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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 13, 2011

Process Chemistry Makes the Headlines

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Posted by Derek

Not a common occurrence, that. But this Wall Street Journal article goes into details on some efforts to improve the synthetic route to Viread (tenofovir) (or, to be more specific, TDF, the prodrug form of it, which is how it's dosed). This is being funded by former president Bill Clinton's health care foundation:

The chasm between the need for the drugs and the available funding has spurred wide-ranging efforts to bring down the cost of antiretrovirals, from persuading drug makers to share patents of antiretrovirals to conducting trials using lower doses of existing drugs.

Beginning in 2005, the Clinton team saw a possible path in the laboratory to lowering the price of the drugs. Mr. Clinton's foundation had brokered discounts on first-line AIDS drugs, many of which were older and used relatively simple chemistry. Newer drugs, with advantages such as fewer side effects, were more complex and costly to make. . .A particularly difficult step in the manufacture of the antiretroviral drug tenofovir comes near the end. The mixture at that point is "like oatmeal, making it very difficult to stir," explained Prof. Fortunak. That slows the next reaction, a problem because the substance that will become the drug is highly unstable and decomposing, sharply lowering the yield.

Fortunak himself is a former Abbott researcher, now at Howard University. One of his students does seem to have improved that step, thinning out the reaction mixture (which was gunking up with triethylammonium salts) and improving the stability of the compound in it. (Here's the publication on this work, which highlights that step, formation of a phosphate ester, which is greatly enhanced with addition of tetrabutylammonium bromide). This review has more on production of TDF and other antiretrovirals.

This is a pure, 100% real-world process chemistry problem, as the readers here who do it for a living will confirm, and it's very nice to see this kind of work get the publicity that it deserves. People who've never synthesized or (especially) manufactured a drug generally don't realize what a tricky business it can be. The chemistry has to work on large scale (above all!), and do so reproducibly, hitting the mark every time using the least hazardous reagents possible, which have to be reliably sourced at reasonable prices. And physically, the route has to avoid extremes of temperature or pressure, with mixtures that can be stirred, pumped from reactor to reactor, filtered, and purified without recourse to the expensive techniques that those of us in the discovery labs use routinely. Oh, and the whole process has to produce the least objectionable waste stream that you can come up with, too, in case you've got all those other factors worked out already. Not an easy problem, in most cases, and I wish that some of those people who think that drug companies don't do any research of their own would come down and see how it's done.

To give you an example of these problems, the paper on this tenofovir work mentions that the phosphate alkylation seems to work best with magnesium t-butoxide, but that the yield varies from batch to batch, depending on the supplier. And in the workup to that reaction, you can lose product in the cake of magnesium salts that have to be filtered out, a problem that needs attention on scale.

According to the article, an Indian generic company is using the Howard route for tenofovir that's being sold in South Africa. (Tenofovir is not under patent protection in India). Interestingly, two of the big generic outfits (Mylan and Cipla) say that they'd already made their own improvements to the process, but the question of why that didn't bring down the price already is not explored. Did the Clinton foundation improve a published Gilead route that someone else had already fixed? Cipla apparently does the same phosphate alkylation (PDF), but the only patent filing of theirs that I can find that addresses tenofovir production is this one, on its crystalline form. Trade secret?

Comments (21) + TrackBacks (0) | Category: Chemical News | Drug Development | Drug Prices | Infectious Diseases


COMMENTS

1. @DerekLowe on May 13, 2011 8:42 AM writes...

Did you post this topic twice? I'm seeing to entries on my browser.

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2. Mat Todd on May 13, 2011 8:46 AM writes...

Very cool story. Never expected to read the words "the Clinton team saw a possible path in the laboratory to lowering the price of the drugs"

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3. patentgeek on May 13, 2011 9:49 AM writes...

Cool indeed; thanks Derek for pointing this out!

The Cipla PCT WO 2009/130437 describes and claims, in addition to the polymorphs and their preparation, a process to make tenofovir disoproxil from PMPA by condensing with chloromethyl isopropyl carbonate and Et3N. Don't know if this is how they make it commercially, or if it's what's alluded to in WSJ.

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4. CMCguy on May 13, 2011 10:38 AM writes...

It would not surprise me if Gilead or some of the Generic places have worked out chemistry adjustments which has not appeared in Patents (and if Chindia facilities don't have they now can "borrow this technology"). Much process work is held as Trade Secrets and some of the best stuff I have seen for actual Manufacturing routes was handled that way.

I would be curious in learning the time frame for the effort. The article mentions "One of Prof. Fortunak's graduate students, Adrian Williams, painstakingly tested many possible methods to improve this step. His eureka moment came when he added a catalyst known as TBAB, short for tetrabutylammonium bromide." In academia normally this would be 12-24 months type project whereas in industry Process chemist may get only 6-12 weeks to work out chemistry before need to run at scale and still have to do under GMP.

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5. Thomas McEntee on May 13, 2011 11:08 AM writes...

Agree completely with CMCguy. Back in the 1970s when I worked in process development at Syntex Boulder, we'd get a "finished" multistep process from the kilo lab crew in Palo Alto and be expected to have it ready for the 2000- to 4000-gallon reactors in a few months. This often meant a serious re-design. Virtually none of the process info ever made its way into patent applications; trade secrets were judged to be much more secure. With respect to dramatic process improvements leading to consumer price reductions, it would happen only if the market forced such reductions. For one of our more notable products, naproxen, it was the ibuprofen-naproxen market share war that was driving everything.

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6. Mitch on May 13, 2011 1:06 PM writes...

Actually, what's making the headline is the fact that getting a PhD is a one way ticket to poverty.

Interesting that the damn of propaganda is finally breaking.

Academics can help their US students (you know the guys you're supposed to be training) by hiring only US citizens for staff positions.

70% of the staff hires in the sciences are foreigners at the joint I work. You'll find the jobs are never even advertised.


http://www.thenation.com/print/article/160410/faulty-towers-crisis-higher-education

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7. Chemjobber on May 13, 2011 1:18 PM writes...

There is indeed a Chemjobber angle to this little article. Assuming the press reports are correct and that Mr. Williams was the bench researcher who made the key PTC breakthrough, it's sort of disappointing to read this:

"He is now living in Canada looking for a pharmaceutical chemistry job."

Oh, dear.

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8. milkshake on May 13, 2011 1:58 PM writes...

@7: Yes, that serves him right (doing thesis on process research at a no-name university). Only people with tot synthesis background from top 5 universities need to apply for US industry positions...

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9. Munter on May 13, 2011 5:19 PM writes...

@8: Lol

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10. Boss on May 13, 2011 7:24 PM writes...

@7 said "He is now living in Canada looking for a pharmaceutical chemistry job."

Canada is a dumping ground for cheap Chinese labor.

Asian kids who get US degrees that are not provided US visas are almost instantly given a Canadian work visa. NAFTA then allows them entry into the US market where they compete for American jobs.

Good to see an American trying to take a Canadian job for a change.

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11. Anonymous on May 14, 2011 9:24 AM writes...

Ultimately the policy of training lots of scientists has worked.

We now can provide companies with very CHEAP labour that industry needs.

Great places are picky. Don't expect them to sift through a ton of candidates when they know they can short list talent.

Process CRO's are famous for squeezing labour. These places are often run by former chemists BTW.

If you see more then 75% foreign labour, turn around and run or expect a very low salary. It's the only way they survive.

Government job are now paying close to double now what many industrial jobs are offering.

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12. weirdo on May 14, 2011 9:13 PM writes...

To echo #11, a lot of the academic drug discovery labs are paying what industry was paying a decade ago -- which is not at all bad money.

Near-six-figure starting salary with solid five-figure sign-on bonus? No. But hardly slave wages.

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13. horse tooth on May 14, 2011 10:27 PM writes...

#8

Even coming from a top group does not mean anything. I'm from a top group and could not get an interview if I tried. Avoid this field like the plauge.

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14. horse tooth on May 14, 2011 10:28 PM writes...

#8

Even coming from a top group does not mean anything. I'm from a top group and cannot get an interview. Avoid this field at all costs.

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15. Anonymous on May 15, 2011 1:44 PM writes...

really, looking for a pharma job in canada by choice? all big pharma has left canada!

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16. sarah on May 15, 2011 3:27 PM writes...

#10, Boss: "Canada is a dumping ground for cheap Chinese labor."

Wow. Clearly, you've never worked in Pharma in Canada, which has, in the last 5 yrs watched 4 out of 5 large pharma-companies exit. I myself did work there, and I can tell you from personal experience that >85% of my colleagues in chemistry were Cdn born, raised, schooled, then Post-doc'd in the US. Also, those that have NOT moved to the US in the last 5 yrs in order to keep their pharma jobs, more than 50% of them have left pharma altogether.

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17. simpl on May 16, 2011 4:28 AM writes...

#4 - Two questions around synthesis improvements:
This is the nub of the argument that generics add value. And although our production guys are always tinkering with their method of manufacture, we have often enough reached a point a few decades after launch where it is cheaper and potentially easier to buy a pharmacopeal quality from Asia.
1) Don't Asians have a better synthesis, if they make cheaper product?
2) Will this also hold true for the biosimilars?

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18. processchemist on May 16, 2011 6:01 AM writes...

"Don't Asians have a better synthesis, if they make cheaper product?"

Sometimes they have good (not better) syntheses, sometimes not (I'm talking about indian companies). Mostly they have cheaper workforce and ludicrous environmental regulations. And this is what's really making the difference.
But IMHO there's a scale economy issue too. For some generic products there are no more western producers, so all the production in currently concentrated in Asia. This means high volumes, and high volumes usually mean lower prices. This can be the explanation of the incredibly low prices of some basic generic APIs .

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19. simpl on May 16, 2011 10:12 AM writes...

@18 process chemist
You're right on all counts.
About economies of scale, I didn't make that explicit, although it was somewhere in my thinking: when a generic is first set up, the originator is the one with the advantage of high and consistent volume.
Our company sems to aim on launch to optimise for flexibility and to use existing multi-purpose equipment - it takes a rare success for us to establish a purpose-built plant. Maybe that also opens the doors to competition.

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20. CMCguy on May 16, 2011 3:03 PM writes...

#17 agree with response by #18 processchemist that labor and environmental cost are main drivers and depending on product certain economies of scale can underly numbers (although Pharma standard practice is to have at least two sites make drug so split supply anyway). There are likely contribution from things like Chindia capital costs (land and equipment), transportation, taxation rates etc. that have nothing to do with having a "better synthesis".

Pharma Process is strange for not always operating in most efficient manner so can be a compromise situation of what a process is verses what it could be. Sometimes Development is constrained early on and then may get to work out a "acceptable" process for initial commercialization. If Market big enough may then get a better process yet I actually think it is not that common for Pharma to continue to "tinker with method of manufacture" post-commercialization and would speculate after about 3-5 years the process is "locked" to whatever it is, largely driven by demands inherent for regulatory submissions. There is a point reached to justify a change requires huge and quick payback to capture ROI prior to Patent expiration so can be hard to introduce improvements and process stops evolving thus will be "dated" with older less efficient technologies. While there are advantages to knowing a process well/repetition there is not much new cost lowering generation after a stage (unless raw materials prices can continue to drive down further). So a more modern facility making Generic can, without changing chemistry route, more readily introduce "advanced technologies" in their ANDA that do result is being more competitive than an original process (so better because not in a time warp). On rare occasions Generics may invest in "alteration of chemical routes" however have to deal with possible impurity profiles, but like innovative companies they have to see significant ROI for doing this.

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21. Eric Stoner on March 2, 2012 2:36 PM writes...

It's good to see process chemistry get the recognition it deserves. The optimization efforts undertaken by process chemists lead to some amazing improvements. The points made in #20 match my own experiences. As development timelines shrink, the opportunities to make significant cost reductions and processing improvements become more and more restricted (primarily by regulatory requirements, but just as much by restrictions to changes in impurity profile).

The big savings for Generics is that they can piggy-back onto published routes/patents without having to have done the research to discover it. Depending upon how the filings/patents are written, variations within covered parameters can make a huge difference in yield and impurity profile in an API. In a sense, optimized trade secrets can be hidden in plain sight.

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