Weighing distributed manufacturing as a route to vaccine equity
Distributed manufacturing would make vaccines in many small sites close to the people who need them, sending information rather than material along the supply chain, to answer the uneven reach of centralised production. Its proponents argue for it on sustainability and preparedness, leave its viability and security open, and see it as needing new education, responsive regulation and new work for writers.
The inequity it answers
Centralised manufacturing, as the pharmaceutical industry commonly practises it, is challenging because it uses extensive supply chains, which are risk-laden during transport of sensitive medicines in remote locations. Centralised vaccine supply chains do not have complete geographical coverage. In 2021 there was pressure for a COVID-19 vaccine to be available for everyone on the planet. An open letter at the time of the World Health Assembly of May–June 2021 said that poverty and geography should not determine access to life-saving vaccines, as the Ebola epidemic had taught.
The vaccine industry had long been in a difficult position: spending on vaccines was insignificant beside other interventions, five multinationals produced 80% of vaccines, financial returns were poor against high production and R&D costs, and manufacturing facilities were capital-intensive. Manufacturing costs are first covered by vaccine sales in high-income countries, and lower-income countries buy vaccines once they are more affordable.
How distributed manufacturing works
Distributed manufacturing, one of the World Economic Forum's top ten emerging technologies in 2015, complements centralised vaccine production and would put production close to the final customer. Much of the material supply chain is replaced by information transmitted electronically directly to local manufacturing sites, which overcomes supply chain issues. In theory, distributed manufacturing could enable regions to access treatments for themselves. Underserved communities exist in high-income countries as well as in low- and middle-income ones. In time, community manufacturing sites could result in business ecosystems that bring more opportunities to those locations, and a broader range of biotechnology products could be manufactured there, such as medicines for other conditions or crops enhanced to grow in difficult environments. The idea requires thought and collaboration from many people, and constructive, transferrable and innovative ideas are needed because the model has challenges of its own. Pharmaceutical and medical device areas that should be considered include various operations, GxPs and regulations.
Small volumes of mRNA vaccine can produce large numbers of doses. A smaller facility footprint would benefit from single-use disposable culture systems, which cut fixed costs dramatically and can be set up faster than hard-piped facilities, and many chemical engineering tools for bioprocess intensification are already available.
Process standardisation and robustness are essential to guarantee the safety, efficacy, quality and consistency of product. Robustness is influenced by variation in environment, equipment, reagents and operator skill, and standardising and measuring these influences shows compliance with the manufacturing limits documented in regulatory dossiers. Automation will make processes at each site more comparable. Safe-by-Design synthetic biology, consistent with the Quality-by-Design the US FDA outlines, will build robustness into the automated engineering cycle. Data format standards include the Synthetic Biology Open Language (SBOL) and Digital Imaging and Communications in Medicine–Synthetic Biology (DICOM-SB).
Biofoundries and manufacturing hubs
A biofoundry has the automation and analytics that support biological systems engineering, and synthetic biology solutions can be examined in it for any given challenge. Building one is challenging and has many technical and operational considerations. A biofoundry could be built at a university, while distributed manufacturing hubs could sit closer to the point of need, at teaching hospitals or in mobile laboratory and manufacturing units. Many successful research and innovation centres in developed countries were built on an idea, and the same sort of centre could be built where there is seemingly nothing.
The Global Biofoundries Alliance, based at Imperial College London, is a worldwide network of institutions that share knowledge, infrastructure and expertise. Its objectives are to develop, promote and support non-commercial biofoundries around the world, intensify collaboration and communication among them, collectively develop responses to common technological, operational and other challenges, enhance their visibility, impact and sustainability, and explore globally relevant and societally impactful grand-challenge projects. Anyone interested in getting involved with biofoundries can contact the alliance directly. RNA technology experts are in university molecular biology departments, and anyone can consider expanding the alliance to include a university of their choice.
The case for it, and the questions it leaves open
On sustainability, proponents argue that a large number of countries could carry out final manufacturing in small facilities, giving global coverage and bringing manufacturing closer to the point of need, and that transferring information instead of transporting material saves money and emissions, lowers the risk of cold-chain failure and speeds innovation.
On preparedness, they point out that the world has been unprepared for every human viral outbreak since 2000, with money arriving for each and disappearing once the immediate danger subsided. Infectious disease outbreaks need quick responses. Electronic real-time tracking and predictive tools help public health decision-making. The University of Cambridge estimated an optimistic loss to the global economy from COVID-19 of $3.3 trillion and, in the worst case, $82 trillion over five years. The World Economic Forum predicted $1 trillion of damage to global tourism in 2020 alone. The World Bank predicted that 150 million more people would enter extreme poverty by 2021 as a result of COVID-19. Beside these costs, spending on a way for the world to respond quickly in future would not seem expensive. Proponents put the opportunities in biomolecules and biosystems innovation at perhaps $500 billion to $1.2 trillion. Biofoundries support in vitro and in silico toxicology testing.
The questions it leaves open include whether it is realistically economically viable, and what happens during periods of low demand. They include how cyber-attacks are prevented, for which blockchain technology is put forward as the obvious solution to enhance cyberbiosecurity, and how talent and education systems can be developed, for which biologists are said to need greater knowledge of computer science and IT systems, and computer scientists of biology. They also include what technical barriers stand between mRNA vaccines and the marketplace, how feasible vaccine production is in very small plants, and what key attributes biofoundries need for the model. Its infrastructure is immature and needs focused development, and several technologies need to be integrated: predictive epidemiology tools, open-access real-time tracking of a virus's evolution and spread, rapid detection of mutants, technologies such as RNA printing, responsive regulation, cyberbiosecurity such as blockchain, and talent and education to create a workforce. The Research Quality Association has set up a special interest group to work through the challenges of distributed manufacturing.
Steps towards local production
In June 2021 the WHO announced support for a South African consortium to establish a COVID-19 technology transfer hub for mRNA vaccines. The consortium's central aim is to build a training facility for mRNA technology development for vaccine mass production, then transfer that entire technology package to multiple recipients in low- and middle-income countries. In February 2022 researchers at a South African biotechnology company said they were on the verge of producing a COVID-19 mRNA vaccine. The WHO also announced it was increasing biopharmaceutical manufacturing capacity in at least 11 countries.
In October 2021 Moderna announced it would build an mRNA facility in Africa to make up to 500 million doses a year, a venture that will probably bring local technology transfer, which will help build capacity and improve access to medicines. Since 1 May 2019 Nigeria has given new pharmaceuticals ten years to transfer to local production, and cancels the registration of a product whose production does not transfer. Other countries could adopt a similar approach.
Educating a workforce
The model would, in the words of a Liberian immunologist working for access to COVID-19 vaccines in Africa, "build an entirely new system of education to support this decentralisation of vaccine and generate market while affording vaccine to people at their point of need".
Business ecosystems will develop, and they need skilled and educated workers. Distributed manufacturing needs university graduates who understand biology, computing, artificial intelligence, machine learning and robotics, and more engineers, mathematicians and computer scientists. More education across fields improves communication between them, as when biologists understand computer information technology and computer scientists understand biology.
Regulating new sites
New vaccine production and new manufacturing sites are risky, and national regulatory authorities ensure that medical treatments are safe and effective. Yet in 2017 only 30% of the national regulatory authorities of the WHO's 194 member states could regulate their own medical products. National regulatory authorities need to be flexible and to follow the evolving science as they develop requirements, and distributed manufacturing of vaccines needs greater regulatory harmonisation between countries, for which the International Council for Harmonisation (ICH) is a global standard resource.
The WHO Global Benchmarking Tool guides countries on registering medicines and points to the established guidelines that national regulatory authorities need to follow to approve them. Under them, critical requirements such as label indication, mode of use, storage conditions and Good Manufacturing Practice certificates and reports need to be reviewed, and information such as where products are deployed, in what quantities and who receives and manages them should be documented and monitored.
The tool also evaluates the maturity of national regulatory systems, and on it only Ghana and Tanzania, of 54 African countries, had regulatory systems robust enough to regulate manufacturing activity. This leaves many educational opportunities, and building strong regulatory systems in the remaining 52 is a challenge. Establishing an information-sharing and cooperation platform is important, and will help transfer knowledge to ensure consistent activity in many regions. Africa was strengthening its regulatory systems: in April 2021 the Africa Centres for Disease Control and Prevention and the Coalition for Epidemic Preparedness Innovations signed a memorandum of understanding to increase African vaccine R&D and manufacturing, and the African Export-Import Bank and the Africa Finance Corporation signed a collaboration agreement at the same time. African countries were working towards greater regional regulatory harmonisation, as was the rest of the world, including the EU and USA. Continuous regulatory development offers opportunities that need investment in education.
At a meeting in January 2022 an industry speaker described global regulatory authorities' solicitations concerning distributed, or decentralised, manufacturing, comments one proponent of the model reads as showing that distributed manufacturing is becoming a reality as regulators begin to engage in dialogue with industry and the general public.
Where writers come in
Distributed manufacturing offers writing opportunities: sharing the idea with communities who might want to take part, and making document templates that already exist across medical writing and communication fit for purpose for distributed manufacturing. Communities will have opportunities to educate their own medical writers along with other skilled workers.