COVID-19 vaccine manufacturing bottlenecks – troubling issues

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With the good news recently regarding the Pfizer and Moderna vaccines, I remain concerned about COVID-19 vaccine manufacturing bottlenecks. This could be an important issue that seems to be ignored by a lot of the public. This isn’t some MBA school consideration, it is a serious problem that could delay these vaccines for a long time.

I constantly joke that people oversimplify how we get a vaccine – throw some ingredients in a blender and, voila, we’ve got a vaccine. If only it was that easy.

This article is going to attempt to review COVID-19 vaccine manufacturing along with some of the bottlenecks that keep appearing. And this isn’t just an issue with the two mRNA vaccines that seem to be the fastest to market, but with all of the leading vaccines.

COVID-19 vaccine manufacturing capacity

There seems to be a misunderstanding that vaccine manufacturing is a plug-and-play system – just convert all manufacturing to a coronavirus vaccine, and suddenly we’ll have the vaccine on the market. But it isn’t.

First of all, not everyone can be approved to manufacture vaccines that can be sold in “developed countries“, usually considered to be the USA, Japan, Australia, New Zealand, Canada, and the EU. All of these countries have strict regulatory standards for the production of vaccines.

Right now, all vaccines sold in the USA and other developed countries are manufactured in the USA, Australia, Japan, Canada, Belgium, France, Germany, and Switzerland.

Countries like China and India have large vaccine manufacturing, but their quality standards may not be adequate. Recently, one Chinese manufacturer sold vaccines that killed numerous children. For the purpose of this article, I’m going to focus on vaccine manufacturing that meets the highest regulatory standards.

It’s difficult to get a handle on the total capacity of vaccine manufacturers in developed countries – it is probably in the billions of doses. However, and this is important, that capacity is spread among many vaccines – seasonal flu, measles, mumps, rubella, chickenpox, HPV, diphtheria, pertussis (whooping cough), tetanus, and many others. 

While there may be common equipment across platforms such as bioreactors, filtration, and chromatography equipment, filling and lyophilization equipment, the sequence of operations and the specific cycles for each may vary from vaccine to vaccine. Generally, each vaccine,  (or group of vaccines within a product family) has its own dedicated facility and production team. This dedicated labor and equipment allows for flexibility to address unpredictable demand, but only for vaccines that it already produces. 

There is some “surge capacity” in those manufacturers, which happens when there is a flu pandemic, but it may just be 100-200 million doses. So, with the current capacity, coronavirus vaccine manufacturing may be far below demand.

To meet the needs of manufacturing billions of doses of COVID-19 vaccine, billions because we need to vaccinate the whole world, vaccine companies have been manufacturing in advance of FDA (and other regulatory agencies) approval and building up facilities.

Sanofi description of the general manufacturing process for vaccines.

Increasing COVID-19 vaccine manufacturing capacity

The first issue is manufacturing equipment. Each manufacturing “line” (which can produce a few hundred thousand doses per day at best) can’t be ordered from Amazon or frankly anywhere. Generally, manufacturing engineers design each vaccine manufacturing line individually for the vaccine (or numerous vaccines). 

You just can’t order a coronavirus vaccine manufacturing line without determining how the vaccine will be manufactured. Generally, we don’t know that until such time the vaccine formulation has been approved by the FDA (or other regulatory authorities). 

And this equipment is expensive – on average, about US$500 million. 

So once this equipment is ordered, it takes months, even a year for it to arrive. I’m sure it can be sped up with extra cash being spent, but these things are hand manufactured from top to bottom. They are mostly made of pharmaceutical-grade stainless steel, which doesn’t corrode, is easier to keep clean, and lasts a long time. And they are incredibly complex.

But it’s not just the equipment that limits coronavirus vaccine manufacturing capacity. You need experienced labor, quality control, and engineers to set up and run a vaccine manufacturing line.

The manufacturing line employees, that is the people who keep the line running, are very high-paid, highly-skilled labor. These are not individuals you find anywhere, you either have to steal them from other companies or manufacturing lines (and they’d have to be replaced), or you train them over a few months. 

Quality control systems have to be developed. Of course, if a company is already producing vaccines, it makes it easier to develop a protocol and get qualified people to run them, but again, there is not an infinite supply of these individuals. In fact, if you’re looking for a high-paying job and have a lot of experience in laboratory science, you can get one soon with this explosion in vaccine manufacturing. 

Finally, you need engineers who can design and troubleshoot manufacturing lines for a new coronavirus vaccine. Again, these aren’t people that grow on trees, they are rare.

COVID-19 vaccine manufacturing

Bottlenecks

I think that the vaccine manufacturers have done a wonderful job over the past 6-8 months building up their capacity. However, there are issues beyond just a manufacturing line that impacts our ability to get COVID-19 vaccines in sufficient numbers.

For example, vaccines are generally (though there are exceptions) manufactured in glass syringes and vials. This is not your average, everyday glass that you might have in your house, it is a “pharmaceutical-grade glass.”

Manufacturers of this glass must meet the same FDA and GMP requirements that are demanded of the drug manufacturers themselves. This glass is “non-reactive,” that is, it won’t cause any changes in the vaccine over time (this is one of the reasons why plastic isn’t used in most vaccines). 

Only a few companies worldwide manufacture pharmaceutical-grade glass, so there is a limited capacity for the vials and syringes to hold the vaccines. Because vaccine manufacturing was kind of stable over the past few years, these companies did not develop additional production capacity. Now they have to scramble to source their raw materials and increase capacity for the COVID-19 vaccines.

Next up are needles. You might think that it’s a commodity product that just about anyone could make in their garage, but you would be wrong.

The largest (by far) manufacturer of syringe needles that would be required for injection is BD (formerly known as Becton Dickinson). Their needles have been designed to reduce pain and are produced in very specialized manufacturing facilities.

Although BD may have a capacity of a billion needless or more per year, it can’t all be moved to coronavirus vaccine manufacturing for all the reasons I mentioned above – like being necessary for other vaccines, insulin, IV needles, and about a thousand other needs.

There are other manufacturers of needles in the USA and Europe that could help fill the supply chain, but those companies have much less capacity.

Vaccine ingredient issues

The first issue is getting the mRNA molecules that are a part of the Moderna and Pfizer vaccines (but not used with the next closest vaccine, from Janssen). One of the reagents needed to produce the mRNA (that codes for the spike protein on the SARS-CoV-2 virus) is proteinase-K. The problem is that this particular substance is required for both diagnostic tests for COVID-19 along with producing the mRNA vaccine. It is now in very short supply, and everyone, including diagnostic companies, is scrambling to either produce it or source it.

It is somewhat amusing that many of us who are fascinated by these mRNA vaccines never considered how much effort is needed to isolate those particular molecules.

The mRNA fragment needs to be encapsulated within a lipid membrane so that it can enter the cell of the vaccinated individual. Again, Pfizer needs to maintain a constant source for those lipids, which has also been problematic.

Of course, Moderna is going to run into the same issues as Pfizer as they use almost the same design as Pfizer. 

Summary

There have been some very reliable reports that Pfizer is experiencing some serious supply chain issues that forced it to cut its production forecast from 100 million by the end of this year to 50 million (and remember that because it requires two doses, that’s really 25 million people who will get vaccinated across all markets where Pfizer is intending to ship the vaccine). 

This article isn’t here to scare everyone, it’s just that I want to make it clear that because of COVID-19 vaccine manufacturing issues, it’s going to delay the plan to get enough people vaccinated to end this pandemic. That’s why we need to continue wearing masks and social distancing. 

Even though development and clinical trials seem to be our focus these days, the COVID-19 vaccine manufacturing is going to determine how many doses we get and how fast. And at this time, it’s not as easy as we would all like.

Notes

Most of the information above comes from this article by Stanley Plotkin et al. and my several years’ expertise in vaccine manufacturing, especially in vaccine container design and development. I may be one of the very few vaccine bloggers that helped design vaccine manufacturing with actual smart engineers. And I got to live in France for a few weeks!

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The Original Skeptical Raptor
Chief Executive Officer at SkepticalRaptor
Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!