Exploring the Supply Chain of the Pfizer/BioNTech and Moderna Covid-19 Vaccines
blog.jonasneubert.comLike many others, I find the LNPs to be the most interesting part. It seems like Moderna was having issues with accumulation and toxicity issues, but changed something to make it safely degrade in the body. [0] Heres an interesting paper that shows some of the challenges. [1] 99% of it went over my head, but I still find the research intriguing.
[0] https://www.sciencemag.org/news/2017/12/can-multibillion-dol...
I used to work there til 2016, can confirm the immune responses were most lethal in pre-clinical trials
Here's something I can only speculate on with the cold chain.
I have mentioned it elsewhere on HN, but I've handle dry ice and liquid nitrogen quite a bit, first in college and then just later for fun. Several years back, I noticed a very large price hike in dry ice, as well as a drop in availability (less available in my city, vanishing from small towns). I was told by someone in my supply chain that federal regulations around dry ice had changed, resulting in only a few players being left in the game and of course the price going up.
I wonder if now, a decade or so later, the law of unindented consequences has reared its often invisible head.
Hi, author of the article here. If you can remember or find any additional details about this, I would be curious to learn more about it. I admittedly didn't research the dry ice section too deeply because it is so ubiquitous.
This NPR All Things Considered clip made me wonder if dry ice might be more complicated than I thought: https://www.npr.org/2020/12/24/950102003/does-u-s-have-enoug... Note how the interviewee's business is located in Miami but the dry ice comes from Georgia. Surely a populous state like Florida has local dry ice production?
Also, fun fact: "[Fearing a dry ice shortage,] the Wisconsin Cheese Makers Association sent a letter to state and federal officials asking that 350,000 pounds of dry ice a week be set aside." Source: https://www.cbs58.com/news/cheese-industry-threatened-by-cov...
If I had to take a stab, I would say 2008, but I could be wrong. I'd have to see if I could get into some "still closed to the public" places to ask for more specifics and go from there, because this was less than a minute of conversation over a decade back.
You're right in that it was once ubiquitous but it has grown steadily less so.
That looks an US thing, I got 50kg of dry ice for close to nothing from a small local outlet last year just to remove some rust and old paint. At scale it might be different so, 50kg are nowhere near enough.
Here we use dry ice to cool our beers at festivals :D
This is one of the best supply chain articles I ever read. Cudos!
As the article is mainly describing the supply chain, I'd like to add some of the challenges, especially downstream / last mile. The Biontech vaccine seems to be a royal pain to distribute. Cold chains are tricky to maintain, let alone at -70 C. Having doses packed in numbers larger than one makes it challenging to vaccinate people at the centers, the unfreezing takes some time, and the vaccine cannot be stored eternally once unfrozen. So you have to closely schedule appointments with the treatment of the vaccine itself for batches of people. Which cannot be allowed to wait in line because of COVID-19. It also means that existing infrastructure, doctors and care and nursing services, cannot be used to get the Biontech vaccine to the people. Yet another pain.
At yet, we are only discussing the purchased doses. Not even the delivery schedules, just the total quantity. As if that was the real bottle neck right now.
That’s the wicked nature of this disease at this point in time. It’s almost like it evolved to exploit the lunacy of modern society.
The politicians are busy blaming each other, and the news people are busy looking for bullshit scoops.
>It’s almost like it evolved to exploit the lunacy of modern society.
I think you're actually correct. If the lunacy of modern society helped it succeed vs genetically similar organisms I would call that a successful adaptation.
Hi, author of the post here. I tried to include some info on temperature requirements and how cold chain distribution works, but it's hard to capture that comprehensively because it varies a lot geographically.
While I do appreciate how difficult it is to distribute the Pfizer-BioNTech vaccine at -70 C, I am still puzzled by how deep into the distribution this temperature gets maintained. As far as I know, the spec is that the vaccine can be stored (and transported) at regular fridge temperatures for up to 5 days. It seems like everyone (in the US anyway) is focused on maintaining -70C all the way to the point of use. What about the alternative of thawing it at some distribution center and focusing efforts on getting it into a person within five days after that?
That's a good question. I didn't research the temp requirements that deep myself yet. Instead I worked from what I read online and in the press. Which is also the way it works in Germany. Now I am intrigued so, I will see what I can find.
EDIT: This really is frustrating. Either I am unable to google stuff or there really is no data sheet on the Biontech vaccine available online. All I found is nice pictures and text without numbers at Pfizer's website and second hand interviews of Biontech CFO saying the vaccine can be stored up to 5 days in a fridge. Real transparency doesn't seem to be a thing with everything Covid-19.
This Pfizer site is intended for healthcare providers in the US so technically not meant for your eyes, but it has all the info: https://www.cvdvaccine-us.com/product-storage-and-dry-ice
The equivalent page for Germany where BioNTech distributes the same vaccine: https://www.comirnatyeducation.de/resources.html
I have read that once unfrozen, it lasts for 30 days while refrigerated at a reasonable temperature.
So why is the -70c an issue at all? It seems totally reasonable that we could just ship it at refrigerated temp and it would all be used up well before the 30 day expiration.
The only explanation I can think of is that the information I read was wrong and it won't keep that long after thawing.
What we have now is the minimum viable product. The convenience features come later. If it weren't urgent, the MVP wouldn't have been shipped.
There are vaccines that are more shelf-stable in development. Merck is working on a pill version. All those features add to development time. The whole clinical testing process has to be re-run for each modification to the delivery chemistry.
A year or two downstream, there will be plenty of supply, competing vendors, fewer side effects, and greater ease of use. But we need something now, so the working prototype had to be manufactured.
I am happy that Biontech was as fast as they were. And their vaccine seems to work. It is just difficult to deploy on scale, that's all. And my impression is, politicians and officials in Germany, and the EU it seems, are underestimating that. Which slows down vaccinations. And then the public and the press jumped in, only to push for increased purchasing. Which doesn't help a bit until the last mile, in Germany handled locally by the states, is figured out.
A pill version, or just one general doctors practices can store and handle, will have a huge impact IMHO.
Several regions in Italy had to stop giving first doses this week because Pfizer is delivering less vials than planned and they would risk not being able to administer the second dose in the proper time frame, so I think the distribution logistics, while complicated, are being worked out alright.
As of now, the supply is the bottleneck.
Pfizer also closed down their facility in Belgium to increase capacity. One core function of Supply Chain management is matching demand and supply, at the point of use. In Germany, we had close to a million doses sitting in depots, at the same time vaccination centers didn't have enough doses.
I do have the impression, that Pfizer is partially increasing capacity to be able to meet the increased orders from European countries. That increase now will impact availability through the end of January and February. Nicely done, because just ordering more doesn't mean more is available right now.
As of December 2020, Germany ordered enough doses from Biontech / Pfizer and Moderna to vaccinate 68 million people. Herd immunity is achieved with 58.2 million. So the problem is not the overall number of purchased doses, it is a mismatch between supply and the vaccination schedule. Since people always ignore the time dimension when it comes t supply chains, the go to solution was to order more. Then everybody ordered more out of fear to not get enough. When politicians and media started to blame manufacturers for the perceived shortages, manufacturers wnet public saying governments didn't order more and they could deliver more.
This hooked back to the initial, and wrong, solution of just ordering more. Then orders flew in, the capacity at the Belgium plant was not sufficient anymore. Now they increasig capacity, not manufactring anythig for a while. Orderig more didn't help solve the perceived, current shortages, instead it aggrevated them.
Source (in German, sorry for that, but it was the best I could find) for the numbers: https://www.dw.com/de/deutschland-hat-genug-impfstoff-f%C3%B...).
This effect, when demand fluctuations (either normal fluctuations or artificial ones expressed in fluctuating order sizes) is screwing up availability and supply, is well know as the Bullwhip effect. We saw that in early 2020 with toilett paper. We saw it with masks. And now, at even larger scale with a more critical product, with vaccines. Looking at that from the sidelines is just frustrating.
EDIT: Somehow, there is no data (easy to find) out there regarding delivery schedules by month and supplier. Which sucks. But I did find this from the EU:
Total ordered doses: "Contracts have been concluded with AstraZeneca (400 million doses), Sanofi-GSK (300 million doses), Johnson and Johnson (400 million doses ), BioNTech-Pfizer 600 million doses, CureVac (405 million doses) and Moderna (160 million doses). The Commission has concluded exploratory talks with the pharmaceutical company Novavax with a view to purchasing up to 200 million doses." In total 2.2 billion doses ordered from various suppliers with options for an additional 200 million. There are 446 million inhabitants in the EU, they ordered almost 5 doses per citizen.
That part of the EU Q&A page is IMHo hinting at the true issue here:
"How will logistics work? How will vaccines be distributed?
Logistics and transportation is a key aspect on which all Member States have to work, as emphasised in the Communication on preparedness for COVID-19 vaccination strategies and vaccine deployment of 15 October.
Delivery to national distribution hub(s) will be ensured by the manufacturers.
Further distribution to vaccination centres will be ensured by Member States, who will also be responsible for the vaccination of their population."
Just having doses sitting in a central hub doesn't do anything. In Germany the 16 states are responsible for getting the doses to the people. With very different results so far. And to be honest, as long as manufacturers can keep production up with their agreed upon delivery schedules, the first mile from the manufacturer to the hubs is actually the easiest part of this whole operation.
Source:https://ec.europa.eu/commission/presscorner/detail/en/qanda_...
EDIT (again): I finally found some numbers, not even Google was helpfull here. Germany will get a total 91.3 million doses by end of Q2 2021 and another 127 million in Q3. Source: https://de.statista.com/statistik/daten/studie/1197100/umfra...
I stil didn't find any numbers for the EU, each EU-country or by month. That fact alone is troubling. These numbers do show so, assuming the delivery shedules will be similar for other EU countries, that ordering more is the wrong solution. instead, the focus should be, besides getting the local vaccination campaigns up and running, to get the already doses earlier. Swamping the manufacturers with additional orders already contributed, I assume, to the partial shut down of Pfizers EU plant. And that had the contrary effect of what everybody wants.
not sure, if me still being surprised by this kind of screw-ups by the German governmant and the EU is good thing or not. Especially the german government as a whole has quite a track record in failing at everything logistics and suplly chain related.
Somehow, there is no data (easy to find) out there regarding delivery schedules by month and supplier. Which sucks.
In the US, prying that information out of the previous administration was difficult. There's a database, called "Tiberius", with inventory info. The transition team only got access to it six days ago.[1]
Bloomberg has stats on how vaccinations are going in the US.[2]
Distribution should pick up soon, now that the nursing homes and medical providers have mostly been vaccinated. The next phase starts to move to big pharmacies doing most of the work.
[1] https://www.washingtonpost.com/health/2021/01/14/transition-...
[2] https://www.bloomberg.com/graphics/covid-vaccine-tracker-glo...
I was amazed how super focused on the essential features Biontech seems. They are not originally from the vaccination business but cancer treatments, but were able to task SARS-COV-2 within days and get the first vaccine out.
Storage requirements? Not essential. Prepackaged syringes? Not essential. I'd bet they are now working on those aspects but went to grab a huge part of the market with their MVP.
The research cooperation by the scientific community seems unprecedented. The Bomb had terrific focus as did the Apollo program. But those were proprietary for the most part, not a world-wide effort. This seems new.
It would be grand if this spirit continues and provides a model for the other sciences. I would like to think this is a potential silver lining that could have wonderful consequences.
Wow amazing article. Thanks a lot. Interesting to see that most of the technology comes from Europe and US. Also interesting to see that it is complete independent from Asia.
I have been trying to find out why the supply of mRNA is limited. This article gives me hope that it can be scaled up with the right focus. As long as there is no fundamental science to be discovered, industrial processes can be scaled with enough money.
It is not possible to grow chicken eggs faster. So it's been impossible to have anything less than a years lead time to get flu vaccines made in sufficient quantities.
Planet money even did a show on the emergency chickens [1] (have they been called into service already ?). So we have the chickens, but no COVID vaccine that can be grown in eggs.
[1] https://www.npr.org/2020/03/13/815307821/planet-money-why-th...
I know we're not supposed to discuss downvotes, but can anyone explain why this is downvoted so much? I want to know if there's some kind of misinformation here that I missed, so I'll spot it in the future.
It's probably the mention of chicken eggs.
Some vaccines are grown in HEK 293 cells. HEK 293 is a cell line taken from an aborted fetus. (HEK -> Human Embryonic Kidney). Many people consider vaccines grown in HEK 293 to be immoral. Chicken eggs are a moral alternative medium.
It doesn't necessarily apply in this case because the Pfizer/BioNTech vaccine was only tested on HEK 293, not grown in it. (Moderna's vaccine, conversely, was grown in HEK 293.) Some people still consider the testing to be immoral. Some don't.
It's true that some people consider it to be immoral but the Vatican has said that it's morally acceptable given the current circumstances and lack of alternatives. [0]
Source on Moderna's vaccine being grown in HEK 293? The things I've read stated otherwise, such as this handout from North Dakota's health department: https://www.health.nd.gov/sites/www/files/documents/COVID%20...
> Moderna's vaccine, conversely, was grown in HEK 293
Do you have a link to confirm that? I thought that Pfizer/BioNTech as well as Moderna used HEK cells solely for testing.
All mRNA vaccines are produced by in vitro transcription, that uses enzymes but involved no cells or any cell cultures like HEK 293.
> Moderna's vaccine, conversely, was grown in HEK 293.
This is false. Moderna's vaccine is synthesized, not grown.
There's a couple innocuous comments here that are downvoted for no discerable reason. Weird.
> Next to it is a picture of a CodexDNA BioXP device that is advertised as producing “custom DNA fragments of up to 7,000 base pairs”. Could this be the next distributed manufacturing revolution? This time with DNA printers making COVID-19 vaccines in our garages instead of 3D printers and plastic widgets?
> I’ll start with the bad news: Nobody will be making an mRNA vaccine in their garage any time soon.
... We're not there in time for COVID19, but technologically, I think we're less far away than this article presumes. Cost of both sequencing and synthesis has been dropping like a rock, albeit not very smoothly. I can get DNA synthesized for less than what I was paying for amateur PCBs as an undergrad.
A lot of the other complexity, I suspect, is specific to getting this out in <1 year. It's worth remembering the earliest vaccines took no technology beyond what I have in my garage. With a little more time and patience, I'm sure some of the other complexity will go down. We can't spare time and patience when we're bleeding billions of dollars from our economy and thousands of lives each day, but....
> Nobody will be making an mRNA vaccine in their garage any time soon.
There was actually a video on YouTube a few months ago about some biohackers, Josiah Zayner and others, who made a DNA COVID vaccine in their garages, and it actually worked. Granted it wasn't mRNA, but very similar.
The most mind boggling fact for me is that glass vials are a bottleneck.
We have all these high tech stuff, $50k a gram chemicals, custom built machines, DNA printers and nano-scale technologies producing a substance where every atom is at the right place.
And all that is produced at a scale where we are limited by glass vials. That's literally ancient technology, and commodity stuff. Ok, it is a bit fancier than what the Romans had, but these are still just glass bottles.
The glass vial part is expected, things get complicated when multiplied by a billion, but it gives a sense of how much vaccine is being produced and how fast it is done.
But the blog post states that preloaded syringes are the bottleneck and that's why they are using glass vials?
Interesting bits about the 'bottleneck' being the lipid envelope. This sounds highly proprietary and very, very new (eg, not widely tested). How can these products be QA'd by an independent lab to be free from significant defects?
Are the doses being distributed produced on the same line with the same procedure as the doses in the trials?
People have been taking the vaccine for almost a year now.
The idea that there are significant side effects that have failed to surface makes zero sense.
I believe for Pfizer the preclinical DART and teratogenicity studies in rats are still ongoing, but nobody expects the readouts to be anything bad. That was in the last update I saw, so my info may be out of date.
Because some side effects like cancer may take a while to manifest.
Don't almost all chemical carcinogens basically raise the probability you will get cancer while the carcinogen is present in you, with higher concentrations raising the probability more? And so your cancer chances are roughly the integral over time of the concentration of the carcinogen within you?
For either of these vaccines even if some part of the delivery/packaging mechanism, such as the lipid enclosure, is carcinogenic, you are only getting a small amount and only getting two short exposures. It seems like that would make the cancer rate from them so low as to be almost impossible to detect.
As you said, the exposure amount is quite low, so barring something really toxic, I wouldn't expect a danger from chemical reactions.
However, the body is a complex system; if something in the vaccine triggers a change in function, that could lead to side effects that are only detected years later; most likely through epidemiologic studies comparing those who got the different types of vaccines with those who didn't.
Of course, the disease itself has potential long term effects as well; and has already been studied to have significant medium term effects.
Maybe in addition to offering immunity to covid-19 it also changes your immune response to a type of cancer cell. Then it's found that people with this change almost always suffer from the same type of cancer.
Some viruses are known to cause: https://en.wikipedia.org/wiki/Infectious_causes_of_cancer#Vi...
Right now our best guess is these vaccines are safe but there is no guarantee of that.
Pandemrix, an influenza vaccine, was associated to an increased risk of narcolepsy for up to two years after administration.
"The Moderna vaccine is also known as “mRNA-1273”, but appears to lack a brand name other than “Moderna COVID-19 vaccine” which is what it says on the product label"
Anyone else find that really refreshing?
...Heartbleed, Spectre, Meltdown...
VaxMod? I have no ideas :(
Having a name for a big CVE is actually quite a good idea because it's much easier to string a narrative together around it to convince people to take it seriously.
Spectre is better than something like "Novel data exfiltration from branch prediction using a cache side-channel, variant 3" or similar.
Haha totally agree. Much like vaccine nomenclature.
that's because Moderna is the brand, this is their first product and they plan to launch other vaccines under that brand
they'll probably conform to the drugs themselves having brand names eventually like the rest of the industry
It’s not surprising. Desperate need for a vaccine and not enough supply means you don’t really need branding. No doubt it will be branded once Covid is under control.
I remember at the start of the pandemic Bill Gates was funding mass production of, I'm not sure but I believe 8, several vaccines before trials were completed. The idea was that there wouldn't be a delay between testing and having enough doses for everyone. He said some of the vaccines would fail their trials and the money would be wasted but he said it was worth it to kickstart production.
I wonder if it made a difference? Does anyone know more how his plan turned out?
Was he actually funding building the plants or advocated for it? My impression was - it is the latter.
I was surprised to learn he backtracked and said he was “exploring” the idea. Curious if anybody has a more recent update.
https://www.vox.com/recode/2020/4/9/21210250/coronavirus-bil...
He certainly put money towards COVID, but it’s unclear to me if the factory building idea went anywhere.
Fantastic write up on the supply chain which is the overlooked challenge to these vaccines. I'll need to reread it (and again). Also good are the "In the pipeline" blog posts by Derek Lowe in Sciencemag about vaccine development: https://blogs.sciencemag.org/pipeline/
most interesting post in a while.
Question, which vaccine to choose given option.
Moderna has 100mg per dose and standard freezer storage
Pfizer has 30mg per dose and extreme cold chain storage.
Seems like there's more potential for Pfizer to spoil along logistics chain.
The shipping boxes are temperature monitored the whole time as mentioned in the article. After thawing, the vials are valid for ~5d. I don't see a bigger chance they spoil. I doubt I get to choose, but if, I would take one of the mRNA/LNP vaccines.