Presented by Ulrich Blaschke, PhD, Vice President, Technical Development, BioNTech AG
At the TIDES Europe 2021 conference, Dr. Ulrich Blaschke began his presentation on mRNA development and manufacturing with a discussion of how the vaccine for COVID-19, BNT162b2 (Comirnaty) works. It is a lipid nanoparticle (LNP) comprised of four different lipids with mRNA located in the core of the particle. The LNP targets and enters the cells whereupon the mRNA, that codes for the spike protein of the SARS-CoV-2 virus, is released. The cell machinery is induced to produce the spike protein which is then broken down into fragments and presented on the cell surface, triggering an immune reaction thereby giving protection against COVID-19 infections.
Dr. Ulrich Blaschke, Vice President, Technical Development, BioNTech AG
He explained that the strategy used in the development of this vaccine included investigation of the different forms of mRNA (unmodified vs modified mRNA, capability for self-amplification or not), design of multiple antigen variants, and early generation of applicable preclinical toxicological data for clinical studies. Four candidates were simultaneously brought into Phase I clinical trials, and at the same time large batches of each of the clinical candidates were synthesized in preparation for immediate supply to clinical trials once the Phase I results were known.
Blaschke described how the company identified partners to help with the ensuing global development and distribution. The manufacturing project was part of the United States Federal Government’s “Light Speed” initiative, and began at the end of January 2020. Phase I began in April 2020, fast-track FDA approval was obtained in July 2020, and by November 18, 2020, documents were submitted for agency approval. Once approved, global roll-out began at the end of 2020. The vaccine had proved to provide strong protection against COVID-19 versus placebo in a clinical trial
with 40,000 people.
Approval for the Marburg manufacturing site was obtained at the end of March 2021, in August 2021 full BLA approval was obtained, by November 2021, two billion doses had been delivered. The manufacturing process was rapid, starting with template production, followed by mRNA synthesis (in a bioreactor without cells), product purification and concentration, formulation, filter sterilization, and final vial filling. Following control studies, it was delivered to market. The DNA template is a linearized plasmid and following transcription it is hydrolysed, using DNAse I, leaving the mRNA product which is then purified. Four types of lipids are used in the formulation process: ionizable lipids that bind the RNA and bring it into nanoparticle, pegylated lipids on outside of nanoparticle to prevent aggregation, and two structural lipids Cholesterol and SPC that make up the main body of the nanoparticle. Following formulation ethanol must be removed and the product concentrated in buffer for vial filling.
Preparations for scale up were undertaken in parallel to clinical studies. This included building new facilities and scale up of raw material supplies. Suppliers provided a lot of support in equipment and disposables during the scale up. Processes for global distribution were already scaled from gram to kilogram quantities before the clinical data was obtained. A complex fill-and-finish network was constructed, which currently uses 10 different sites. Since an mRNA vaccine was a new technology, the global regulatory agencies supported the manufacturing process to allow for rapid development.
Formulation is a key aspect of an mRNA drug, as it protects and relays the mRNA to the correct site. For more mRNA vaccines to be developed to treat infectious diseases, controlling LNP cost and stability (-80oC temperatures required) needs to be addressed. For protein replacement therapy uses of mRNA, non-immunogenic formulations are required. Organ and/or cell targeting will require a mixture of biological and chemical targeting multi-component formulations. As of the time of the event, in September 2021, vaccine programs against tuberculosis and malaria had been initiated and manufacturing facilities were being expanded to Africa.
Ulrich Blaschke, PhD, is Vice President, Technical Development, at BioNTech AG
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