Current Status and Future Perspectives on MRNA Drug Manufacturing.
Cameron WebbShell IpNuthan V BathulaPetya PopovaShekinah K V SorianoHan Han LyBurcu EryilmazViet Anh Nguyen HuuRichard BroadheadMartin RabelIan VillamagnaSuraj AbrahamVahid RaeesiAnitha ThomasSamuel ClarkeEuan C RamsayYvonne PerrieAnna K BlakneyPublished in: Molecular pharmaceutics (2022)
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.
Keyphrases
- sars cov
- binding protein
- respiratory syndrome coronavirus
- coronavirus disease
- clinical trial
- emergency department
- gene therapy
- nucleic acid
- healthcare
- stem cells
- cell therapy
- risk assessment
- squamous cell carcinoma
- drug induced
- young adults
- single cell
- bone marrow
- oxidative stress
- adverse drug
- induced apoptosis
- cell death
- cell cycle arrest
- loop mediated isothermal amplification