by Öner Tulum, William Lazonick, and Ken Jacobson
In March 2020, as a number of developers announced COVID-vaccine candidates that would begin clinical trials, vaccine manufacturers around the world embarked on capacity-expansion projects. They set up facilities designed to mass produce vaccines that were being developed on specific RNA- and DNA-technology platforms. By mid-2020, vaccine developers had already entered into several advance-purchasing agreements that would require the delivery of billions of doses if and when candidates obtained emergency use authorization.
In the pre-manufacturing design and setup stage of the manufacturing process (see the graphic below), the vaccine developer transfers technology knowhow to the manufacturing partner. Even with well-known vaccine technologies, this transfer of knowhow generally takes anywhere from 18 to 30 months. BioNTech/Pfizer, Moderna, and Oxford/AstraZeneca each accomplished this technology transfer in about two months. This rapidity amplifies known but unavoidable risks related to production efficiency, as well as unforeseen risks related to security, accidents, weather, or contamination.
Stages of the vaccine-manufacturing processThe risks are further multiplied by the magnitude of the undertaking, aimed at manufacturing several billion doses of vaccine within an unprecedentedly short period of time. The global effort involves over 150 partnerships among vaccine developers and producers. Following the signing of its licensing agreement with Oxford University in April 2020, AstraZeneca took responsibility for constructing a complex production network involving supply and sublicensing agreements with more than 20 external partners in 15 different countries to manufacture three billion doses of the Oxford vaccine in 2021.
As the Oxford/AstraZeneca vaccine rollout illustrates, when each procurement contract with a nation or coalition has a dedicated production site, differences in scaling productivity across different sites can create inequalities in delivery of doses to the different procurers. As a specific example that has been highly publicized, the delays experienced in vaccine delivery to the European Union led to a standoff between the top executives of UK-based AstraZeneca and the European Commission when productivity problems arose at the EU manufacturing site in the company’s production network. Among several production sites supplying AstraZeneca with viral vectors, that at Seneffe, Belgium, suffered major production setbacks that resulted in output significantly lower than that of the site serving the UK.
Another unavoidable scaling challenge is securing reliable supply flows of the more than 100 different components that are inputs into the production of COVID vaccines. Many of these components had been in short supply even before the COVID-19 pandemic. For instance, the rapid increase of gene therapies in clinical pipelines was already absorbing the viral-vector output of a small number of specialized manufacturers, some of which have since signed supply contracts with AstraZeneca and J&J to deliver this critical component of their COVID vaccines.
Several components used in COVID vaccines are also key ingredients in various antibody therapies, which are among the few clinical interventions available for the treatment of severe COVID infections. As the demand for antibodies has surged during the pandemic, their developers – among them, Eli Lilly, Roche, and Regeneron – have competed for access to several essential raw materials that are in limited supply.
Over the past decade, the growth of gene-therapy developers has also rapidly increased the demand for production equipment, particularly single-use bioreactors, which enable contract manufacturers to serve more customers. Before the pandemic, this supply constraint was overcome by using special, disposable liners in single-use bioreactors, enabling manufacturers to quickly switch from one product to another. During the pandemic, however, as the demand for single-use systems has increased dramatically, there have been reports of serious material shortages of not only the equipment but also the disposable liners.
The manufacturing of bulk vaccine is subject to quality checks as it proceeds from drug substance through drug product, including the fill-and-finish stage, which prepares the vaccine for delivery to the procurer. For authorization of the release of the initial vaccine batches manufactured at a given facility, a vaccine developer must provide regulators with evidence that the safety and efficacy profiles of the vaccine sampled from the first commercial-scale production batch matches that of the previously manufactured vaccine that was used during its clinical trials. The release of each consecutive batch is subject to the same verification process.
In this post, we have focused on scaling problems in the early phases of vaccine manufacturing. In the next post, we follow the manufacturing process to highlight difficulties that must be overcome in the later phases.