As of October 2021, 6-7 billion doses of COVID-19 vaccines have been provided under emergency measures. The vaccines roll out has peaked at 45 million doses/day and has remained broadly stable (Our Word in Data & WHO), so we can assume that this is the current global manufacturing capacity. But with only 35% of the worlds’ population fully vaccinated, we must also assume, along with conclusions from a recent slew of pandemic preparedness reports1-3, that this capacity is:
- not enough and/or,
- is not flexible enough and,
- should be more geographically distributed.
mRNA and Virus-based Vaccines
At a recent conference in Boston (Cambridge Healthcare Institute, The Bioprocessing Summit), Philippe-Alexandre Gilbert from the Bill and Melinda Gates Foundation presented mRNA manufacturing scenarios for regional production of mRNA vaccines in Africa at $1 per dose. In this blog, we use the new BioSolve mRNA model to compare the values presented and provide additional information on distributed manufacturing.
Obtaining available cost data for the mRNA supply chain is not easy, so using some of the data from P-A Gilbert’s presentation, we calculate that a facility able to produce 100 M doses per year (100ug dosage, 50M patients) will have a capital budget of $14M and able to reach drug substance costs of $3/dose.
A capital cost of $14M for a facility to produce 100M doses compares favourably with an equivalent capacity, virus-based vaccine facility, which would require an investment of $50-$60M to service 2000-4000L single-use bioreactors. The lower capital outlay of the mRNA facility might seem very attractive for the drive to localised manufacturing, servicing individual countries or groups of countries. The BioSolve mRNA model scales down accurately 10 fold, to a facility serving 5M patients per year; with a capital outlay of $10M. 70% of that outlay is process equipment, including equipment needed for QC testing. So an extra $4M outlay could give a 10-fold increase in production capacity. Unless new automated modular equipment, with integrated process analytical controls is marketed soon (developments are in place), then facilities with a production capacity serving 50M patients per year would be more cost effective.
Although the capital costs may be smaller for mRNA vaccines, the supply chain for mRNA is less mature, more complex and costly.
Most of the costs for mRNA vaccine manufacture are associated with critical raw materials. Table 1 explores their cost impact and future direction. Many of the critical raw materials (RM) have not been manufactured at larger quantities before the pandemic. Given that the mRNA platform is predicted to expand in the number of manufacturing facilities and expand in the scope of therapeutics generated4, this would mean a larger and more mature supply chain will be established, along with a reduction in prices. We modelled a reduction in those RM costs to 10% of current value (see Figure 1). Even at these costs, the specialist lipids used in nanoparticle formulation remain the largest single cost, closely followed by the GMP enzymes, but at least the drug substance costs reduce to $0.6/dose (100ug/dose).
BioNTech reported, at the same conference, a requirement to scale-up production of 2 novel lipids, with 750 kg made to date. This shows the importance of the contracted supply base and their ability to respond in an emergency, but those critical raw materials are only made from facilities in the US and EU5,6 Similarly with many other critical raw materials, no completed manufacturing transfers have yet been announced for of these GMP enzymes and chemicals into Latin America, Africa or the Middle East, or most of Asia (except China, which had developed its own capabilities7).
Demand for single-use bags, tubing kits, filters, and purification devices is still out stripping supply. The mass of single-use plastic required for mRNA vaccine manufacture will be lower than virus-based vaccines, because the in-vitro mRNA systems can operate at higher concentrations in the production phase. But the manufacturing burden from single-use component supply is not just about the quantity of plastic. The complexity of single-use flow paths can dictate lead times because they are manually assembled and often customised. As with raw material supply, the supply chain complexity must be minimised and expanded in parallel, globally, to make distributed vaccine manufacturing successful.
BioSolve Process modelling can assist in understanding investment costs and risk for both drug product and supply chain raw materials. Modelling can seek to optimise operating efficiencies for cost per dose value and for a range of important sustainability metrics. It can also assist manufacturing technology transfer through Bill of Materials creation; all of which will be key to any push toward decentralised manufacturing.
Table 1. Critical Raw Material Supply of mRNA Vaccines
|Raw Material||Cost Impact||Supply/Issues||New Developments|
|Plasmid DNA||High (decreasing)||Unique template, but multiple CMO capabilities for pDNA||Increase in pDNA CMO landscape. In-vitro DNA amplification technologies now established|
|Enzymes||High (decreasing)||Shipped cold, stable for 1 year frozen. Multiple manufacturers, but not GMP||Further optimisation of the expression/function of these critical raw materials is planned (see for example the partnership between Ginkgo & Aldveron8) which should enable their availability.|
|Chemicals - Lipid-based nanoparticles, Nucleotide Triphophates. Capping reaction||High (decreasing)||mRNA capping technology (single source supplier?), nucleotide triphosphates (unstable)||Local supply of triphosphates and other biochemicals through supporting cellular/synthetic biology activity or lysates9.|
Figure 1 – Reduction of the main raw material costs associated with mRNA vaccine manufacturing to 10% of their current estimated value, mimicking a more mature supply of the reagents. The full cost of single-use flowpaths, bags, etc have not been exhaustively applied to the current mRNA model.
1 “100 Days Mission to respond to future pandemic threats – a Report to the G7”. 84 (2021) https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/992762/100_Days_Mission_to_respond_to_future_pandemic_threats__3_.pdf
2 “From Worlds Apart to a World Prepared: Global Preparedness Monitoring Board report 2021”. Geneva: World Health Organization. https://www.gpmb.org/annual-reports/annual-report-2021 (2021).
3 “Towards Vaccinating The World Landscape of Current COVID-19 Supply Chain and Manufacturing Capacity, Potential Challenges, Initial Responses, and Possible ‘Solution Space’ – a Discussion Document”. https://www.ifpma.org/wp-content/uploads/2021/03/Summit_Landscape_Discussion_Document.pdf (2021).
4 Xie, W., Chen, B. & Wong, J. Evolution of the market for mRNA technology. Nature Reviews Drug Discovery 20, 735–736 (2021).
5 Start of production in record time: Evonik delivers first lipids from German facility to BioNTech – Evonik Industries. https://corporate.evonik.com/en/start-of-production-in-record-time-evonik-delivers-first-lipids-from-german-facility-to-biontech-157106.html.
6 Exploring the Supply Chain of the Pfizer/BioNTech and Moderna COVID-19 vaccines.
7 China’s first self-developed mRNA vaccine to enter mass production in October with annual capacity of 200 million doses – Global Times. https://www.globaltimes.cn/page/202109/1233797.shtml.
9 Blake, W. J., Cunningham, D. S., MacEachran, D., Gupta, M. & Abshire, J. R. Cell-free production of ribonucleic acid – GreenLight Biosciences. (2017), US20170292138A1