Vial bodies

The urgent need for a Covid-19 vaccine has fast-tracked new and exciting technologies to upscale and accelerate manufacturing capacity. But what started as a pledge to bring a halt to a global catastrophe has turned into a race for international prestige – a race that will have a far-reaching impact on pharmaceutical manufacturing in the years to come. Covax – the global initiative to develop, manufacture and distribute Covid-19 vaccines – has set an ambitious target of two billion doses by the end of 2021. That will require a lot of scaling up and scaling out to maximise output in multiple geographies, says Jim Robinson, senior CMC consultant and vice-chair of the scientific advisory committee at the Coalition for Epidemic Preparedness Innovations (CEPI), which co-leads Covax with Gavi and WHO.

By matching manufacturers with developers that share common production platforms, CEPI has identified the capacity to produce two to four billion doses of Covid-19 vaccine by the end of 2021. As such, if existing resources are used efficiently, no new manufacturing capacity should be required to meet the Covax target.

For that to be realised, Robinson says collaboration will be key – and it’s a view shared by Thomas Cueni, director-general of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).

“It is not just the manufacturers of vaccines that have stepped up: suppliers of equipment, components and fittings are all working in close collaboration with manufacturers to provide the infrastructure needed to ramp up production,” he says.

To secure capacity, larger manufacturers are looking to secure contract manufacturing partners globally. Sufficiently speedy tech and knowledge transfers will require processes to be as simple as possible, says Cueni, with some manufacturers sacrificing yield in return for reduced timelines and maximum capacity. “The focus is on reducing the number of steps it takes to manufacture the vaccine, as well as the amount of equipment and range of different skills needed,” he explains.

Flexible, modular and continuous manufacturing systems, including prefabricated or ‘plug-and-play’ technologies, will also play a crucial role. These technologies reduce cleaning and sterilisation between batches, leading to less down time, says Robinson. They are also easier to upscale, meaning full-scale production can start sooner. It’s here that single-use technologies (SUTs) – which are largely made of disposable plastics for use in bioreactors, mixers, containers, tubing and other manufacturing equipment and components – come into play.

“Perhaps the most significant time advantage is coming from the use of SUTs, such as single-use bioreactors, which are the large vessels in which bulk vaccine is produced before it is formulated and filled into vials and syringes,” says Chris Larkins, senior vice-president of global operations for Seqirus, part of the CSL Group. CSL is partnering with the University of Queensland, Australia, and CEPI to develop and manufacture a vaccine using molecular clamp technology and the Seqirus MF59 adjuvant.

Stainless steel bioreactors require long manufacturing timelines, and can take up to 12 months to get up and running. “By comparison, single-use bioreactors can be produced and installed and in use within months,” says Larkins. Indeed, they can be bought pre-sterilised, reducing the need for extra equipment, and as they are disposable, there is no need to carry out the extensive cleaning validation required between batches with stainless steel. After being used at smaller scales for a number of years, the technology was gaining popularity for large-scale production of up to 2,000L even before the pandemic, but Covid-19 has accelerated its use.

There is a similar shift happening around ‘fill and finish’ processes. “Ramping up production requires sufficient capacity for filling bulk vaccines into vials,” says Larkins. “There is no point having large amounts of bulk vaccine capacity if we can’t fill the vials just as quickly.” Like single-use bioreactors, self-contained filling machines have existed in this space for a while, but demand had been limited due to manufacturers preferring their own large-scale facilities. The Covid- 19 rush has forced a rethink of this strategy, says Larkins. “Building a large fill-and-finish facility may take three years, whereas one of these self-contained units can be pre-built and installed in six to nine months.” As such, there’s suddenly a strong uptake for the technology among manufacturers looking to avoid production bottlenecks.

New model vaccines

But it’s not just equipment: vaccines themselves are also undergoing something of a revolution as the pace of research accelerates. Robinson says CEPI has backed a range of vaccines and platforms to guarantee “multiple shots on goal”. The Covax portfolio includes the innovative messenger RNA (mRNA) platforms being used by CureVac and Moderna, as well as the DNA technology that Inovio is exploiting, all of which turn the human body into its own “vaccine factory”. Robinson also says that these plug-andplay technologies could be repurposed for future pandemics, as they allow the DNA or RNA sequence of an antigen to be inserted into a pre-validated platform to rapidly create a vaccine candidate.

“Before Covid-19, there was a view that this technology was possibly up to a decade away from commercialisation,” says Larkins. “All of a sudden, the manufacturing efficiency of mRNA technology has been recognised, so there has been a lot of investment by industry in this novel platform. There are still challenges to overcome, but necessity is the mother of invention, as they say.”

The same goes with the supply chain, where CEPI is exploring alternatives to glass, including a vaccine delivery bag – produced by MEDInstill – that holds up to 200 doses. Robinson says the bags would offer advantages in terms of filling speed and cold chain footprint. In the meantime, CEPI has partnered with the Stevanato Group to supply the 100 million multidose glass vials required to store Covax’s two billion vaccine doses. Work has also been done to secure packaging components and to offset shortages of bioreactor bag liners, tubing, chromatography resins, filters and other equipment.

All that effort and innovation, however, may still not be enough. Associate Professor Adam Kamradt-Scott of Sydney University, who specialises in global health security and pandemic planning, says the production and distribution of Covid-19 vaccines is one of the greatest logistical challenges the international community has ever faced.

“With Covax – which is a great initiative – we are looking at two billion doses by the end of 2021. But when you consider some of the more promising vaccine candidates may require two or three doses, you are halving that Covax figure straight away.

“WHO’s own numbers suggest that up to 50% of vaccines are destroyed as a result of cold chain supply issues, so that reduces Covax’s two billion to half a billion doses. When you consider the world’s population is almost eight billion, you realise there are a lot of people who won’t be vaccinated by the end of 2021, if you are just relying on Covax.”

According to Cueni, that’s why governments all over the world are leveraging their own manufacturing networks, while also still committing to Covax. “We are seeing a nationalist approach from some countries as there simply is not enough capacity to ensure everyone around the world can be vaccinated at the same time when a vaccine becomes available,” he explains. “This is why multiple approaches are needed.”

This scramble for autarky is a challenge that’s proving easier to navigate in some markets than others. Dr Stavros Nicolaou, chairman of the Pharmaceutical Industry Association of South Africa, points out that his country is already heavily reliant on imports, with pharmaceutical products the fifth-largest contributor to its trade deficit. “So it’s not a pretty picture in terms of local capability and capacity. It’s very difficult to just go and put up a new plant and expect it to be up and running in 12 months. It’s virtually impossible.”

While South Africa is looking to develop its own vaccine, capacity is limited. “By my assessment, there are two major plants in South Africa that potentially have the capability and some capacity to manufacture a vaccine,” Nicolaou says. “The situation is very much going to depend on the various licensing and distribution arrangements.”

Kamradt-Scott says the world needs to come together as if it were fighting a war against a common enemy – something a nationalistic approach may hinder. “There are more than 160 vaccines in development,” he says, highlighting some of the issues with a number so often presented as evidence of the best things about the world’s Covid-19 response. “Even if 10% make it through phase III, that’s 16 vaccines – but we don’t need 16 vaccines, we need two or three that are effective.” As he sees it, that extra energy and investment could have been redirected to other initiatives for scaling up production and increasing access, as well as ensuring the production of medicines for other diseases that continue uninterrupted.

With the potential for so much variation in the effectiveness of different vaccines, the industry also needs to safeguard public trust, he says. “What happens if we have variations in quality? What if one vaccine offers lifelong immunity but another doesn’t? When you present your yellow fever vaccination card, it’s accepted that the vaccination is reputable. That may not be the case for Covid vaccines produced in all countries.”

World-system problem

Despite their geographical and professional spread, Robinson, Cueni, Larkins, Kamradt-Scott and Nicolaou are all thinking about nationalism. The global pandemic is having local impacts that are likely to outlast it.

“I find it hard to believe there is a single country that hasn’t learned some very material and very significant lessons from Covid-19,” says Nicolaou. “I think there will be significant reorientation from governments – how do we boost local capacity and capability for the future, particularly in areas where we are most vulnerable? I do see that as a positive consequence of the pandemic.”

Cueni agrees this will be a worldwide trend, and believes the investments in R&D and domestic manufacturing should help lift global capacity for future pandemics. Even so, he says any new facilities will need to be kept in a constant state of readiness to remain useful – plants and skills can’t be mothballed. That means a commitment to robust, long-lasting vaccine policies across the world, and high levels of vaccine uptake to justify production

Kamradt-Scott also sees an opportunity to refocus. “I would love to think that we could see Covid-19 as not only a crisis but as an opportunity,” he says, “particularly when it comes to vaccine manufacturing and getting us in a better place for next time. These events are not going to suddenly disappear – all the evidence suggests that outbreaks that have global impacts are accelerating. Soon, we will switch from a health crisis to an economic crisis and governments will move on. “We risk making the same mistake we did in 2009 after H1N1, when we had what was described as ‘pandemic fatigue’. We have a very small window whereby we have an opportunity for change. If we are not careful, that window will pass us by.”