When the first Covid-19 vaccines were approved in the UK and elsewhere three months ago, many thought the end of the pandemic was almost within reach.

Few, however, had anticipated the vast logistical problems involved in mass-producing and delivering billions of doses globally. This has been underlined by the high-profile political squabbles between the UK and EU over who should get which deliveries of vaccines from which factories amid shortages of doses.

After the UK announced an imminent squeeze on its own vaccine supply, we look at what is behind the holdups.

Mass-producing the new vaccines is complicated

There have been two broad approaches to large-scale production of Covid vaccines. The Oxford/AstraZeneca jab relies on a largely well-tested approach in which lab-produced cell cultures are produced in large bioreactors – a bit like brewing, but for vaccines.

The second, newer technique, producing mRNA vaccines such as the Pfizer and Moderna jabs, involves the “messenger RNA” (genetic material) for a modified spike protein being produced in the lab and then combined with enzymes and nucleotides before being packaged into tiny, fatty bubbles.

Each technique has its own issues when it comes to scaling up mass production.

What are the issues with Oxford-style vaccines?

Typically a production facility for a vaccine like Oxford’s can take six to nine months to get going, although in this case it has been faster. The biggest issue is with so-called yields, which depend on the health of the underlying cell culture. Any quality control issues – for instance relating to temperature, humidity or compromised sterility – can lead to less vaccine at the end of the process, an issue that has been seen at some AstraZeneca production facilities around the world.

While you might expect more or less identical production facilities to produce the same amount of vaccine, in fact yields can vary wildly, by as much as an order of three, especially in a new production process, which experts say is as much an “art as a science”.

And with Pfizer-style vaccines?

While mRNA vaccines are in some ways more straightforward to produce and much less vaccine is needed to produce a strong antibody response, the newness of the technology means key ingredients – such as the fatty bubbles and the nucleotides required for the “vaccine soup” – have been in short supply.

And while vaccine manufacturers of both kinds have attempted to scale up quickly, there has also been a shortage of manufacturing facilities for sites that need to be built to the highest biosecurity standards.

One issue is that some manufacturers that supply key elements needed for such vaccines have waited for the new jabs to advance in their development before taking the risk of committing to scaling up their own production.

One recently reported example is the giant disposable plastic bags used as sterile liners inside bioreactor tanks for the Pfizer, Moderna and Novavax vaccines, which have emerged as a bottleneck in production in the EU and elsewhere.

The bags are produced by a small number of suppliers, and vaccine producers have been struggling to source them, leading Merck recently to announce it would expand its facilities to eliminate this chokepoint.

Shouldn’t someone have anticipated all this?

Some people did, including Bill Gates who wrote as long ago as last April that the scale of the pandemic meant that facilities needed to be built on spec. But while organisations such as Gavi, the global vaccine alliance, and some governments did invest in vaccine research and production facilities, there has been noticeable shortfalls in global preparedness that have created bottlenecks and led to a scramble for vaccines in short supply.

More widely, some experts say the pharmaceuticals industry, while huge, is not structured for the kind of integrated global effort required to produce billions of doses of vaccine at short notice, including manufacturing of items for the fill and finish, such as glass vials, many of which are sourced from a handful of countries including India and China.

Is there a pattern here?

Liz Breen, an academic at the University of Bradford who studies health operations including supply chains, thinks so. “The effort to create new vaccines has been amazing, but along the way it’s as if some of the fundamentals have fallen by the wayside – the bread and butter stuff that makes scaling up possible,” she said. “I really do think people were so focused on the vaccines, they didn’t think further about what needs to come with it to make happen.”

What about vaccine nationalism?

With so many countries chasing insufficient doses, vaccine nationalism has become a real issue with threats of export restrictions of finished vaccines and raw materials. The UK has now been wrongfooted by a temporary shortfall in deliveries of the Oxford vaccine from the Serum Institute of India, which has been contracted to produce it. With most vaccines requiring two doses delivered within a finite period, this has a knock-on effect for vaccination programmes.