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Materials and Gases, Vials and Vaccines

Let’s talk about some details that might sound small or even ridiculous, but (as you’ll see) they’re just the sorts of things that you have to worry about at the intersection of chemistry, biology, and physics. That makes it sound like I’m going to be going into something really high-tech here, but you be the judge – we’re going to veer off into beer cans in a minute or two.

Here’s a detail for you: how many vials will we need to put all those coronavirus vaccine doses in? What will they be made out of? Are there even that many vials of the right size in the world at the moment? The answer is, well, no there aren’t. Not yet. And the companies that manufacture them are getting orders that are beyond what they are currently able to produce. Here’s a good piece at Wired that goes into the details. In short, if someone waved a wand and made several huge vats of effective vaccine appear tomorrow, we wouldn’t have enough containers to get it rolled out to the general population.

The traditional glass companies (Corning, Schott, etc.) are ramping up as quickly as they can, but as the article notes, timing will be crucial. If we are rolling out a vaccine in the middle of next year, the vial supply should be in pretty good shape. But if we’re trying to do that by the end of this year, well, there might well be a gap. We are, of course, talking about glass vials – if you think back to all the shots you’ve been given in a doctor’s office over the years, the little vial that the syringe goes into is invariably made out of glass.

Why not plastic? That term covers a lot of different materials, of course, but each of them tend to have their own strengths and their own problems. Glass is in many ways a wonderful substance for containers in biology and chemistry, with some advantages – particularly on longer-term storage –  that are hard to beat. A big one is that glass is basically impermeable to most gases. You probably don’t spend a lot of time thinking about that as a feature, but believe me, people in packaging sure do. For example, people my age and older will remember the days when carbonated drinks of all sorts were to be found almost entirely in glass bottles – vending machines, larger bottles in the stores, etc. Cans (at first tin-plated steel and then aluminum) moved up in popularity in the 1960s after the invention of the now-reviled pull tab, but I well recall the glass-bottle-dispensing machines.

Now it’s either metal cans or plastic bottles, and the rise of plastic depended on getting polyethylene glycol terephthlate (PET) worked out. Shorter-chain polymers of that sort were already big in the 1950s (Dacron polyester, Mylar, etc.). Resins with longer polymers are now used for water bottles, and even longer-chain ones for carbonated drinks. There’s more to it than that (small amounts of copolymer additives, drying the resin before processing, the heat treatment to control the degree of crystallization in the polymer), but all of these are optimized to produce a plastic that is clear, moldable, and does not let carbon dioxide pass through it. Otherwise the unopened bottled drink would go flat in a few days.

Unfortunately, that sort of PET will let oxygen through. Ever wondered why you don’t see many plastic wine or beer bottles? No one worries too much about oxygen in their bottle of cola, but oxidation will throw off the taste of wine and beer pretty noticeably. It’s especially problematic considering that wine is kept around for years at a time. You can get around this with another oxygen-impermeable polymer (ethylene vinyl alcohol is the standard). But EVOH is expensive to produce, and there are only a few suppliers in the world – what you see in actual use is a thin layer of EVOH sandwiched with cheaper polymers, which still makes the manufacturing harder than good ol’ PET.

This would be a good time to note that even metal cans are more complicated than they might appear (and see the epilogue below if you want even more). They’re pretty impermeable to oxygen and carbon dioxide, but there is that direct metal contact to think about. Cola drinks have a lot of phosphoric acid in them, just to pick one problem, and this is not a good match for a metal surface. Beverage and food cans invariably have a thin plastic layer (generally an epoxy resin) on their inner side to be a barrier. According to that link, beer is actually pretty benign and doesn’t even need the polymer barrier, which explains why beer cans were a thing many years before soda cans appeared (although World War II and its need for metals rather slowed that process down!) Some energy-drink formulations, on the other hand, still can’t be packaged in cans because they’re just too corrosive.

As with cola and wine, so with vaccines and monoclonal antibodies. All of these considerations apply: you want a material that’s gas-impermeable, because oxidation will degrade those complex biomolecules as surely as it will make a bottle of wine taste funny on storage. The cysteine amino acid residues are an obvious starting point for trouble, and there are others. You want as inert an interior surface as you can get, too. That means chemically inert, of course, but also physically inert, since it’s also well-established that some plastic surfaces can adsorb both small molecules and larger protein species in troublesome ways. Glass performs quite well in all these characteristics.

That link back at the top of the post has some interesting details about a company that’s trying to help fill things in, SiO2 of Alabama. They were making plastic milk jugs as those were becoming a thing back in the early 1960s and have been supplying the pharma industry for several years now with an unusual packaging alternative: plastic containers that have extremely thin silica layers inside them, applied by a plasma vapor deposition technique. Glass has all the desirable chemical properties noted so far, and plastics are unbreakable and can be made to more precise physical specifications, which makes it easier for high-speed manufacturing lines. So glass on the inside, plastic on the outside gives you some of the advantages of each substance, albeit at a price – but for high-value products like this it can make a lot of sense.

Epilogue, not relevant to vaccines: I mentioned above that metals are basically impermeable to oxygen and carbon dioxide, but there is a gas that gives them trouble: hydrogen. The permeability varies a great deal between metals (and alloys thereof), and also varies with pressure and temperature, as you’d expect. But it’s a real engineering problem, made worse by the fact that some metals (high tensile strength steel in particular) actually become brittle over time if hydrogen is allowed to permeate them: in practice, tanks and pipelines used for compressed hydrogen are lined with a polymer such as high-density polyethylene (HDPE) which is much more impermeable to the gas than the metal outer layer is. And there’s been a lot of work put into the idea of non-metallic pipelines made out of some sort of fiber-reinforced polymer entirely. Meanwhile, if you need extremely pure hydrogen, one way to get it is to let it diffuse through a membrane made of palladium alloy. Chemists are familiar with how easily palladium and platinum take up hydrogen gas, and such membranes have effectively infinite selectivity: no other gas can get through them at all!

102 comments on “Materials and Gases, Vials and Vaccines”

  1. myst_05 says:

    Would it be possible to use large containers instead of small vials? Say, package the vaccine into huge 5L glass jugs and then setup a “vaccination pipeline” to quickly inject the entire jug into hundreds of people.

    1. Barry says:

      Multidose vaccine vials are certainly used where lots of people (e.g. military induction centers) will be inoculated in rapid sequence. In other places, the single-dose vaccine vial is best. It’s a real question:

  2. Giannis says:

    Why not put 10-20 doses of the vaccines in one vial?

    Multidose vaccine containers are pretty common, especially in developing nations.

    1. Nameless says:

      Then you need 100 million bottles, not 1 billion. Makes the problem easier but doesnt solve it.

      1. Patrick says:

        Yeah, but I’ll take a factor of 10 any day. In an important sense, it may well solve the problem. If we make 50 million of something a year, then doubling? Doubling may not be so bad – Redirect other stuff, upgrade the factory, run it 24/7 with extra staff and whatever expensive measures you wouldn’t normally use.

        A factor of 10? Jeepers. I dunno – It’s going to depend. What related capacity is available? How broad are the other steps in the supply chain – Do you have a key ingredient in your item that you’re the main consumer for? Well, shit – That layer probably doesn’t have capacity *either*.

        So now you’ve got to scale up *multiple* layers.

        A factor of 10 sounds really nice.

        But, then, so do individual vials of vaccine.

    2. mymagoogle says:

      Multidose are also used for pandemic flu stockpile, usually 10x doses per vial, possibly 20x. Note that such vials also require some kind of preservative that is not in the formulation for single dose vials or single use prefilled syringes, so one cannot just load up the machine with whatever pick-a-mix you happen to have that morning.

      But the corollary issue for any of this is do we have the syringe and needle supply to deliver? Sure, there are glass+metal versions that can be autoclaved, assuming all of these potential future dosing sites have an autoclave. But the industry is used to using certain sizes single use, and specified very clearly in the Instructions For Use which brands / skus if it isn’t supplied as a pack with the vial/s, because one of the tests to do is if the vial-syringe-needle combo actually delivers the labelled dose within a certain range. Lord help us if the 10ug turns out to 1ug just because of the needle used.

      And all of the above affect shelf life, not that this stuff is going to sit for a year on the shelf this year, but also to be noted. And the sterility testing.

      1. John Hasler says:

        Substantial numbers of needles and syringes (vials, too) are used for vaccination of animals. Those could be diverted to human use.

    3. Anon says:

      For multidose vials for injectable products, it is necessary to add a preservative…like Thimerosal…Hg-based…or others. Cue the loud shrieks from the anti-vax mobs….

      I will see myself out.

      1. Max says:

        And I’m assuming you feel that mercury injected into a person’s body is perfectly harmless. Correct?

    4. FoodScientist says:

      Remember that thing with the spread of hiv in Africa. If something like this happens even once, vaccine trust will plummet.

  3. mike says:

    Great post Derek, enjoyed reading about your encyclopedic knowledge of materials that seems to transcend from the Chemistry Book.

    As a sidenote, does anyone else here really dislike Science’s banner that comes up when you scroll up? It actually makes reading difficult for those who scroll as they read. Am I the only one??

    1. Thoryke says:

      No you’re not the only one. But I think that’s way out of Derek’s control.

    2. John says:

      No, I hate this too

    3. enl says:

      There are tools to suppress elements. Check the plugins for your browser.

      Or, you can do like I did and write your own, should you desire. But I’m weird that way.

    4. En Passant says:

      Ditto mike, Thoryke and John. It’s not within Derek’s control.

      It’s a dancing doggie: something that “expert web programmers” throw in to demonstrate how clever they are.

      Without it, readers would have to endure the horror of scrolling all the way to the top or bottom of the page to log in, or to find the link to join NAAAS.

      The “web experts” are likely shocked that readers don’t thank them for their thoughtful consideration.

      1. gippgig says:

        While on the subject of annoying things about the site, is there any way to force it to connect using http instead of #&!@ https?

        1. Patrick says:

          Why on earth would you want that? Encrypting the entire web is basically the only realistic or useful defense against mass surveillance by the various intelligence agencies. (Note I said *mass*, it doesn’t protect targeted individuals much. But suppressing mass surveillance seems a pretty obvious social good.)

          At this point, HTTPS should be pretty near mandatory.

          1. gippgig says:

            I don’t care who knows that I read In the Pipeline. I don’t want my newspaper delivered by armored car & I don’t want my blogs delivered by https.

        2. EJ says:

          Try the HTTPS Everywhere extension. Its even on FF Android now.

          On its necessity:

          Also, its a rather minuscule use of computing resources on the server end. Its a comically small use of resources on your smartphone.

          1. EJ says:

            Ah, I got that mixed up

      2. x says:

        The “expert web programmers” most likely have a mandate from some manager to increase engagement with the site, and someone came up with the notion that omnipresent access to the header and its various hyperlinks improved that metric.

        So you might want to direct your ire to the company; demand that they make their site less engaging to satisfy your preferences. I’m sure they’ll get right on it, yes sir, right away sir.

    5. Paul Bristow says:

      No, this annoys the heck out of me too. It seems to be too sensitive, popping back up when not needed.

    6. LdaQuirm says:

      Yes. In Chrome, right-click on it, then select “inspect element”. Then in the HTML that pops up, right-click on the tag that looks like “<header class="gh gh–down " id="gh_header" …" (It will be near the highlighted text) and select "Hide element". Done.

    7. An Engineer says:

      The best minds of a generation have gone into making the web as frustrating as possible. It’s dangerous to go alone, here take this:

  4. Some idiot says:

    Here’s another one regarding air in medications which took my by surprise to start with, but is quite logical… For some biologics, hydrophobic collapse can lead to formation of fibrils, which is a bad thing, for several reasons. Therefore glass is good, since the surface is pretty well much hydrophilic (compared to many plastics, at least). But the water-air interface is a very hydrophobic one. Therefore, in order to extend the shelf-life of some of these formulations, exclusion of air is important, both for reasons of oxidation, but also as a source of hydrophobic-induced clumping…

  5. The anonymous mous says:

    There was a key bit in the Tom Clancy book ‘The Sum of All Fears’ that swung on the antagonists not knowing to filter tritium through a palladium membrane to get rid of helium!

  6. lfert says:

    I was involved with a project to make resorcinol di-glycidyl ether, used as an additive to reduce oxygen permeability for plastic beer bottles. So basically, the reaction was resorcinol + 2 epi. In the end, it never panned out due to the fact that the resorcinol was too expensive.

  7. Rhenium says:

    Excellent discussion, and I wonder what impact it will have on other areas of chemistry (e.g. traditional synthesis) that use glassware regularly.

    Also “It’s especially problem” should be “It’s especially problematic”. Sorry for the editorial pedantry. There’s so many long posts these days, so thank you.

  8. Nick K says:

    I believe that hydrogen embrittlement of steel was a real problem during the early days of the Haber-Bosch ammonia process.

    1. Patrick says:

      Do you know how it was solved, particularly back at the beginning? It seems to me that the environment of high pressure hydrogenation would make embrittlement an absolute nightmare.

      1. Anonymous says:

        It’s a promulent situation.

      2. APAJ says:

        I believe they built the reactors double walled: the inner inert and resistant to the reaction inside, yet unable to resist the high pressures needed. The outer of steel, I presume, which kept the pressure in. In between pressurized gas (N2?) kept the inner wall at neutral pressure. Neat engineering!

        1. Mausling says:

          I really need to read up more on this! There was a reason Bosch (and Bergius) got the Nobel prize for the high-pressure methods, independent from Haber’s catalyst work. (He is also a less complicated person to honor than Haber.)

  9. wildfyr says:

    That factoid about obtaining pure H2 by diffusion through a metal membrane is truly amazing. I’ll pull that badboy out to blow the minds of some fellow chemists. They take more than the usual amount of effort to impress with material properties.

  10. FormerWyeth says:

    Since the vials are glass isnt it possible to collect them after usage, sterilize, and then refill?

    1. Marko says:

      Too obvious , so it will never be considered.

      Think of all the vaccine vials that are used every year globally , then tossed into the biohazard bag and sent off to be incinerated. Probably enough to handle a couple of extra pandemics.

      1. FormulationFanatic says:

        It’s not obvious, it’s foolhardy at best.

        The two largest issues in process development are sterility and degradants. Reusing old vials fails both of these fronts. After injecting the contents of a vial drug product residue is left behind that can become infested with bacteria. This would need to be cleaned out of the vial, and go through an intense sterilization cycle then be tested. Even after this you would have to verify that there were no trace degradants left behind in the process, as a large portion of pharmaceutical degradants are heat catalyzed the sterilization would induce a worst-case scenario that could provide dangerous levels of degradants that are tightly controlled in the drug. And then after all of that you have to prove vial integrity, and show that the wear and tear on the vial didn’t increase the likelihood of extractables, leachables, and elemental impurities getting transferred into your product.

        The FDA maintains tight controls on container closures for a reason, when you overlook small aspects of these controls people are at risk of injury and illness.

        1. Marko says:

          Yes , I’m sure you’re right. And the logistics alone would would be daunting even if it was somehow technically feasible.

          Plus , can you imagine the reaction of the antivaxxers if they found out we were re-using vials ?

  11. Stanley says:

    But won’t that hydrogen purification process eventually lead to nuclear fusion?

    1. loupgarous says:

      Nuclear fusion’s dirty secret isn’t so much hydrogen embrittlement (not enough D and T to matter), but neutron embrittlement. The deuterium-tritium fusion reaction creates a large neutron flux. The resulting embrittlement is cumulative.

      1. Barry says:

        While Hydrogen embrittlement is expected in any metal (Iron, Nickel, Palladium, Platinum…) that breaks H-H bonds and forms covalent H-M bonds, neutron embrittlement may be general for all solid-phase matter.

  12. atp says:

    In the southwest Mexican Coke sells at a premium because it’s made with sucrose and it comes in glass bottles. Is this common in the rest of the country?

    1. Average banker says:

      My Coke is cut with lactose and comes in plastic bags. I would prefer something without dilutents though.

    2. Jim says:

      Costco sells it by the case in California.

    3. Alan Goldhammer says:

      During Passover, Coke specially label things so that those that are observant can make sure they are getting Coke made with sucrose. High fructose corn syrup is not kosher for Passover.

      1. Steve says:

        I didnt know that. Turns out they are concerned with the amylase enzymes used to make HFCS which may have come from Barley. God certainly works in mysterious ways.

    4. loupgarous says:

      We have a “Mexican brands” aisle at the local Wal-Mart with Coca-Cola made the way John Stith Pemberton intended, cane sugar and all.

      1. Olandese Volante says:

        The extra special ingredient that originally gave the drink its name will still be missing, though. Pity, that.

  13. Steve Scott says:

    Company making pre-filled plastic syringes for Covid-19 vaccines:

    “Seeking to ramp up the nation’s capacity to administer a possible COVID-19 vaccine, the Trump administration has signed a $138 million deal with the makers of an innovative syringe designed to be used in developing countries.

    The goal of the public-private initiative, called Project Jumpstart, is to facilitate the production of 100 million prefilled syringes by the end of 2020 and more than 500 million in 2021 in the event a vaccine becomes available, officials announced Tuesday.

    The Health and Human Services Department and the Defense Department are partnering with ApiJect Systems America, which manufactures inexpensive prefilled syringes made of plastic.”

    1. Marko says:

      If prefilled syringes are OK , then plastic vials should be as well.

      I wonder if lyophilization might help overcome stability and container issues as well. Quite a few vaccines are currently sold as lyophilized preps , which are reconstitued with sterile DI water or other diluent just before administration.

    2. On Paper says:

      According to ApiJect’s published “Blue Book”:

      “A low-heat sealing process enables almost any drug or vaccine to be aseptically flled. Medical-grade plastics are used, specifcally well-understood types of TPE (Termoplastic Elastomer) and PP (Polypropylene).” pg 19

      “One key consideration for BFS technologies is the question of whether any of the plastics used to manufacture the containers could interact in a negative way with the vaccines or medicines that fill them. For example, no “leaching” must occur (plastic molecules dissolving into medicine).
      BFS manufacturing predominantly employs two resins: polyethylene and polypropylene. The FDA generally views these substances as inert. They contain no additives. Their permeability by water vapor is minimal. In addition, containers made of these plastics may be handled safely and easily in critical care sites, including clinics and hospitals. International regulators have broadly classifed BFS resins as acceptable for pharmaceutical liquids.” pg 51

      1. On Paper says:

        Source link

        I don’t have the background to evaluate any of the claims they’re making, but if they hold up it sure sounds like a Very Useful Thing.

    3. overthetop says:

      Nearly all prefilled syringes have a SiO2 coating on the inside of the barrel, so the contents aren’t in contact with the plastic part of the barrel. Schott has at least one patent on this technology (US 8,747,962). The coating is deposited using a plasma vapor deposition process.

  14. Anon says:

    Aducanumab? Biggest day in the history of the universe? Anyone?

    1. Marko says:

      “Doctors don’t think Biogen Alzheimer’s drug should be approved, but they’d still prescribe it: survey”

      “…Among 30 Alzheimer’s doctors who are “very familiar” with aducanumab’s data—20 academic doctors and 10 community docs—most said the drug should not be approved, the analysts wrote. Even still, many of the doctors will prescribe the drug if it is, the firm’s expert survey found.”

      Big day for Biogen shareholders , at least…

      1. anon says:

        PMID: 27582220 Figure 2 c (right subfigure blue subgroup)
        Prosecution rests.

    2. loupgarous says:

      I forsee a nationwide effort by Biogen when they submit their Phase III findings, to assemble photogenic (but pathetic) AD patients, a real Hollywood production with background music from “Chariots of Fire”, anything to get the same results Sarepta did with their exon-skipping drugs.

      This administration’s FDA seems more than ready to serve ‘unmet needs’, even if what you serve the patients are troublesome side effects and little or no evidence of a therapeutic effect.

      1. JasonP says:

        >>>even if what you serve the patients …. and little or no evidence of a therapeutic effect.<<<

        Hmmm, here we go again with that "thinking."

        No efficacy? Aducanumab’s ability to remove brain amyloid is beyond question, as is any number of anti-AB antibodies.

        Why such a rush to judge on a yes-no basis? The drug clearly works for its intended purpose – clear AB from the brain. It takes what 20-30 years to build up AB and start the dementia phase, why does anyone think one pill or one shot, is going to solve dementia? Afterall, how long does it take the brain to "heal?" Seems like getting 'clean' from opioid addiction is step one and "healing" the brain takes months or a couple of years. So perhaps it takes longer for function to return once the garbage is removed?

        Perhaps we need a second drug to direct microglial and astrocyte response/actions? Perhaps some stimulation of a bit of neurogenesis? How about tamping down some of the inflammation responses, or Tau? Complex situation. Things like AIDS and cancer aren't solved by one magic bullet, why this? So this appears to be one piece of the puzzle, why such a negative outlook that suggests – it's no good, move on?

        Is this standard industry thinking? If we can't "win" with a blockbuster, silver bullet, ditch it and move on? I see this apparent thinking over and over again and it makes no sense. Researchers are some of the brightest people in the world. How is it that a bifurcated solution is so oblivious? I wish someone would edumacate me on how this thinking works? Indoctrination? The 95% CL issue? Blockbuster or bust? Something else?

        1. Barry says:

          You define a desire Clinical Outcome before you run your Clinical Trial. Phase II teaches you how big/how long a Phase III will have to be to achieve that. Having run that Phase III and failed it, scientists acknowledge a failure.

        2. Derek Lowe says:

          I can’t state it more clearly than this:

          Aducanumab’s purpose is to help people with Alzheimer’s disease. What if removing brain amyloid does not help people with Alzheimer’s disease? I believe that the results of Biogen’s clinical trials show that this is indeed the case: that aducanumab does not help people who have Alzheimer’s disease, not to any extent that anyone, including the patients and their family members, would ever notice.

          If a drug does not help people with Alzheimer’s disease, I do not want it approved for Alzheimer’s disease. If Biogen wants this one approved, they should go back and actually prove it helps. Which they have not done so far.

        3. Barry says:

          This speaks to the heart of scientific research.
          -You observe the world (amyloid plaques correlate with dementia)
          -You formulate an hypothesis (clearing plaques would change the course of AD)
          -you design an experiment to falsify* your hypothesis
          -you run that experiment
          -you retire that disproven hypothesis

          That–outside mathematics, where deductive works–is how inductive logic (“science”) works

          *because proof is impossible

        4. loupgarous says:

          What Barry and Derek said. Jason, you’re still writing as though the aducanumab studies hadn’t just been the latest nail in the coffin of the amyloid hypothesis. Again, and again, and again, there’s been no correlation between amyloid level and drug effectiveness. Aducanumab is just the latest and most pronounced example of that.

 Clinical endpoints are what matter in the treatment of Alzheimer’s Disease.

          Biogen needs to hire an objective CRO to look at their Phase III findings, because no one else sees what they say they do in their Phase III numbers – namely, a reason to re-do the Phase III work. All they’ll do is hurt patients worse than they benefit them, and raise expectations among the families of the patient cohort unduly.

          All Biogen’s work with aducanumab shows is that FDA ought to be hiring CROs for contentious safety and efficacy studies directly.

          In too many cases (Biogen/aducanumab and Sarepta/all their exon skipping drugs) equivocal or even outright negative safety and efficacy study results combined with clever lobbying of FDA upper management to overcome clear statements from ADCOMS to walk away from drugs that probably don’t work as advertised – the exact opposite of the Kefauver Amendment’s firm charge to the FDA to confirm drug safety and effectiveness

  15. Philip Sargent says:

    Sorry, but I think you need to look at the hydrogen comments in a bit more detail. Monatomic hydrogen diffuses through iron very fast at room temperature, as produced by e.g. corrosion in water, dilute acid or when using damp welding rods. But normal molecular hydrogen not so much.

    Long distance hydrogen pipelines are made of steel…

      1. Rhenium says:

        From the NIST paper…

        “…the new code would allow a 24-inch pipe made of high-strength X70 steel to be manufactured with a thickness of 0.375 inches for transporting hydrogen gas at 1500 pounds per square inch (psi).”

        Imagine just one bad weld in a 24 inch pipe carrying 1500 psi hydrogen gas… this should be filed under “Things I won’t work in the same city with”.

        1. Barry says:

          We make 10million metric tons of hydrogen gas annually in the U.S. alone, but very little of that gets shipped anywhere. It’s made on-site for Haber fixation of Nitrogen, or saturating lipids, or hydrogenating petroleum distillates, or other big industrial processes. Shipping and storing Hydrogen is not a solved problem.It’s a potent greenhouse gas, and we cannot accept pipes oozing it into the atmosphere.

          1. Derek Lowe says:

            Absolutely – the steam reformers are right next to the Haber-Bosche reactors (and the pressure-shift purifiers for the natural gas are right next to those!)

          2. Rhenium says:

            Wait a second, how can hydrogen be a greenhouse gas? H2 is symmetric ((D infinite h point group) with a single (3n-5 = 1, symmetric stretch). With a center of inversion it can’t induce a IR visible dipole.

            As for Haber-Bosch(e), I love love to teach an entire course on chemistry and chemical engineering around just that one process. Equilibria, hydrogen embrittlement, and all the flow on processes occurring in a multi-acre industrial plant in New Jersey or the Gulf Coast…

          3. anon says:

            Molecular hydrogen is apparently considered an “indirect” greenhouse gas because it affects methane and ozone levels by reacting with hydroxyl radicals.

    1. Rich says:

      Would this be why you aren’t supposed to MIG weld rebar (moisture in the argon?)

  16. Glen L Weaver says:

    Caps with septa could be another bottleneck.
    Returning bottles to vaccine factors for reuse would be a huge logistics problem in itself, and I’m doubtful it would speed things up.
    A huge project. I’d expect roll out to begin in the richest and most developed countries, and roll out from there. Maintaining the vaccines in allowable temperature range during shipment and distribution is not a trivial task.

  17. Stuart says:

    Yes the banner is terrible. You can make a bookmarklet called Kill Sticky, and then when you open Derek’s page (or any with the sticky header panel), just click the bookmarklet that you have saved.

    Poof, troubles are gone:

    1. Eugene says:

      I love the fact that the authors bio is in a sticky header and when you run the bookmarklet it deletes it.

    2. gippgig says:

      It also solved (at least it did in Chromium) the problem of the sticky header obscuring part of each page when printing (at least to a file). Fantastic tip!

  18. Anonymous says:

    I’m already too late for some comments, but here goes.

    1. In the days of Combi Chem and SPPS and SPOS, some organizations were describing how they would be able to provide 10^n (n is large, like 20-30) compounds by combinatorial synthesis with a x b x c … x y x z starting materials for lead testing or optimization. At then common loadings (nanomoles per gram of polystyrene resin), there was not enough carbon on earth to make enough PS to make 2 mg of each compound. And, there weren’t enough vials to store the finished products. And so on. There was a huge explosion in the demand for microtiter plates for synthesis and storage … there’s an idea. … Cast large glass blocks (40 cm x 40 cm x 2 cm?) with deep wells, ~1 mL. Serum cap each well. Return the used blocks for sterilization and refill. (High school geometry – algebra problem: optimize the multi-well glass block design.)

    2. Permeability: Tygon is great stuff and used all over the lab. However, lab grade Tygon is gas permeable to many things, including N2, O2, and H20 vapor (different rates, of course). That’s why most chemists use a bubbler to monitor actual N2 (or Ar) FLOW on their Schlenk lines. Static N2 (a balloon or other ballast) will exchange N2 O2 and kill sensitive reactions. (Lab grade Tygon is a lot of PVC with various platicizers and additives additives.)

    3. Banner Drop Down: I also find it to be a nuisance. Get rid of it.

    4. Pre-loaded Syringes: Already mentioned. I am nearly certain that my last couple of seasonal flu vaccinations were from pre-filled syringes, packed in sterile paper packages like MANY standard bio lab products (pipettes, syringes, needles, …). I ASSUMED that everything was TESTED for efficacy and proper dose delivery before being approved. But it’s still a lot of plastic.

    5a. Lyophilized powders: Already mentioned. Another common practice for some polypeptides / proteins. It does take some training and skill to properly reconstitute a solution that isn’t too frothy and is homogeneous, etc. And you also need a supply of sterile water. Maybe easy at a pharmacy but in the field? Oooh! Package aliquots of sterile water in small vials! Not.

    6. I am almost certain that it was a fairly recent comment In The Pipeline about how much drug is needed to deliver a given dose. Maybe it was one of the cancer drug scam topics (doctors diluting drugs by 2x or more and billing 2x for half-doses). That is, single-use vials contain a large excess of drug because you can never remove the entire contents of a vial by standard syringe technique. I used to know the approximate overfill for some drugs but I’m blanking. Anyone? 40% overfill, 1.4x, to deliver a dose of 1x?

    I can’t remember the other comments – I can’t type fast enough AND keep my thoughts bouncing around. More as I recall them.

    1. Scott Stewart says:

      At least for veterinary drugs, the overfill is generally assumed to be 10% for small vials

  19. DTX says:

    One of the issue with multi-dose vials is that each time a new needle is each time a needle (even a new clean one) is inserted into the vial, it can bring trace amounts of fungi or bacteria.

    Fortunately, there is a safe & effective solution for this: thimerosal i.e., that inappropriately vilified compound that CDC, FDA & others concluded was safe & effective when used in vaccines. Thimerosal is key to making multidose vaccines safe.

    This said, despite the decades of science showing the safety of thimerosal & the fact that would alleviate some of the vial shortage, I can’t imagine it would be accepted. Environmental groups, antivaxxers & other antiscience groups wouldn’t/couldn’t accept it (regardless of the science & regardless of the # of lives it would save). Saving lives with mercury, what anathema ….

  20. Nathan Williams says:

    This all seems to assume that the hypothetical COVID vaccine vials are in addition to all other vaccine vials being produced. It would be good to have a sense of scale here – do we need to double the usual annual production of vials, 10x it, or something else? If it’s 10x, then yeah, we have all the problems you describe. But if it’s more like 2x or less, it seems entirely possible that edging out some other vaccines for a season or two would be a good move for a society. Push the second childhood doses of varicella, MMR, and polio out a year, for example.

  21. Yuri Kudinov says:

    A Covid vaccine does not have to be liquid. Dissolvable microneedle patches are better than hypodermic needles in many ways. The patches are painless because microneedles are too short (0.5 mm) to reach nerve endings.

    DNA, RNA and most proteins can last for years when they are embedded in a dry “glass-like” matrix made of trehalose, sucrose, arginine+glutamate, PVP, reduced dextran, etc. Trehalose particles containing viral proteins can be embedded into dissolvable polymer microneedles.

    Vaccine patches can be packaged by machines that make instant coffee sticks. 3M DriShield film has very low water vapor transmission rate, plus you can add oxygen absorbers and silica gel. One “coffee stick” can accommodate a dozen vaccine patches. Trehalose-embedded proteins can last for years at +25°C; they can even survive brief temperature excursions to +45°C (think of a UPS truck in Arizona).


    A microneedle patch for measles and rubella vaccination: a game changer for achieving elimination.

    Stabilization of proteins in solid form

    Pubmed -> microneedle vaccine review[pt]

    1. PV=nRT says:

      These itch like you would not believe. I’d definitely rather have an IM needle. Hell, I almost would prefer to have covid.

    2. wubbles says:

      Maybe if the winner is spike protein in that form. But would inactivated virus or some of the active virus hybrid approaches work here?

  22. gippgig says:

    Hook a 5 liter jug of vaccine to a pressure injector and dose 10,000 people (wild guess) at a time (which is what needs to be done anyway). No vials, no syringes, no needles. Now, how many pressure injectors would be needed?
    On the subject of soda bottles, wouldn’t oxygen react (slowly) with sugar etc. in the soda?
    How much of a problem would gas permeability be for 3D-printed lab equipment?

    1. matt says:

      Does this look like a nail gun?

      1. Barry says:

        U.S. military used “jetgun” that blew droplets of vaccine (from a large reservoir) through the skin w/o need of a needle to vaccine military inductees. See images in the attached:

  23. gippgig says:

    If anyone’s interested I just ran across a report on similar issues in the semiconductor industry:

  24. Pierre Lebeaupin says:

    Fun fact: in winter 2009-2010, France had its swine flu vaccination campaign moment, this time for influenza A. And among the many reproaches made to the then-minister of health was the choice to bypass the family physicians and set up dedicated dispensiaries (in town halls mostly); it turned out to have been necessitated by the use of 10-dose vials by the vaccine supplier, which meant handing them over to points seeing limited vaccination activity would have been incredibly wasteful (once commenced, a vial has to be used by the end of the day, or discarded).

    Of course, that raises the question of why France did not insist on more practical packaging in the first place (it was a supplier’s market, so the cabinet might have had little choice), but shows this kind of thing matters. A lot.

  25. loupgarous says:

    Thanks, Derek, for enlightening me on many things I’d never considered.

    As with modern warfare, logistics is everything –

    “For want of a nail, the shoe was lost,
    For want of a shoe, the horse was lost,
    For want of a horse, the rider was lost,
    For want of a rider, the message was lost,
    For want of a message, the battle was lost,
    For want of a battle, the war was lost,
    For want of a war, the kingdom was lost,
    For want of a nail, the world was lost”
    ‘The Want of a Nail”, Todd Rundgren

    1. Mike G says:

      Couldn’t a text message have worked as well as a nail?

      1. loupgarous says:

        Neville Chamberlain tried hand-carrying a message on paper and waving it over his head. DIdn’t end well at all.

  26. Norrie says:

    Derek, I have enjoyed your blog for many years now. Please keep your overviews and opinions coming for us. Should we all take a moment to consider a scenario where a few vaccines show promise but they can never be manufactured and distributed in a timely fashion to serve the huge demand across the world. What happens then? Who decides who gets what and when? Can you imagine a black market in vaccine that was outsourced to other countries for manufacture showing up for sale to the highest bidders? We are already seeing the thin edge of the wedge with the US administration being shamelessly nationalistic. I also read that the Oxford UK vaccine, should it prove effective, will be first and foremost for UK use.And so it would go on around the world.

    1. A Nonny Mouse says:

      Not quite true; 400m doses for Europe plus

      ……The Company has recently completed similar agreements with the UK, US, the Coalition for Epidemic Preparedness Innovations and Gavi the Vaccine Alliance for 700 million doses, and it agreed a licence with the Serum Institute of India for the supply of an additional one billion doses, principally for low- and middle-income countries. Total manufacturing capacity currently stands at two billion doses……….

  27. Blow-Fill-Seal Containers (BFS) have long been used for stable ophthalmic applications. Availability of these polymers makes this format fast and ready to step up to the plate. Because the parenteral world is the highest risk packaging application, the concept of using BFS has long been stymied by regulatory bodies. Shelf-life is also a concern. Fact is that vaccines also have a shorter shelf-life, so it is almost a match made in heaven. It is very likely vaccines coming down the pipe will be delivered in parenteral BFS formats. Weiler and Rommelag have been at this for quite some time and interesting discussions are happening within industry groups such as the PDA and ISPE. I really enjoyed reading this article!

    1. Barry says:

      But ophthalmic small-molecule drugs don’t face adsorption/denaturation issues on the lipophilic plastic surface that a proteinaceous vaccine would

  28. Dan says:

    Hydrogen diffuses through metals as atomic hydrogen, dissociation first, so the rate goes as the square root of the partial pressure.

    There is been a lot of interest in COC in recent years. How is this shaping up for vials?

  29. Eric Nuxoll says:

    The appearance of beer in single-serving plastic bottles coincided closely with the approval of a patent for bottles with a layer of aliphatic polyketone which scavenges oxygen as it diffuses through the bottle wall. My thesis proposal was on such coupled diffusion/reaction systems, so when their first limited distribution began (in Wisconsin, as Miller was the brand using them) I made a beer run to Wisconsin to get a cooler of beer for my comprehensive exam. None of my committee chose to partake, but they passed me anyway.

  30. regdoug says:

    I had never really looked closely at the vials used for vaccinations I have received, so I was surprised to learn that they are typically glass. Most of my experience with vaccines is from my parents (mainly dairy cow) veterinary practice, which typically sells vaccines in 10 or 20 dose plastic bottles. The only special handling used on cow vaccines is that they are nearly always refrigerated, while most other drugs don’t need to be.

  31. gippgig says:

    Somewhat related topic: Modeling, design, and machine-learning based framework for optimal injectability of microparticle-based drug formulations
    Science Advances Vol. 6 no. 28 eabb6594 doi: 10.1126/sciadv.abb6594

  32. Barry says:

    Except for Schiemann and high-pressure reactions, I have the predictable chemists’ fondness for glass. But others do keep looking for options:
    “Many cartons made out of paper have a plastic coating inside to stop the drinks leaking out. Diageo, however, said its drinks bottles will not have that plastic coating.”
    How exactly uncoated “paper” would work in this application is too subtle for me.

    1. loupgarous says:

      Barry, re-reading the BBC article, I found

      “Diageo said its bottles will be made by pressurising pulp in moulds which will then be cured in microwave ovens.The bottles will be sprayed internally with coatings that are designed not to interact with the drinks they will contain.”

      So, coatings are going to be involved. Just not plastic ones.

      Those 1-liter room-temperature storable paper milk cartons seem be to internally coated with wax. I’m sure our fellow readers who are organic chemists can come up with a long list of ethanol-inert coatings which are not plastics and won’t leave a fresh unintended toxic taste in one’s scotch.

  33. Yorkie says:

    For the sheer numbers involved in this vaccination program, the traditional way has scalability / time-frame issues as this post points out.
    Time for a Star Trek solution?
    The Portal company appear to be getting there with a single dose device:
    A multi use bulk device would seem the ideal solution this problem.

  34. Mausling says:

    It has been mentioned several times, but I do not agree with any of the counterarguments: what is the problem with multidose vials for a potential vaccination campaign such as this one? Which, as with testing, will probably be administered by dedicated centers.

    AFAIK, the typical problem with multidose vials is bacterial contamination, which need time to grow to problematic levels. In the initial stages of any vaccination program, a ten-dose vial won’t last an hour. You should not need Thimerosal or other preservatives for a one-hour period. Waste in dedicated centers would be minimal and could even be avoided completely, even for higher-doses vials, with a bit of logistic planning.

    Single-dose vials will be needed, but more in the later stages and for decentralized use, but not for the initial “get everybody vaccinated” campaign.

  35. Vincent says:

    What is being done to recycle the Covod vaccine vials? With the need for so many, and the carbon footprint of making borosilicate glass at the necessary high temperatures, this could be a practical solution to solve manufacturing capacity issues as well?

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