limited, highly centralized and in its infancy. For this recent technology to reach its full potential, process and platform development appear necessary. While multiple manufacturing routes are being explored, the switch to continuous operations has yet to be accurately evaluated. This study offers a robust assessment of this transition, elucidating the potential impact on cost, process capability, transferability and facility footprint.

Methodology

The modelling framework integrates kinetic process modelling and process simulations to encompass the different unit proceduresoperations. Distinct batch and continuous models are developed and calibrated with experimental data. This holistic approach allows the prediction of critical quality attributes and techno-economic assessments under different realistic scenarios. Since many variabilities remain in these processes, a variance-based global sensitivity analysis is performed. 10,000 quasi-random sampling are is used to obtain a risk-based assessment for each model. Then, RS-HDMR metamodeling is implemented to accurately estimates of the sensitivity indices.

Results

The switch towards RNA continuous manufacturing appears highly attractive, greatly reducing manufacturing costs and footprint. First, the transition to Continuous In vitro Transcription (IvT) should be set as a priority, as the use of a plug-flow and packed-bed reactors significantly improves process performance. It also debottlenecks the end-to-end manufacturing process in most scenarios. In addition, for the same productivity, the IvT reactor scale can be divided by up to ten, resulting in smaller and more efficient facilities. Life cycle of resins and membranes could be also optimized, and the number of single-use equipment reduced. Capital Expenditure, for example, decreases by more than threefold. Continuous flow also drastically lowers IvT raw materials requirement, while process streamlining enables their partial recycling. Production costs can be thereby halved. Ultimately, this digital process replica can be readily used for process design in continuous mode. It allows the identification of numerous manufacturing trade-offs and the definition of a cost-effective design space. Beyond RNA titer, continuous manufacturing can steer the design space towards more e gentle, efficient and sustainable operating regions.

Conclusions and future perspectives

Overall, this analysis showcases the great potential of continuous processing. While international technology transfer is urgently needed, it our modelling framework provides investment and research directions towards sustainable, small-scale production platforms. Although regulatory and scientific barriers need to be overcome, a globally distributed network of such facilities can reshape the current manufacturing landscape. A more rapid, local and flexible RNA response can thus be envisioned. In the future, the integration of lifecycle assessment and supply chain modelling into this analysisthe framework would help to assess the feasibility and sustainability of this paradigm shift.