https://blogs.sciencemag.org/pipeline/archives/2021/02/02/myths-of-vaccine-manufacturing Skip to main content ScienceMag.org Search X [ ] Advanced Search * Contents * News * Careers * Journals Share In the pipeline Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek's own, and he does not in any way speak for his employer. Derek Lowe By Derek Lowe * * * Myths of Vaccine Manufacturing By Derek Lowe 2 February, 2021 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: [Hamblin-tw] 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/BioNTech and Moderna 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 twenty to twenty-five 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 and Sanofi and ask them what happened to their initial candidate, and while you're at it, call up Merck 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 how 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 themselves in Saint Louis, and Moderna outsources this to the large and capable Swiss firm Lonza (update: a good part of the Lonza work is being done in Portsmouth, NH). 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. But we don't. That's not the rate-limiting step. Nor is Step Two, the transcription into mRNA. Pfizer and BioNTech do this in Andover, MA and at BioNTech facilities in Germany. They have manufacturing in Idar-Oberstein (a town I recall visiting in the cold rain one weekend in 1988 during my post-doc!) and last fall they bought another facility in Marburg which is just getting revved up for such production now. The Moderna mRNA step is also handled in Switzerland by Lonza. Now this is not so common as an industrial process, for sure, because it's only relatively recently that people have been treating RNA species as actual drug substances themselves, worthy of scale-up manufacturing. If I had to ask someone else to make me some more bags of bespoke mRNA, I might turn to Alnylam (who have a manufacturing facility in Norton, MA although to be sure, they're using it for their own drugs!), but doing so would not increase the number of vaccine vials coming out the other end of the process. RNA production is certainly closer to being rate-limiting than Step One, but it's nothing compared to the real bottlenecks that are coming. Now to the lipids in Step Three. This doesn't have to be done in sequence like the DNA/RNA step, of course - the lipids needed for the formulation are an entirely different production process. As the Neubert article will show you, Pfizer and BioNTech are getting all of theirs from a UK company called Croda, with production likely going on in the town of Alabaster, Alabama, which (unlike Idar-Oberstein) I am certain that I have not visited. Now, each of these vaccines needs some odd lipids with positively charged groups on them; that's a crucial part of the formulation. These are surely not trivial to make on scale, but they're still small molecules with relatively straightforward structures. I'm sure that barrels of these things aren't stacking up at the factory for lack of demand, but I don't believe that they're the limiting reagent in manufacturing, either. If you had to, you could surely get some other manufacturers up to speed on the process. I'm going to skip ahead to Step Five and Step Six. These are surely running at a good clip, but they are more traditional functions of a drug company (or of any manufacturing company). It's true that pharmaceutical vial fill-and-finish on this scale narrows you down to fewer players than would be involved in, say, canning tuna. But these folks are already involved. Pfizer is doing this in Kalamazoo and in Puurs, Belgium, and BioNTech is doing this in several locations in Germany and Switzerland, both at its own facilities and via at least two contract firms. Moderna, meanwhile, outsources this to some of the big players in the US and Europe: Catalent, Rovi, and Recipharm. Everyone in this part of the manufacturing business has known for months that a Big Vaccine Push has been coming, and has been cranking up vial manufacturing, bringing all available production lines up to speed, and signing deals all over the place with everyone who has any kind of advanced vaccine effort. Ah, but now we get back to Step Four. As Neubert says, "Welcome to the bottleneck!" Turning a mixture of mRNA and a set of lipids into a well-defined mix of solid nanoparticles with consistent mRNA encapsulation, well, that's the hard part. Moderna appears to be doing this step in-house, although details are scarce, and Pfizer/ BioNTech seems to be doing this in Kalamazoo, MI and probably in Europe as well. Everyone is almost certainly having to use some sort of specially-built microfluidics device to get this to happen - I would be extremely surprised to find that it would be feasible without such technology. Microfluidics (a hot area of research for some years now) involves liquid flow through very small channels, allowing for precise mixing and timing on a very small scale. Liquids behave quite differently on that scale than they do when you pour them out of drums or pump them into reactors (which is what we're used to in more traditional drug manufacturing). That's the whole idea. My own guess as to what such a Vaccine Machine involves is a large number of very small reaction chambers, running in parallel, that have equally small and very precisely controlled flows of the mRNA and the various lipid components heading into them. You will have to control the flow rates, the concentrations, the temperature, and who knows what else, and you can be sure that the channel sizes and the size and shape of the mixing chambers are critical as well. These will be special-purpose bespoke machines, and if you ask other drug companies if they have one sitting around, the answer will be "Of course not". This is not anything close to a traditional drug manufacturing process. And this is the single biggest reason why you cannot simply call up those "dozens" of other companies and ask them to shift their existing production over to making the mRNA vaccines. There are not dozens of companies who make DNA templates on the needed scale. There are definitely not dozens of companies who can make enough RNA. But most importantly, I believe that you can count on one hand the number of facilities who can make the critical lipid nanoparticles. That doesn't mean that you can't build more of the machines, but I would assume that Pfizer, BioNTech, Moderna (and CureVac as well) have largely taken up the production capacity for that sort of expansion as well. And let's not forget: the rest of the drug industry is already mobilizing. Sanofi, one of the big vaccine players already (and one with their own interest in mRNA) has already announced that they're going to help out Pfizer and BioNTech. But look at the timelines: here's one of the largest, most well-prepared companies that could join in on a vaccine production effort, and they won't have an impact until August. It's not clear what stages Sanofi will be involved in, but bottling and packaging are definitely involved (and there are no details about whether LNP production is). And Novartis has announced a contract to use one of its Swiss location for fill-and-finish as well, with production by mid-year. Bayer is pitching in with CureVac's candidate. This is all good news, but it's a long way from that tweet that started this whole post off. There are not "dozens of companies who stand ready" to produce vaccines and "end this pandemic". It's the same few big players you've already heard of, and they're not sitting around and watching, either. To claim otherwise is a fantasy, and we're better off with the facts. 39 comments on "Myths of Vaccine Manufacturing" 1. [215] James Turner says: 2 February, 2021 at 1:13 pm Just a comment regarding Lonza's facilities. I know a significant piece of the production is happening in their Portsmouth NH facility, not in Switzerland. I have family that works on it there, and they're pulling heroic shifts to get it out the door. Reply 1. [8f8] Amity Morin says: 2 February, 2021 at 4:44 pm I just hope we get the vaccine and this will all come to an end. We still have the whole year of 2021 for companies to be able to do it. In the meantime I'm always taking natural supplements to stay healthy in this time of global health crisis. Reply 1. [1b7] DataWatcher says: 2 February, 2021 at 4:53 pm We may have the whole year of 2021 left, but with mutations occurring at their current rate, I'm not sure we can wait that long. In just the past two months, we have discovered at least three mutations that are more contagious and possibly more virulent than the "original" virus that was our standard for the vaccine trials, and at least two of them appear able to evade immunity -- meaning that most of the data from those trials need to have an asterisk appended to them, at best. The nightmare scenario is the development, through mutagenesis, of a virus as contagious as measles that then continues to mutate at a rate outpacing treatment and vaccine development. Reply 2. [209] Joseph M Severs says: 2 February, 2021 at 1:13 pm All excellent points and all true. Validation of such processes is also a big, big deal. Reply 3. [209] Joseph M Severs says: 2 February, 2021 at 1:23 pm My spouse also adds that you need to incorporate obtaining necessary regulatory approvals. Reply 4. [1b2] Mic says: 2 February, 2021 at 1:27 pm Thanks Derek! I was just getting the same questions by friends and family and, as usual, you have done a great job. Another question that is often asked is: "why do we not suspend patents, so other companies would be free to produce the vaccines?". Reply 5. [865] Lorenzo Lucchini says: 2 February, 2021 at 1:33 pm Is the process potentially any simpler for Novavax, which is a protein-based vaccine, not an mRNA one, but appears to have very good efficacy? I guess in theory, producing the protein would be harder than producing the mRNA that then causes the proteins themselves to be produced... but given the mRNA production process doesn't look simple at all, maybe my "guess in theory" is wrong. Reply 1. [338] Sam Weller says: 2 February, 2021 at 2:39 pm Canada actually announced today that it reached an agreement with Novavax to produce its (yet to be approved) vaccine in Montreal. Even in this case, the first vaccines are only expected towards the end of the year. Granted that this is not an established pharma company that is pitching in, so maybe the path could be a bit shorter in principle. https://www.cbc.ca/news/politics/ vaccines-canada-production-trudeau-1.5897343 Reply 6. [58a] BA says: 2 February, 2021 at 1:44 pm Most of these analyses come from outside people looking in (e.g., Neubert). I find the lack of transparency from the manufacturers is eroding my trust. I've not seen anyone that will definitely say: no, not even an extra $10b will speed things up. Reply 1. [801] Anonymous says: 2 February, 2021 at 3:23 pm Have you seen someone try to claim that extra $10billion. I'm sure someone could cough it up were it that easy to step up. Reply 7. [c07] Malthus_2024 says: 2 February, 2021 at 1:45 pm Ideally, someone should be planning how to vaccinate the entire global population of more than 7 billion people. Is WHO, or anyone else doing planning and implementation for what will be needed to fully vaccinate everyone world wide? Does it make sense to engage in the multi-year process of bringing new production facilities on-line? if so, how soon will that begin if it hasn't already? Reply 1. [f4d] mous says: 2 February, 2021 at 2:05 pm Yes, WHO is looking into that (the 7 billion question) via Covax / GAVI and the ACT-Accelerator (link in name). And now that the recent changes in DC means the US is on board with those efforts (alongside pretty much every other country in the world who have been there since the beginning of the pandemic) it may actually work... Reply 8. [ca0] Willy Chertman says: 2 February, 2021 at 1:50 pm Is this true across the board, for all vaccine candidates, or is this most true for the mRNA vaccines, and less true for the adenovrius-based candidates and Novavax's candidate? Reply 9. [a70] Andrew Clough says: 2 February, 2021 at 2:10 pm Earlier today there's been some reporting that for Moderna at least it's actually step 5 that's their current binding constraint. That is, they're asking for permission to putt 15 rather than 10 doses in each vial so that they can speed up production. https://www.cnbc.com/2021/01/29/ moderna-asks-fda-to-allow-more-doses-in-each-covid-19-vaccine-vial.html Reply 1. [bb6] Karl says: 2 February, 2021 at 2:25 pm I can think of a couple ways to read that. The article doesn't actually say that vial fill is their overall rate-limiting step today. It's possible that Moderna is looking to bring more nanoparticle production online, and they want to make sure that later steps aren't a bottleneck when that happens. It wouldn't make sense to open up step 4 and then bump your nose on fill, when it's something that can be alleviated by a regs change pursued in parallel. Reply 1. [73e] CMCguy says: 2 February, 2021 at 5:01 pm I agree this does not imply fill/finish as rate limiting as appears more as option to gain higher output using same vials and operations thus increases efficiency. The key question for such an alteration would involve what stability data supports greater volume per vial. Does help manufacturing plus possibly distribution as get more doses in the supply chain. I think Derek is correct that Step 5 is a less prevalent technology that requires specialized equipment/facilities therefore can not just drop in to most pharmaceutical manufacturing plants (unlike most the other Steps) Reply 10. [9f8] CB says: 2 February, 2021 at 2:15 pm SENSE OF URGENCY April 4, 1947, New York: a smallpox outbreak and announced plans to vaccinate everybody in the city. The mayor called an emergency meeting with the heads of the seven American pharmaceutical companies involved in vaccine production and asked them for a commitment to provide 6 million doses of vaccine asap. The pharmaceutical companies accomplished the task by putting the vaccine into round-the-clock production. One year later most New Yorkers were vaccinated. Reply 1. [d91] Mammalian scale-up person says: 2 February, 2021 at 5:00 pm Um, no. Pharmaceutical companies knew how to make smallpox vaccine in 1947. I used to work at Wyeth back when we still had a farm in PA full of critters. Herds of cattle were not hard to come by, we didn't have to import them from China, we had loads of the things just laying around (literally). You know what the bill of materials for smallpox vaccine was in 1947 (it's not now)? "grass" and "vials" and "steel scratcher prongs". That's it. Occasionally you need to buy a new cow, but they also tend to increase on their own if you add enough grass. I wish we could make covid vaccine out of grass, since I too would love to go back to normal life and eat in a sit-down restaurant indoors, travel and go to the spa, but it ain't happening. Pharma employees are as miserable as anyone else, I assure you. The more I see restrictions lifted due to political pressure instead of due to dropping infection rates, the more I think we may be cursed with this for a long, long time. Reply 11. [a7b] Chris Phillips says: 2 February, 2021 at 2:16 pm Apparently James Hamblin is billed as "Journalist, improv comedian, and physician". Are we sure which hat he was wearing when he wrote that tweet? Reply 12. [c6f] Smokerr says: 2 February, 2021 at 2:28 pm And why would the EU not accept the UK and US test results? While not huge, another delay so their regulator people can put their finger in the pie and justify their existence and yell Hallelujah ! A Western population si a Western population, sheese. Of coure Japan takes the cake for drag feet and we are dong the Olympic come hell or high Covd rates. Reply 13. [8a0] JB says: 2 February, 2021 at 2:31 pm "We had a vaccine in March" reminds me of the complaint about HTS and medchem, "Why did you screen 1M compounds and make 5k analogs when you could have just made the molecule that works?" Reply 14. [310] iunggyeon says: 2 February, 2021 at 2:41 pm Now this post comes just in time for posting about one component that I had heard worries about being a potential bottleneck(sic) over the last few weeks: https://www.bbc.com/news/business-55808640 "The tough little bottles crucial to fighting Covid" Astonishing how much care has to go into seemingly trivial parts. Reply 15. [a6d] RK says: 2 February, 2021 at 2:52 pm I found this (somewhat older) BioNTech talk regarding LNP manufacturing: "Nanoparticle engineering by microfluidics" - Ferdia Bates, BioNTech, 2016: https://www.youtube.com/watch?v=oPnetNtyR7Y Reply 16. [2fe] Ezra Abrams says: 2 February, 2021 at 3:16 pm Is it true that mRNA reagents are not in short supply ? RNA polymerase NTPs the pseudobase and stuff for purification (? industrial scale HPLC or sephadex) RNAse qualified I mean, 100 liter sephadex columns (yes, they use them for insulin mfr) do exist, but they don't grow on trees) see the figure on page 9 of this PDF http://www.nvi.go.th/index.php/files/large/257712873fa8f34 Reply 17. [785] Scott Underwood says: 2 February, 2021 at 3:42 pm Derek, this is great information! You have explained it well enough to understand where the bottleneck is, and by what you are saying it's obviously solvable. Our real problem is the whole industry, of course not because they are evil or lazy by any means, but because of the limitations they are operating under. It is the system, it is the system of Just In Time manufacturing. It works well for a corporation if they make things when they are needed. The cost of storage, spoiled product, the expense of machines that sit around and do nothing, it all makes perfect sense in that system. The world works with this method and has for a long time. That is the real problem because it is built on profit and it is that way to avoid losing money and decreasing profit. Derek your explanation is an excuse really for what our system is ABLE to produce. So the person you rail against is a person that is really saying the same thing I just did and hasn't explained that part for you. Not in any way do I believe that you need this explained to you and yet you excuse what we have instead of screaming at the top of your lungs that it is not right for human beings' health, especially in the face of a global pandemic. It's not the best of what humanity can produce. The best we can do is far away from what this system can produce. It is the system that is the problem and I'm tired of people trying to rationalize an inhuman system of heath. Nothing personal. Reply 1. [4cc] Lappan says: 2 February, 2021 at 5:24 pm The possibilities for prophylactic spending are limitless: the richest country could devote all of its spare capital (both financial and brain-power) to stockpiling things that seem likely to be useful and still be caught out. We could build a fire station on every city block and probably succeed in reducing the damage from fires, but now that's a larger proportion of the population being firemen rather than teachers or doctors, and when the hospital needs a new radiography unit perhaps a choice must be made: reduce the fire dept budget? increase taxes? and are more fire stations the best answer, or instead should we spend the same additional funding on fitting smoke detectors everywhere and drilling the population in safe evacuations, so that fires damage buildings not people? That's not to say that a more determined pursuit of the technologies wouldn't have been wise: after SARS faded out most countries shelved their research on novel viruses, vaccines, treatments, and civil preparedness. Reply 18. [bc3] mymagoogle says: 2 February, 2021 at 4:31 pm Also add all the QC testing along the way. I presume for the in process (between step) testing, given the urgency, that they are always proceeding to the next steps at risk, before the tests are completed with a thumbs up to proceed. Or maybe process time is so scarce that they don't want to waste that slot just in case that batch is bad. Regardless, the release testing is always at the end - or in Derek's scheme somewhere in the middle of step 5, and let us not forget that sterility testing takes a month. Reply 1. [eab] A Nonny Mouse says: 2 February, 2021 at 4:48 pm Under the EUA here in the UK, the regulators have to test each batch before release. I believe it is now down to about 5 days with 24h working. Reply 19. [686] Julien says: 2 February, 2021 at 4:40 pm Maybe a dumb question, but don't you think that drug companies that are able to make liposomal drug products (i.e. AmBisome = liposomal amphotericinB by Gilead; Doxil = pegylated liposomal doxorubicin by Baxter) could quickly be taught how to encapsulate these mRNA strands in the right lipid nanoparticles? Reply 1. [d91] Mammalian scale-up person says: 2 February, 2021 at 4:48 pm No, the problem is that the process == the product in biologics, to a very large extent. There is limited acceptance even of biosimilars identical in structure, sequence and posttranslational modification - there is certainly no "just as good" for RNA. Once the process methodology is filed, it's really set in stone, for all biologics, even when it's clearly nonsense that has no impact on the finished product. I've seen startups without previous experience in regulatory filings misunderstand the requirements and put in the number of doors and windows in the building in the actual BLA, under the section that asks them to describe the facility. Worse, they counted wrong, and when the inspector came through they put paper and a large piece of equipment in front of the extra door...and then they were unable to transfer manufacturing to another site, even when their original site was fit for nothing but a bulldozer, so the company that bought them was stuck trying to re-file. You have to really know what you're doing when you write that manufacturing process out on paper.... Reply 20. [d91] Mammalian scale-up person says: 2 February, 2021 at 4:41 pm LNP manufacturing isn't all THAT different from liposome manufacturing - and there are a handful of ways to do that, but at commercial scale we do not use microfluidics chambers, ever. That would be ridiculously inefficient, we've known how to make emulsions at scale for a long time. I am 95% sure Moderna and Pfizer have not even tried the more traditional liposome compounding methods (membrane shear, sonication, high shear blenders) all of which are off-the-shelf and most definitely make uniform particles of whatever size you like, provided you play around with flow rates and the spinning shear head designs a bit. Everything I've seen from them is...highly academic and has zero consideration for scale or normal engineering stuff like "Class 1 Div 2 limits" or "semi-continuous vs batch process." They have not had time to develop a platform - THAT is the problem and creates a bottleneck, everything they do is a one-off and highly specialized. Playing around with different methods takes time, usually upwards of 5 years. That shouldn't be surprising - most startups don't even bother to make a platform until they've produced several successful commercialized drugs, because it's financially more rewarding to put all your resources into meeting investor milestones and getting some revenue streams going. Years later, is when you worry about platform development because all this capex and overhead for little one-offs is starting to cramp your cash flows. At commercial scale, we like to (need to, after a while) have things on a platform: standardized equipment modified only slightly to meet the new process requirements, with off-the-shelf reagents and no weird catalysts or single source components. If there's only one vendor in the whole world (e.g. who makes GMP quality polymerase, or GMP quality capping enzyme) then you are going to find yourself in a world of hurt very quickly, as soon as they have the slightest delay. Can we make these things? Sure, just like you can use phenol and hexane as starting material, but it's adding an awful lot of work to your life and you probably would much rather buy something more ready to use. You can definitely buy dNTPs and enzyme from Sigma and NEB, but these are extremely large quantities that are NOT lab quality crap - they have to be produced under much more rigorous conditions, and that takes time. Basically whatever would take you an hour or two at most in the lab, takes a solid day or two at commercial scale in GMP conditions. Unfortunately, anything you create on a new platform has to go through clinical trials. AGAIN. So for this vaccine it is just not going to happen. We will not get a platform for RNA anything for many years and it will continue to be miserable to make. Hence why I think we should focus on what can be done to accelerate adenovirus-based and Novavax's stuff, because that we CAN make lots of. Adenovirus, in comparison, does have a platform: viral vector development has been ongoing for some years now. It's made on pilot-scale standard equipment we do happen to have laying around, doing pilot scale development stuff, but that doesn't mean it can't be repurposed or that we couldn't get more with 3-4 months of lead time. Re: large IEX columns, I have...let me think... a few 2m x 20-25cm columns, three 1.4m x 25 cm in use at the moment just at one site (multiply by 4 sites), probably a few thousand additional liters out in cold storage. IEX columns are cheap cheap cheap for me, and there are also now charged membranes we can use for the same purpose, made by Pall and Sartorius. All standard reagents, media, buffers I already have laying around the warehouse. Adenovirus vaccines are great! We can make those as quick as we make anything, which is to say we can have batches out the door in 6-9 months. Novavax uses a baculo expression method that is...slightly weird? We mostly only used baculo in the mid-late 2000s, and only when mammalian expression failed to produce enough material for HTS / X-ray crystallography. The posttranslational modifications are highly immunogenic and it's a legitimate question to ask "if they are not normal modifications, how relevant a model protein is this?" That said - it's made in similar equipment as mammalian cell culture, of which we have lots, but it does need to be made at larger scale than adenovirus cultivation, so there is a real question about who in the world has capacity to run X000L systems for a couple of years, making nothing else. I mean, I don't, because of the expense of running the things we tend to keep them fully occupied. But, basically: source material for the RNA vaccines is just as much of a bottleneck as the emulsion manufacturing. They both suck. Let's not focus on RNA vaccines please as there is no serious chance we will be able to scale them quickly or meaningfully in the quantities needed, while we CAN! DEFINITELY! make loads of adenovirus and with some moderate effort of capacity sharing probably come up with some locations to make baculo stuff too. Reply 1. [c68] Marko says: 2 February, 2021 at 5:32 pm "Unfortunately, anything you create on a new platform has to go through clinical trials. AGAIN. So for this vaccine it is just not going to happen. We will not get a platform for RNA anything for many years and it will continue to be miserable to make." So you think that an mRNA vaccine for a new variant will have to go thru a full set of clinical trials? I'd agree that that's what probably SHOULD happen, but I don't believe it will. Fauci has already said as much. I can see that you may mean that if anything about the platform except the payload changes significantly that it would require a whole new approval process, in which case I'm sure you're right, even in this rushed environment. Reply 1. [d91] Mammalian scale-up person says: 2 February, 2021 at 5:35 pm The second one - if anything about the platform (equipment, lipid, home-brewed enzyme as opposed to purchased) changes, clinical trials must be re-done. Reply 1. [c68] Marko says: 2 February, 2021 at 5:39 pm OK, thanks. Reply 2. [6f2] sgcox says: 2 February, 2021 at 5:50 pm But surely not the full scale Phase 3 trials as for the original approval ? That would be insane. And yes, I do not know much about it but is very curious. Reply 2. [e09] Robert says: 2 February, 2021 at 5:49 pm Great comments on manufacturing advantages with the virus vector vaccines. Do you think AstraZeneca is having manufacturing issues with their Belgium plant producing their Covid-19 vaccine for the EU or is it more just getting the materials sourced and delivered to the plant? Reply 21. [3fb] Mandark says: 2 February, 2021 at 4:47 pm "Five years ago we simply could not have gone from sequence to vaccine inside of a year." But it's not just RNA vaccines that proved capable of achieving this feat. The viral vector-based vaccine by the University of Oxford was developed at the same time as vaccines from Moderna and BioNTech. Of course it's also a fairly new platform and the Oxford team had an advantage in that they had been working on a vaccine for MERS-CoV when the pandemic hit, so 5 years ago its development might not have been as fast. But vaccines based on viral vectors were also developed at comparable speed by the Gamaleya Research Institute in Russa and by CanSino in China (the latter is still in phase 3 trials, but phase 2 results were published already in July 2020). More traditional, inactivated whole-virus vaccines, also saw rapid development in China. Reply 1. [c68] Marko says: 2 February, 2021 at 5:15 pm Agreed, but you have to admit, the name "Operation Warp Speed" WAS catchy. Reply 2. [4eb] Michele P. says: 2 February, 2021 at 5:57 pm But the Gamaleya Institute also had an advantage because they also worked on a vaccine against MERS (BVRS-GamVac), with the same vectors rAd26 + 5. Reply Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * [ ] [ ] [ ] [ ] [ ] [ ] [ ] Comment [ ] Name * [ ] Email * [ ] Website [ ] [ ] Save my name, email, and website in this browser for the next time I comment. Time limit is exhausted. 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