Abstract
In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle “from design to production” of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell’s genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.
Highlights
During recent decades, biopharmaceuticals, such as monoclonal antibodies, peptides or nucleic acids, have gained impressive attention as revolutionary therapeutics and vaccine strategies, attempting to fulfil the high expectations of resolving serious health conditions.Regarding nucleic acids, DNA- and mRNA-based technologies have been established as extremely promising approaches in therapy and prevention of numerous diseases, as part of so-called gene therapy
We present an overview of all the steps taken for in vitro transcription (IVT) mRNA, in both laboratory and industrial setting production, according to the latest advancements
They constitute an integral part of the mandatory quality control as well as the isolation of high purity intermediates required for products whose synthesis is performed serially
Summary
Biopharmaceuticals, such as monoclonal antibodies, peptides or nucleic acids, have gained impressive attention as revolutionary therapeutics and vaccine strategies, attempting to fulfil the high expectations of resolving serious health conditions. The inherent variability of biological agents coupled with the strict quality requirements poses a big technical challenge and overcoming this major challenge has garnered considerable attention from the scientific community and biotech industry [20,36] To tackle this challenge, companies are trying to expand their facilities in order to meet the growing demands for clinical trials and product commercialization, such as CureVac, that have invested recently in considerable budget to commission a new GMP-qualified RNA production facility [37]. Once IVT mRNA GMP process manufacturing, with optimization, protocol validation and standardization, is accomplished, batch-to-batch reproducibility of highly pure, stable synthetic mRNA products, capable of supplying standard clinical trials and market demands, can be achieved [38] Such a process is flexible, highly scalable, standardized and can be carried out cost-effectively in a few weeks, including all the essential quality controls for a GMP production [39]. The information presented here contributes to the realization of a continuous manufacturing line under 4.0 pharma principles, one able to produce stable and effective mRNA therapeutic products that meet the ever-increasing quality standards and global demand
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