Pharma 4.0 Continuous mRNA Drug Products Manufacturing.

ABSTRACT

Continuous mRNA drugs manufacturing is perceived to nurture flow processes featuring quality by design, controlled automation, real time validation, robustness, and reproducibility, pertaining to regulatory harmonization. However, the actual adaptation of the latter remains elusive, hence batch-to-continuous transition would a priori necessitate holistic process understanding. In addition, the cost related to experimental, pilot manufacturing lines development and operations thereof renders such venture prohibitive. Systems-based Pharmaceutics 4.0 digital design enabling tools, i.e., converging mass and energy balance simulations, Monte-Carlo machine learning iterations, and spatial arrangement analysis were recruited herein to overcome the aforementioned barriers. The primary objective of this work is to hierarchically design the related bioprocesses, embedded in scalable devices, compatible with continuous operation. Our secondary objective is to harvest the obtained technological data and conduct resource commitment analysis. We herein demonstrate for first time the feasibility of the continuous, end-to-end production of sterile mRNA formulated into lipid nanocarriers, defining the equipment specifications and the desired operational space. Moreover, we find that the cell lysis modules and the linearization enzymes ascend as the principal resource-intensive model factors, accounting for 40% and 42% of the equipment and raw material, respectively. We calculate MSPD 1.30-1.45 €, demonstrating low margin lifecycle fluctuation.