Exterior the Field: A Easy Clarification of Why “Dozens” of Companies Can't Make Extra COVID-19 Vaccines

In the past few days the question has been raised why not more pharmaceutical companies were hired to manufacture vaccines. It's mainly because of this tweet:

The problem is, as far as I can see, this is just wrong. There aren't "dozens of other drug companies" "ready" to make these mRNA vaccines. To me, this betrays a lack of knowledge about what these vaccines are and how they are made.

Although I am not a pharmaceutical manufacturer, I am indeed a pharmaceutical researcher in general. I would be happy to fill this gap. Therefore, it is not possible to suddenly lay off dozens of companies in order to bring the Pfizer to market
/ BioNTech and Moderna
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The first thing to understand is that, of course, these are not traditional vaccines. That's why they came so quickly. As far as I can see, mRNA has been worked on as a vaccine technology for about 20-25 years, and (as I never tire of mentioning) we are very fortunate to have developed several (and recently) several of these open issues just before this pandemic. Five years ago, we just couldn't have switched from sequence to vaccine within a year. And I mean that "we" mean both "we the biopharmaceutical industry" and "we humanity".

At this point, let me briefly address an even less well-founded attitude that has also got around. I've seen a number of people say something like "We had the vaccine in February! Due to the FDA, it only took until the end of the year to get it started!"

The main thing I'm going to say about this idea is that no one who is actually working on vaccines in any form has time for this statement. Not all vaccine ideas work – we can already see that with the current coronavirus. If you want to talk to some people about this, you should give GlaxoSmithKline a call

and Sanofi

and ask them what happened to their original candidate and give Merck a call while you're at it
and ask her what happened to her two.

Note that I just named three of the largest, most experienced pharmaceutical companies in the world, and they all fell short. So no, we didn't have a vaccine in February.

One of the other reasons we didn't have it back then is the whole problem of figuring out how to make the stuff, and that brings us back to today's discussion. How do you make the Moderna and Pfizer / BioNTech vaccines? And what's stopping "dozens of other drug companies" from doing the same? Let's get into those details and pause again to introduce ourselves asking James Hamblin above to actually name "dozen" of drug companies. Does anyone have a good over / under on how many names would rattle off?

OK, let's look at the actual supply chains. The most informative piece I've seen on this is by Jonas Neubert – I've recommended it before, and this is absolutely the time to recommend it again. I must also mention this lengthy article on the Washington Post that focuses on the Pfizer / BioNTech vaccine, and this one on KHN on making bottlenecks in general. You should also read this twitter thread from Rajeev Venkayya who knows what he's talking about when it comes to making vaccines too. All of this will cover details that I won't even go into today!

It's not in my nature as I'm a person in early drug discovery myself, but I will totally bypass any R&D questions behind the various components and simply treat this as a manufacturing process that fell from heaven in his eyes final Shape.

To break down a large amount of background and detail into the simplified steps we have:

Step one: Produce the appropriate stretch of DNA that contains the sequence you need to have transcribed into mRNA. This is generally done in bacterial cultures.

Step two: Produce this mRNA from your DNA template using enzymes in a bioreactor.

Step three: Produce the lipids you need for formulation. Some of these are pretty common (like cholesterol), but the main ones aren't (more on that below).

Step four: Take your mRNA and your lipids and combine them into lipid nanoparticles (LNPs). I've just passed the biggest technological hurdle in the whole process, and here's why it's such a beast.

Fifth step: Combine the LNPs with the other ingredients of the formulation (phosphate buffer, saline, sucrose, etc.) and fill them into vials.

Step Six: Get these vials in trays, in packages, in boxes, in boxes and out the door on trucks and planes

OK, you have now made the mRNA coronavirus vaccines and shipped them to the world. So sit back and open a cold one. However, you will not reach this stage without significant challenges. Let's take this step by step.

The DNA production in Step One is not bad. As the Neubert article describes in detail, Pfizer is doing this in St. Louis, and Moderna is outsourcing this to the large and capable Swiss company Lonza


The industrial scale production of DNA plasmids is pretty well worked out (and remember that “industrial scale” for DNA means “a few grams.” You can't do this in your garage as it does at every step in the process There's a lot of cleaning and quality control to make sure you're doing exactly what you think you're doing and that it is exactly to the same specifications as last time, but that's exactly what the folks in biopharmaceuticals can do, and there are many People who can.

That said, a good number of them are busy doing this just for the vaccines, but if we needed more of that DNA we could safely produce more.

But we don't. This is not the rate capping step. Step two is also not the transcription into mRNA. Pfizer and BioNTech do this in Andover, Massachusetts and in BioNTech plants in Germany. It has a production facility in Idar-Oberstein (a city that I visited on a weekend in 1988 during my post-doc in the cold rain!) And last autumn it bought another factory in Marburg, which is currently being used for such a production in Is put into operation. The Moderna mRNA step is also taken over by Lonza in Switzerland.

This is certainly not as common as an industrial process, since it was only relatively recently that humans themselves began to treat RNA species as actual drug substances worthy of scale-up manufacture. If I had to ask someone to make me a few more bags of bespoke mRNA, I could turn to Alnylam
(with a manufacturing facility in Norton, Massachusetts, although they do use this for their own drugs) but this would not increase the number of vaccine bottles that come out at the other end of the process.

RNA production is certainly closer to the rate limit than it was in Step 1, but nothing compared to the actual bottlenecks we are facing.

Now for the lipids in step three. Of course, this does not have to be done one after the other as in the DNA / RNA step – the lipids required for the formulation are a completely different production process. As the Neubert article will show, Pfizer and BioNTech source all of their products from a British company called Croda
The production will probably take place in Alabaster, Ala., Which I (unlike Idar-Oberstein) certainly did not visit.

Now each of these vaccines need some strange lipids with positively charged groups; That is a crucial part of the formulation. These are certainly not trivial to produce on a scale, but they are still small molecules with relatively simple structures.

I'm sure kegs of these things don't pile up in the factory due to a lack of demand, but neither do I think they are the limiting reagent in manufacturing. You could certainly update some other manufacturers if you had to.

I will continue with step 5 and step 6. These certainly go with a good clip, but they are more traditional functions of a pharmaceutical (or manufacturing company) company.

It is true that filling and finishing pharmaceutical vials on this scale restricts you to fewer players than would be the case with canning tuna, for example. But these people are already involved.

Pfizer is doing this in Kalamazoo, Michigan and in Puurs, Belgium, and BioNTech is doing this in several locations in Germany and Switzerland, both at its own facilities and through at least two contractors. Moderna, meanwhile, is outsourcing this to some of the big players in the US and Europe: Catalent
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and Recipharm
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Everyone in this part of the manufacturing business has known for months that a big vaccination rush is coming. He's sped up the manufacture of vials, updated all available production lines, and signed contracts everywhere with anyone who has some sort of advanced vaccination effort.

Ah, but now we come back to step four. As Neubert says: "Welcome to the bottleneck!" Converting a mixture of mRNA and a range of lipids into a well-defined mixture of solid nanoparticles with consistent mRNA encapsulation is the difficult part.

Moderna appears to be doing this step internally, although few details are available, and Pfizer / BioNTech appears to be doing this in Kalamazoo and likely Europe as well.

Everyone will almost certainly have to use a purpose-built microfluidic device to achieve this. I would be extremely surprised to find that this could be done without such technology.

Microfluidics (a hot research area for several years) involves the flow of liquids through very small channels, which allows for precise mixing and timing on a very small scale. Liquids on this scale behave very differently than when pouring out of barrels or when pumping into reactors (as we are used to in more traditional drug production). That's the whole idea.

My own guess as to what such a vaccination machine entails is a large number of very small, parallel running reaction chambers in which there are also small and very precisely controlled flows of the mRNA and the various lipid components that enter them. You need to control flow rates, concentrations, temperature and who knows what else, and you can be sure that channel sizes and the size and shape of the mixing chambers are also critical.

These are tailor-made special machines. If you ask other drug companies if they have one, the answer is "of course not".

This is nothing like a traditional drug manufacturing process. And that's the biggest reason you can't just call those "dozen" other companies and ask them to convert their existing production to mRNA vaccine production.

There aren't dozens of companies making DNA templates on the scale required. There are definitely not dozens of companies that can make enough RNA. Most importantly, I believe that on the one hand you can count the number of facilities that can produce the critical lipid nanoparticles. That doesn't mean you can't make machines anymore, but I would assume Pfizer, BioNTech, Moderna (and CureVac)
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also) have largely taken up the production capacity for this type of expansion.

Read: GSK and CureVac are jointly developing vaccines against new COVID-19 variants

And let's not forget: the rest of the pharmaceutical industry is already mobilizing. Sanofi

One of the major vaccine suppliers (and one with its own interest in mRNA) has already announced that it will help Pfizer and BioNTech.

But look at the schedules: here is one of the largest and best-prepared companies that could get into vaccine manufacturing, and it won't have an impact until August. It is not clear what stages Sanofi will be involved in, but bottling and packaging are definitely involved (and there are no details on whether LNP production occurs).

And Novartis

has announced a contract to use one of its Swiss locations for bottling and completion by the middle of the year. Bayer
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joins the candidate from CureVac.

This is all good news, but it's a long way from this tweet that started this whole post. There aren't "dozens of companies ready" to make vaccines and "end this pandemic". They're the same few great players you've heard of, and they don't sit around and watch either. To say otherwise is a fantasy and we are better off with the facts.

Derek Lowe has worked for several large pharmaceutical companies on drug discovery projects for schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases since 1989. This was first published by Science Translation Medicine – "Myths of Vaccine Making". Follow him on Twitter @Dereklowe.

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