Table 3.

Important vaccine manufacturing, production and utilisation requirements.

Cost driver	Major cost	Relative Impact of Overall Cost	Cost range	Energy-related values	Options to reduce the cost of goods sold	Potential Impact of lower vaccine distribution strategy	Vaccine Examples
Product Development	R&D Laboratories and personnel	High fixed costs/possible to be shared across antigens	>500 M US$ Risk-adjusted* cost of 135–350 M US$ *Risk adjusted cost incorporates the cost and probabilities of moving to the next phase of development [62].	Each manufacturing pharmaceutical required 3.34 kWh of power/g of vaccine (1 dose = 100 μg of mRNA. Let's considered energy emissions for the 10 key manufacturing companies for COVID-19 vaccines [64]. A total of ten manufacturers required a total energy consumption of 2.37 × 102 kWh of power*. *These energy estimates were converted to their carbon emission equivalents at the rate of 2.7 kg CO2/L of fuel, 1.64 kg CO2/kWh of grid electricity and 0.43 kg CO2/kWh of solar-generated electricity [65]	Copy originator process post-patent expiration	High	MR (measles and rubella) vaccine copied from originator vaccine
					Perform technology transfer with established product	High
					Leverage correlates of protection to avoid large efficacy studies	Medium
					Purchase antigens and execute form/fill as a means of gaining experience before full manufacturing end-to-end	Medium	OPV (oral polio vaccine) bulk can be sourced from approved manufacture and formulated/filled
Direct Labour	Employee costs directly attributable to a specific vaccine Salaries Benefits	Low/typically less than 25% of total manufacturing cost	Costs can be significantly lower in China and India (25% lower for some manufacturers). The difference is shrinking due to increasing labour cost as the requirements of good manufacturing (cGMP) practices increase [66]		Increase automation and single-use production technologies (balancing with a potential increase in equipment or consumables costs	Medium	Single-use, or disposable, bioreactors reduce cleaning and sterilisation requirements, and complexity of qualification and validation Pneumococcal conjugate vaccine assays are streamlined across multiple serotypes.
					Standardise and streamline processes across as many steps and vaccines as possible. Develop capacity progressively through reverse integration (packaging purchased products, filling and packing purchased products, form/fill/pack purchased products, then production of bulk drug substance for internal form/fill/pack) [67]	High	–
Licensing/Regulatory and vaccine commercialisation	Expenses paid for the right to use product-related IP (technology) Expenses to comply with regulatory requirements to produce either for the domestic market or export	Low if experienced teams are engaged early to prepare facilities and processes for regulatory review and higher if the review process requires considerable rework or if delays result in lost revenue	In addition to staff and consulting costs, the new WHO process assesses the following fees: A site audit fee of 30 k US$ and for: Simple/Traditional vaccines: Evaluation fee of 25–100 k, and Annual fees of 4.8 k to 140 k US$ Combo or Novel Vaccines: Evaluation fee of 66.5–232.8 k US$, and Annual fees of 8.4–250 k US$ [63]	Energy is calculated based on one manufacturing company is under one licencing authority, product commercialisation, and utilities*. The 6.68 × 102 kWh/y power needed for each vaccine company [68]. The cost of electricity for a commercial user is 0.109 US$/kWh in the Czech Republic [69]. The total cost needed for a company based in the Czech Republic cost is 7.2 M US$/y. * The energy was calculated by considering one unit of licensing, management, IT or utilities section. Each unit assumed to be operated with a staff of 5 persons, which using energy in the form of electric power for 40 h of work per week.	Pursue WHO PQ as required by UNICEF/PAHO only when intending to access markets for which they procure (e.g., Global Alliance for Vaccines and Immunisation)	–	–
					Request royalty reductions or waivers for vaccine sold in low-income countries (LICs)	Low	Royalty for human papillomavirus vaccines antigens waived for volumes sold in Global Alliance for Vaccines and Immunisation
					Produce reagents in-house or seek viable alternatives rather than a license.	Medium	CRM produced in-house to avoid licensing cost.
					Differentiate originator production processes sufficiently to be considered a novel process	–	–
					Accelerate approval by seeking NRA or WHO priority review for vaccines for neglected diseases or emergency use.	High	–
					Utilise FDA priority review vouchers for another product and allocate savings to the vaccine that secured the voucher.	High	Apply priority review voucher to a product intended for high-income markets to maximise the value of approval
Over head	Management, quality systems, IT systems	High if a company has few products and low if overhead can be allocated across multiple products	Up to 45% of the cost of raw materials and labour combined [70]		Invest in quality systems that can streamline quality practices and reduce costs	Medium	Introduce enterprise quality management software
					Ensure the management team has broad expertise to be leveraged across a portfolio of vaccines
Facilities and Equipment	Capitalised costs that depreciate over time Land Buildings Machinery Ongoing costs of upkeep Repairs Maintenance Utilities	High fixed costs/design for minimising maintenance and utilities	50–700 M US$ Example: It took Pfizer five years and 600 M US$ to build a manufacturing site in the US		Design for very high facility utilisation. Limit the number of production platforms; force-fit new processes into established platforms to reduce the need for new facilities; increase utilisation of existing facilities. Use multi-dose vials.	High	Share filling lines across multiple vaccines when possible Shift production volumes to multi-dose vials to reduce filling costs (at the risk of higher vaccine wastage in the field).
					Use single-use disposable systems to reduce capital cost	Medium	Reduced capital offset by higher operating (consumable) cost
					Minimise classified production space with closed systems and RABs. Limit automation and process/equipment Leverage blow-fill-seal filling technology to shrink cleanroom footprint and reduce final product component cost, and reduce labour [71]	Low/medium
					Utilise Contract Manufacturing Organisations (CMO) for low volume products or until demand supports facility construction.	Low/medium	Seasonal influenza vaccines produced at a CMO. Reduced capital offset by CMO contract fees.