I’m still trying to get my bearings with this new paper from the Cronin group at Glasgow. What it proposes is a new style of API (active pharmaceutical ingredient) production. Instead of being done in bench- or process-scale lab glassware or in production-plant reactors, these syntheses take place in 3D-printed reactors, connected together in ways so that the whole process can be moved forward with solvent and/or nitrogen pressure.
That’s a pretty ingenious idea. They have various modules for things like filtration, lighter-than-water (and heavier-than-water) extraction, etc., as shown in the scheme and photograph at right (in the photo, the various reactors are built already connected). These are produced by 3D printing with polypropylene, which gives a good intersection between “printability” and chemical reaction capability). Those of us who have taken up all kinds of nasty reagents over the years in the commonly available PP syringes can attest to its durability. One disadvantage, as noted in the text, is that the rough surfaces inherent to current 3D printing techniques lower the recovery from each vessel somewhat as compared to similar glass reactors (on the other hand, you can’t shatter the things). Overall, I find this printed-small-reactor idea more interesting than I do the drug synthesis part. I hope that 3D printing will allow the development and prototyping of all sorts of new lab apparatus, and I don’t want to take away from that aspect of this paper at all.
But as written, the paper is more aimed at drug synthesis. It demonstrates several (known) synthetic pathways to common drug substances, such as two steps to lamotrigine, three steps to zolimidine, and four steps to baclofen, starting from available industrial precursors. I should note that these synthetic steps require numerous operations, though (addition, mixing, heating, cooling, extraction, filtration, transfer into the next vessel and so on), and they seem to have these working quite well in the PP reactor suites.
A natural next question is why one would want to do API synthesis this way. Here’s the paper’s rationale:
The distribution model for fine and specialty chemicals, such as the APIs implied by this approach, would lead to a decentralizing of logistical approaches to chemical manufacture. Here, any location with access to a sufficiently diverse market of chemical precursors and suitable cartridge fabrication facilities could be used to produce chemical products, which could previously be achieved only in a fully equipped synthesis laboratory with highly trained staff. This approach not only holds promise for eventually delivering on-demand personalized medicines manufactured at, or near, the point of use, but also has short-term potential applications in the synthesis of APIs that are currently out of production. . .
. . .Our methodology will have the most rapid impact for chemicals that are currently produced on demand in small batches and that occupy a gap in the market where the demand for a product is sufficient for it to be commercially viable but insufficient to justify plant-scale production. This gap lies between the high cost of bench-scale versus reactor- scale synthesis, and thus the digitization benefit of compounds in this zone is high
I’m not completely convinced by this, for several reasons. My first impulse is that any region with a sufficiently diverse market of chemical precursors and cartridge fabrication facilities may be able to make APIs in the “traditional” ways. If not, then I come to the same question I had about the Jamison lab’s compact flow machinery for DARPA: if you can ship that machine and the reagents needed for it (or in this case, if you can ship the reagents and the 3D printer and its supplies), then you can ship in APIs, too, for less cost and trouble. I understand that Cronin et al. are picturing a situation where these machines and this technology are already distributed, ready to be configured for what syntheses may come, but I’m not sure how we get to that world from the one we’re in now.
In other words, if you’re in a location where there’s a bottle of methyl p-chlorocinnamate on the shelf, that shelf could usefully also hold a bottle of baclofen as well, which is what you’d make from that precursor. Similarly, if it’s a place where someone can ship you a supply of the cinnamate, they can ship you a supply of baclofen, too, and relieve you of the trouble of keeping all the other reagents around that are needed for its synthesis. Another thing to remember is that the number of reagents, solvents, and precursors needed for a reasonably-sized pharmacopeia is actually quite large.
Here’s another, much larger consideration: if someone ships you a bottle, crate, or shipping container of baclofen, it’s probably going to be baclofen tablets. Not the powder that comes right out of the reactor suite. There is usually a difference. The words “formulation”, “tablet”, “capsule”, “excipient” and “particle size” do not appear in this paper, and those are just the kinds of words and concepts that are usually needed to take you from a bulk chemical to a drug that’s suitable for patients to put in their mouths. Now, if I’m in a real medical jam, I’m going to happily swallow whatever API powder I can get, washed down with any liquid to hand. But that’s not how you want to run things if you can help it. This is certainly not an insurmountable problem, but it is a problem, and the paper sort of glides over it.
To Prof. Cronin’s credit, though, the paper does address another problem: regulation:
The regulatory framework necessary to produce complex materials in this fashion will need thorough attention; indeed, our approach would require a completely new system for the regulation of API manufacture. This system would have to be developed alongside the evolution of this approach as a method for pharmaceutical synthesis, which we have presented here in proof- of-concept form; however, we can envision a situation in which regulatory agencies certify specific cartridge or module designs as soon as a digitized process is fully established (including the embedded quality-control protocols.
That’s a tall order, and it’s worth remembering that it will only happen if there’s enough perceived utility and enough demand. Let’s go back to the chemistry, then, for another thought. What scale are these APIs being made on? The baclofen synthesis starts with 200mg the cinnamate and produces 98mg of API, and that seems to be what’s envisioned here:
This approach not only holds promise for eventually delivering on-demand personalized medicines manufactured at, or near, the point of use, but also has short-term potential applications in the synthesis of APIs that are currently out of production. An immediate impact of digitization is that the cost for synthesis at the bench scale (milligrams) could decrease markedly owing to savings in labor and infrastructure with only a one-off digitization cost (and allow operators to make 5 to 10 different products at the same time).
That paragraph (to my mind) is mixing two different things. Bench-scale synthesis of milligram amounts is (or can be) a very different thing than the synthesis of APIs that are out of production. Put simply, these reactors will need further work if they’re to be scaled up. As any industrial chemist knows, the procedures for mixing, heating and cooling, filtration, extraction, and transfer become quite different as you move to larger scales, and if you’re starting on the 200mg scale they’re going to become different pretty quickly. (That’s not to mention the likely need for a completely different model of 3D printer in order to make the reactors themselves). The paper does suggest using smaller reactors in parallel, although I should note that that complicates things under the current regulatory framework.
I bring this up because the demonstrated synthesis of baclofen is enough to make four or five tablets (if you had the facilities to make tablets, that is). There may well be benefits to making such compounds at the point of delivery, but there are significant benefits to making them on scale, too. I note in passing that baclofen itself is available from at least 13 suppliers (although, to be sure, I don’t know if they’re all making it themselves).
And that leads to another large argument I have with this idea. As the quotes above show, one of the propositions behind this work is that manufacturing costs are a key barrier to the availability of drugs. But in my experience, that is rarely the case. To be sure, I have not spent my career in the generic-compound end of the industry, and the low margins in that business can make manufacturing costs more of a factor. But the barriers to generic drug availability are more often regulatory and legal ones than they are manufacturing ones. It’s true that the cost per milligram for such compounds could come down through this small-reactor technique, but only if you just need milligrams. If you need much more compound, then it becomes far less expensive to make it on scale in a defined batch and ship it somewhere.
So here’s my question, and it’s a similar one to what I had with the DARPA-funded synthesizer work: can someone lay out a general situation where this sort of point-of-use drug synthesis would be the best way to go? I don’t mean in general terms; the paper itself does that. But does the real world overlap with those general terms, and if so, how? What APIs are currently produced “on demand and in small batches” where that part itself is the limit on availability? I’m willing to be convinced, but I’m not convinced yet.
Note: there have been a couple of clueless headlines about this work that talk about “3D printed drugs”, but the paper itself makes no such claims. of course. It’s been a safe bet for some years now that any press coverage with that phrase in it was written by someone who has no idea what they’re talking about, and that rule still holds.