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.

Long Non-Coding RNAs Might Regulate Phenotypic Switch of Vascular Smooth Muscle Cells Acting as ceRNA: Implications for In-Stent Restenosis

“…Nowadays, improvement of RNA transfection techniques and development of new biomaterials represent promising therapeutic alternatives [ 64 ]. The application of gene expression-modulating stents able to release specific small interfering RNAs (siRNAs) [ 65 ], mRNAs [ 66 ], microRNAs [ 67 ], or lncRNA into the vascular wall may have the potential to both improve regeneration of the vessel wall and inhibit adverse effects.…”

mRNA vaccines: the most recent clinical applications of synthetic mRNA

“…mRNA precipitation techniques, which have been used on the laboratory scale in the past, are not suitable for large-scale good manufacturing processes (GMP) because they are time-consuming and require organic solvents such as alcohols. Currently, instead of mRNA precipitation methods, the TFF method is used in many cases, including SARS-CoV-2 mRNA vaccine manufacturing (Corbett et al 2020 ; Zhang et al 2020 ; Ouranidis et al 2021 ). The TFF technique is expected to be suitable for various IVT mRNA formulations, without affecting mRNA stability and compliance with GMP.…”

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

“…In their review Rosa et al also highlight the need for the development of a continuous, scalable procedure that can minimize costs, adumbrating its layout from the IVT reaction towards the TFF filtration of the product. While such a system has not yet been put into practice, a recent publication by Ouranidis et al analyzes in silico and proposes scalable, continuous, end-to-end cGMP manufacturing processes that encompass all steps from plasmid-containing bacterial cultivation to final mRNA LNP formation (see Figure 3 ) [ 43 ]. The system utilizes a continuous perfusion bioreactor for bacterial cultivation ( Figure 3 a) which is also known as the upstream bioprocessing stage, namely the stage in which the product is being produced.…”

“… Process flow diagram of the Pharma 4.0, GMP compliant mRNA production ( a ) perfusion bacterial culture upstream; ( b ) cell lysis and plasmid purification; ( c ) linearization and in vitro transcription; ( d ) lipid nanoparticle microfluidic formulation [ 43 ]. …”

“…Moreover, QbD is ideally applied by continuous pharmaceutical processes controlled by automation, robustness, reproducibility and real time validation. To this end Pharma 4.0 enabling tools of digital design such as spatial and charge arrangement formulation analysis, machine learning and systems-based simulations are empowering smart biomanufacturing strategies that pertain to unparalleled plant-wide quality assurance policies [ 43 ]. In addition, the thermodynamic stability and product performance of nanosuspensions may be predicted towards the assessment of solubility, predicting critical drug quality attributes linked to corresponding key process parameters also measured in real time by process analytical technology (PAT) [ 44 ].…”