By Derek Lowe
In the last few days, the question of why more drug companies haven’t been enlisted for vaccine production has come up. It’s mostly due to this tweet:
The problem is, as far as I can see, this is simply wrong. There are not “dozens of other pharma companies” who “stand ready” to produce these mRNA vaccines. To me, this betrays a lack of knowledge about what these vaccines are and how they’re produced.
Even though I’m not a pharma manufacturing person, I am indeed a pharma researcher in general. So I would be glad to fill in this gap, and here’s why it’s not possible to suddenly unleash dozens of companies to crank out the Pfizer /zigman2/quotes/202877789/composite PFE -0.15% /BioNTech and Moderna /zigman2/quotes/205619834/composite MRNA +6.79% vaccines.
The first thing to understand is that these are not, of course, traditional vaccines. That’s why they came on so quickly. mRNA as a vaccine technology has been worked on for some 20 to 25 years now, from what I can see, and (as I never tire of mentioning) we’re very fortunate that it had worked out (and quite recently) several of its outstanding problems just before this pandemic hit. Five years ago we simply could not have gone from sequence to vaccine inside of a year. And I mean that “we” to mean both “we the biopharma industry” and “we the human race”.
At this point, let me briefly dispose of an even less well-founded take that’s been going around as well. I’ve seen a number of people say something like “We had the vaccine back in February! It only took until the end of the year to roll it out because of the FDA!”
The main thing I’ll say about that idea is that no one who actually works on vaccines, in any capacity, has any time for that statement. Not all vaccine ideas work — we’re already seeing that with the current coronavirus, and if you’d like to talk to some folks about that, then I suggest you call up GlaxoSmithKline /zigman2/quotes/209463850/composite GSK +0.48% /zigman2/quotes/200381158/delayed UK:GSK -1.40% and Sanofi /zigman2/quotes/201967021/composite SNY +1.19% /zigman2/quotes/206928357/delayed FR:SAN -0.85% and ask them what happened to their initial candidate, and while you’re at it, call up Merck /zigman2/quotes/209956077/composite MRK -0.52% and ask them what happened to their two.
Note that I have just named three of the largest, most experienced drug companies on the planet, all of whom have come up short. So no, we did not “have the 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 pharma companies” from doing the same? Let’s get into those details, stopping briefly again to imagine asking James Hamblin above to actually start naming “dozens” of pharma companies. Anyone have a good over/under on how many names would get rattled off?
OK, let’s look at the actual supply chains. The single most informative piece I have seen on this is from Jonas Neubert – I’ve recommended it before, and this is absolutely the time to recommend it again. I also have to mention this detailed article at the Washington Post , which focuses on the Pfizer/BioNTech vaccine, and this one at KHN about manufacturing bottlenecks in general. You should also read this Twitter thread from Rajeev Venkayya, who knows what he’s talking about when it comes to vaccine manufacturing, too. All of these will cover details that I’m not even going to get to today!
It’s not in my nature, since I’m an early-stage drug research person myself, but I’m going to totally sidestep all the R&D questions behind the various components and just treat this as a manufacturing process that fell from the sky in its final form.
To distill a huge amount of background and detail down into the simplified steps, we have:
Step One: Produce the appropriate stretch of DNA, containing the sequence that you need to have transcribed into mRNA. This is generally done in bacterial culture.
Step Two: Produce that mRNA from your DNA template using enzymes in a bioreactor.
Step Three: Produce the lipids that you need for the formulation. Some of these are pretty common (such as cholesterol), but the key ones are very much not (more on this below).
Step Four: Take your mRNA and your lipids and combine these into lipid nanoparticles (LNPs). I have just breezed past the single biggest technological hurdle in the whole process, and below you will learn why it’s such a beast.
Step Five: Combine the LNPs with the other components of the formulation (phosphate buffers, saline, sucrose and such) and fill those into vials.
Step Six: Get those vials into trays, into packages, into boxes, into crates, and out the door into trucks and airplanes
OK, you have now produced the mRNA coronavirus vaccines and shipped them out into the world, so sit back and open a cold one. You will not reach that stage, though, without some significant challenges. Let’s take those step by step.
The DNA production in Step One is not too bad. As the Neubert article details, Pfizer does this in St. Louis, and Moderna outsources this to the large and capable Swiss firm Lonza /zigman2/quotes/206849989/delayed CH:LONN -0.15% /zigman2/quotes/205537756/delayed LZAGY +2.05% .
DNA plasmid production on an industrial scale is pretty well worked out (and keep in mind that “industrial scale” for DNA means “a few grams”. It’s not something you can do in your garage; as with every step in this process there’s a lot of purification and quality control to make sure that you’re making exactly what you think you’re making and that it looks exactly within the same specs as the last time you made it. But that’s what biopharma manufacturing folks are good at, and there are a lot of people who can do it.
That said, a goodly number of them are occupied doing that for just the vaccines, but if we needed more of this DNA, sure, we could produce more.