Skip to main content
Menu

Covid-19

More on mRNA Vaccine Manufacturing

Here’s a good article from the Washington Post that updates some details that I talked about in this post on the lipids used in the mRNA vaccines and in this one about their overall manufacturing process. It focuses on Acuitas, who make the two proprietary lipids that are used in the Pfizer/BioNTech vaccine. Actually, if you go back a step, you get to Avanti Polar Lipids down in Alabaster, AL (as mentioned in Jonas Neubert’s terrific dive into the supply chains for these vaccines). Update: fixed some hosed-up links.

As you would imagine, everyone involved is having quite a time meeting demand. As the article says, though, it’s hard to get a clear picture of where the exact pinch points are, because the terms of the various contracts are not public, nor are even the identities of the raw material suppliers further up the chain. But anyone who’s had to source intermediates or starting materials in the drug business at any kind of scale will appreciate that the fastest way to find out what those weak points are is to place a Big Ol’ Order for something.

Among the interesting things you can uncover with that experiment is that what looks like several suppliers for Important Ingredient X are nothing of the kind, because they’re all (surprise!) sourcing it from the exact same place, likely as not somewhere back in China. That effect definitely happens with the Chinese suppliers themselves – a list of supposed sources across southern China will turn out, on closer inspection, to resolve to a single shop out in Chengdu or (even more worryingly) a bunch of drums in a warehouse near Shanghai from a big manufacturing overrun a few years back. The general tendency of many suppliers in every country to give you quotes for things that they don’t quite have yet, but are pretty sure they can round up if you place an actual order, also has to be taken into account.

In this case, you can be sure that everyone got down to the proverbial brass tacks very quickly, but it seems clear that there have been some difficulties sourcing starting materials on the scale needed and/or running some of the chemistry. These lipids involve multistep syntheses, and that’s just going to chew up time no matter what. This article at C&E News will give you some more details on that process, and I especially like this part:

Matthieu Giraud, global director of CordenPharma’s peptides, lipids, and carbohydrates business, says the synthesis requires about 10 steps and several product isolations. A complete manufacturing campaign is measured in months.

That does sound delightful. That team gets eaten up by all kinds of things: what sorts of purification are needed before the next step can be run, what the batch-versus-continuous-processing landscape is like, what scale the chemistry can be done at in the first place, and how that matches up with the sheer physical capacity of the plants doing the work. That scaling question alone is the door to a world of headaches: maybe one of the steps has an exotherm in its chemistry, which can mean special mixing conditions and size limitations. Or the product is especially thick and viscous and is thus harder to transfer and purify. There might be something tricky about the addition of a particular reagent – it’s corrosive unless you use certain alloys, or has to be warmed up to flow reliably and not all your reactors have that capability, or it doesn’t mix easily when it goes into the bulk reaction, or maybe something is theoretically available from several suppliers, but only one of them can furnish it in the sort of pellets that work best on scale. It goes on and on.

The topic of mixing brings up the formulation question that is one of the key steps in the whole process, forming the lipid nanoparticles with the appropriate amount of mRNA in each. I found this part quite interesting:

Companies have had to build equipment from scratch, including machines that shoot two streams of solution — one containing mRNA and one containing lipids — into a high-speed collision to fuse the nanoparticles and encapsulate the genetic payload. 

Exactly the sort of thing I was picturing here. No, this is a pretty weird process compared to most production lines. There are two ways to look at this whole business, and they both have validity. The first is “Why the hell didn’t we anticipate this? Why didn’t we put more money into the raw materials supply chain and the manufacturing capacity, and plan for success?” I’m sure that there are parts of this that could have been done better, but at the same time I’m also sure that Acuitas and the other players in this area have been scrambling since early last year to try to meet a vastly scaled-up demand as well (that C&E News story above confirms this). Some of these problems could have been solved or at least ameliorated by throwing money at them, and some couldn’t – and remember, buckets of money were in fact showered on every part of the process. But even more could quite possibly have helped.

The second viewpoint is to be struck by how much we’ve been able to scale up these things anyway. That might sound too happy and rosy, but there’s something to this take as well. When you look at that WaPo article, one thing that hits you is that the Acuitas people and others who have been involved in this area for a long time are stunned by how far it’s come and how quickly. I’d be willing to bet that if you’d called any of them up in (say) December 2019 and asked them if they could get to where they actually are by February 2021 they’d have been terrified.

My guess is that the truth is in between those two: I certainly doubt that the mRNA scaleup process has been flawless, but I don’t think that people have exactly been bumbling around, either. I continue to be thrilled that the vaccines work, and work as well as they do, and I will be rolling up my sleeve for them the first chance I get.

26 comments on “More on mRNA Vaccine Manufacturing”

  1. Paul Duncan says:

    Hi Derek,

    The “good article” link refers to your 2021-01-11 “RNA Vaccines And Their Lipids
    ” post, rather than to a Washington Post article.

    Thanks,

    1. Paul Duncan says:

      For anyone else following along, I think this is the article that Derek is referring to:
      https://www.washingtonpost.com/business/2021/02/18/vaccine-fat-lipids-supply/

      1. sgcox says:

        That was precisely the first link (links are in blue) in Derek post…
        Still, it asks for subscription so will rely on insightful comments here.

        1. Derek Lowe says:

          I had messed up the link at first, so it should be right now.

  2. Jack says:

    I would be interested in your comments on vaccine transmission, particularly this study that came out today where everyone was regularly tested: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790399

  3. Red Fiona says:

    Avanti, now there’s a blast from the past for me. I always had good experiences, but was working on much smaller scales.

  4. luysii says:

    This is all very lovely, but vaccines won’t work unless people take them. My cousin’s son works in a nursing home and says that about 1/3 of the staff won’t take them.

    On a larger scale it’s even worse. My wife and I received the booster dose of the Pfizer vaccine today. We live in a town that is 45% Latino (mostly Puerto Rican). Both times we were there, the vaccinees were almost all Caucasian, a disaster in the making.

    The setup was a marvel of efficiency. The time of vaccination was written on a sticky, which was to be placed on the (widely separated) chairs we sat on for 15 minutes, watched by several nurses for any symptoms. As soon as we got up, someone (a Latino wouldn’t you know) zoomed over and sterilized the chair. The nurse I spoke with said that what we’d seen about Latinos not getting vaccinated was typical in her experienced. She also noted misinformation going around among them, such that vaccination would make you sterile.

  5. Walt Pickett says:

    I agree Avanti is top notch. It was the best lipid company in the 1970s. Does anyone remember their name before Avanti?

  6. bootsy says:

    I did some work on LNPs a while ago and lipid starting material suplies were weird then. Small impurities can make a big difference and most of the common chemical vendors wouldn’t supply better than 90% purity. One of the best outfits was this place in Minnesota called Nu-Chek Prep. We used to order hundreds of grams of different lipids from them. One of our team members met them at a conference and found out it was this tiny outfit of just a few people and they knew us by name because of our large orders. Apparently, it was really annoying to them to have to scale up every time we ordered.

  7. Richard says:

    Hello Derek,
    Congrats for your great blog. Here are some insights in the many companies participating in the development of MRNA vaccines. For BioNTech, I have counted 153 of them. https://www.pearltrees.com/richardetienne/covid-vaccines-and-logistics/id39519376
    Best regards from Switzerland,

  8. No says:

    Great post!
    I suppose the “team” in “That team gets eaten up by all kinds of things” should be time?

  9. JohnP says:

    While I am sympathetic to complex supply chain issues, and those problems are to some degree inevitable and not solvable with DPA or the like, what I am not sympathetic to is how much of this remains secretive. If these companies won’t help our collective effort to figure out the bottlenecks, they should be called up in front of Congressional committees and forced to divulge. Open patents do no good if the actual manufacturing process and supply chain is being deliberately kept secret even in the face of a global pandemic.

    For instance, from the article we have:

    – The production problems — which the companies have declined to discuss in any detail — underlie the difficulty of the quest for vaccine shots
    – Pfizer said in response to questions that it has made unspecified changes to its facilities and manufacturing that will allow it to double vaccine output.
    – Moderna did not respond to a request for comment.
    – He said it is difficult to know the extent of any shortfalls because companies typically do not make such details public.
    – Vaccine companies have released minimal information publicly about how they have used their money to support vaccine manufacturing.
    – The raw materials supply chain also has been shrouded in secrecy relating to proprietary licensing deals and contract manufacturing arrangements.
    – The company producing the Acuitas lipids used in the Pfizer-BioNTech vaccine, Avanti Polar Lipids, of Alabaster, Ala., declined to comment.
    – CordenPharma, which has plants in Europe and Boulder, Colo., and is supplying Moderna with lipids, also declined to comment.
    – TriLink, through the parent company, declined to comment.

  10. Ricky Marvin says:

    Hypothesis: Covid-19 mRNA vaccines are associated with unusually high adverse reactions.

    Results:
    CDC Vaccine Adverse Event Reporting System (VAERS), US data 2015-2021

    covid-19 vaccine has these temporally associated events in its database on 02/23/21:
    deaths/life-threatening/hospitalizations = 799/610/1851
    65000000 doses administered, assume undereporting by 2x (low) and 10x (high),
    probability of dose/event becomes
    deaths/life-threatening/hospitalizations (1 in) 2x (low) 40676/53279/17558 and 10x (high) 8135/10656/3512

    ie high estimates could be 1 in 8135 doses is temporally associated with death
    deaths per 100 million US population = 12292
    deaths per 330 million US population = 40565

    ie 40565 US vaccine deaths temporally associated with vaccination of entire population per year

    compare to 6 years of seasonal influenza vaccine administrations at 1965000000 US total population at 0.59 coverage = 1159350000 doses
    as above, probability of dose/event becomes = 1091/2745/15158

    rate covid-19/flu vaccine = 13x deaths/4x life threatening/2.2x hospitalization

    SARS-Cov-2 deaths in US total = 536566
    SARS-Cov-2 deaths in US not associated with comorbidities = 536566 * 0.06 = 32193

    rate of vaccine deaths (high)/SARS-Cov-2 deaths (single cause) = 40565/32193 = 1.26

    1. Marko says:

      (since you’re spamming here, I’ll have to do the same)

      Even if your numbers are accurate, the vast bulk of vaccine deaths are not happening among strapping, healthy 30-yr-olds, they’re happening among the frail elderly and those with comorbidities, just as for Covid-19, so your final comparison is not remotely fair or valid.

      The question about getting vaccinated is the same for a healthy young person as for an elderly frail person: Am I more likely to die from Covid-19, which I will almost certainly contract eventually if not vaccinated, or am I more likely to die from the vaccine? If you want to argue that for some the latter is the case, you’ll have to present a much better analysis than the one above.

    2. Chris Phillips says:

      “covid-19 vaccine has these temporally associated events in its database on 02/23/21:
      deaths/life-threatening/hospitalizations = 799/610/1851”

      You say that is after 65 million doses of the vaccine. Suppose that’s 32.5 million people (in reality it will be more). In a random sample of that many people, just in the normal course of things about 6,000 will die every week. And yet you say just because these deaths are “temporally associated”, that the vaccine is “the causative agent”!

  11. ricky marvin says:

    Covid-19 is the causative agent for all 536566 deaths and the Covid-19 vaccine is the causative agent for all 799 vaccine deaths. Both are true, one is true, or neither are true.

    The last line is simply a ratio of a high projection of collateral damage due to the vaccine over Covid-19 deaths whereby covid-19 is the causative agent using official CDC data. Since as you have noted that the VAERS data is difficult to deconvolute from conflating variables at the present time, we can take the number in its entirety to give the upper most morbid bound.
    We can then ask what percentage of this upper bound would be acceptable collateral damage to society.

    What is the status on sterilizing immunity confered by the vaccines?

    (missing VAERS influenza data: deaths/life-threatening/hospitalizations = 1091/2745/15158
    as above, probability of dose/event becomes = 1062649/422350/76484)

    1. Marko says:

      “Since as you have noted that the VAERS data is difficult to deconvolute from conflating variables at the present time, we can take the number in its entirety to give the upper most morbid bound.”

      Yes, and to compensate for your inability to determine whether vaccine deaths occurred mostly to people with one foot already in the grave, the only valid comparator is all Covid-19 deaths, not your “single cause” confabulation.

      Sterilizing immunity is not an issue here. If vaccines prevent 90% of deaths or more , the pandemic is over.

  12. K sidhant says:

    Does this process do decent work flawless

  13. Mary says:

    This has not taken into account the possibility of long term morbidity and mortality. Research suggests that the spike protein disrupts the blood brain barrier resulting in neural inflammation with its sequela.
    https://www.sciencedirect.com/science/article/pii/S096999612030406X

    1. Good Point says:

      Sounds like an excellent reason to get vaccinated – you wouldn’t want that COVID virus infecting you for months and producing all of that spike protein. Best to be exposed in limited fashion (the mRNA is quite short lived) and get that immune response going quickly.

  14. debinski says:

    The FDA briefing document for Friday’s Janssen vaccine meeting is now available:
    https://www.fda.gov/media/146217/download

    1. debinski says:

      Some very good news in the results is that the vaccine was 100% effective against Covid requiring medical intervention after 28 days and 86% effective after 14 days.

  15. exGlaxoid says:

    Given that the covid vaccine has mostly been given to elderly and very sick people so far, I would expect the number of anticipated deaths to be much higher than average. In most large nursing homes, there is a death or life threatening crisis almost every day or more often. Having cared for 5 people over the last decade who were in them, I know that almost everyone there is at risk of death at any time, but deaths in older people have dropped dramatically a few weeks after vaccinations started, so clearly the vaccine is safe and effective, compared to not being vaccinated.

    Studies from Israel, the UK, and Scotland all show that, as well as early US data. Given the current data, only a fool would make claims that the vaccine is not safe and effective, compared to the risk of covid, at least in older people. But I would not rush to vaccinate people under 18 or even most people under 30, as they have a very low risk of severe illness from covid, so I am happy to work down from oldest to youngest in vaccination.

    Frankly, I don’t care if some people don’t want the vaccine, that will make it easier for the rest to get it quicker. When they get sick, they will either get well get some level of immunity, or die, and that will solve the issue. Eventually we will have herd immunity, just much faster and safer via vaccine. As long as we get to the point that everyone who wants it gets it, the rest can gamble on it. But once everyone has had a chance to get the vaccine and a month has gone by, I don’t think you will be able to force people to wear masks and avoid crowds any more, and most every airline, venue, school, and workplace will eventually mandate vaccination to go there, so it will happen in good time.

  16. anon the II says:

    I was driving home from the beach last night on I-40 and heard Derek on NPR. He was talking about vaccines. I told my wife, “I know who that guy is”.

  17. TallDave says:

    “As the article says, though, it’s hard to get a clear picture of where the exact pinch points are, because the terms of the various contracts are not public, nor are even the identities of the raw material suppliers further up the chain.”

    ha, yes, well, I’ve worked in a few medical ERP chains and quite often no single person, corporation or system has that information, it’s the “I, Pencil” essay in action

    you push your orders through your own link in the chain as best you can

    we so often don’t know what we think we know

    e.g. how many times now have we been told NZ has this pandemic licked”As the article says, though, it’s hard to get a clear picture of where the exact pinch points are, because the terms of the various contracts are not public, nor are even the identities of the raw material suppliers further up the chain.”

    ha, yes, well, I’ve worked in a few medical ERP chains and quite often no single person, corporation or system has that information, it’s the “I, Pencil” essay in action

    you push your orders through your own link in the chain as best you can

    we so often don’t know what we think we know

    e.g. how many times now have we been told NZ has this pandemic licked

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.

This site uses Akismet to reduce spam. Learn how your comment data is processed.