Current status and future perspectives on MRNA drug manufacturing

Cameron Webb, Shell Ip, Nuthan V. Bathula, Petya Popova, Shekinah K. V. Soriano, Han Han Ly, Burcu Eryilmaz, Viet Anh Nguyen Huu, Richard Broadhead, Martin Rabel, Ian Villamagna, Suraj Abraham, Vahid Raeesi, Anitha Thomas, Samuel Clarke, Euan C. Ramsay, Yvonne Perrie, Anna K. Blakney

Research output: Contribution to journalReview articlepeer-review

Abstract

The coronavirus disease of 2019 (COVID-19) pandemic launched an unprecedented global effort to rapidly develop vaccines to stem the spread of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Messenger ribonucleic acid (mRNA) vaccines were developed quickly by companies that were actively developing mRNA therapeutics and vaccines for other indications, leading to two mRNA vaccines being not only the first SARS-CoV-2 vaccines to be approved for emergency use but also the first mRNA drugs to gain emergency use authorization and to eventually gain full approval. This was possible partly because mRNA sequences can be altered to encode nearly any protein without significantly altering its chemical properties, allowing the drug substance to be a modular component of the drug product. Lipid nanoparticle (LNP) technology required to protect the ribonucleic acid (RNA) and mediate delivery into the cytoplasm of cells is likewise modular, as are technologies and infrastructure required to encapsulate the RNA into the LNP. This enabled the rapid adaptation of the technology to a new target. Upon the coattails of the clinical success of mRNA vaccines, this modularity will pave the way for future RNA medicines for cancer, gene therapy, and RNA engineered cell therapies. In this review, trends in the publication records and clinical trial registrations are tallied to show the sharp intensification in preclinical and clinical research for RNA medicines. Demand for the manufacturing of both the RNA drug substance (DS) and the LNP drug product (DP) has already been strained, causing shortages of the vaccine, and the rise in development and translation of other mRNA drugs in the coming years will exacerbate this strain. To estimate demand for DP manufacturing, the dosing requirements for the preclinical and clinical studies of the two approved mRNA vaccines were examined. To understand the current state of mRNA-LNP production, current methods and technologies are reviewed, as are current and announced global capacities for commercial manufacturing. Finally, a vision is rationalized for how emerging technologies such as self-amplifying mRNA, microfluidic production, and trends toward integrated and distributed manufacturing will shape the future of RNA manufacturing and unlock the potential for an RNA medicine revolution.
Original languageEnglish
Pages (from-to)1047-1058
Number of pages12
JournalMolecular Pharmaceutics
Volume19
Issue number4
Early online date3 Mar 2022
DOIs
Publication statusPublished - 4 Apr 2022

Keywords

  • RNA
  • manufacturing
  • in vitro transciption
  • scale-up
  • vaccines
  • lipid nanoparticles
  • formulation
  • preclinical studies
  • human clinical trials
  • gene delivery

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