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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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July 14, 2009

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Posted by Derek

What does it take for a new technology to catch on in the labs? There's an endless stream of candidates (I hope it's endless, anyway), from small gizmos that you can keep in your drawer to multi-hundred-thousand-dollar machines that need their own air handling systems. But all of them start out in the "is this thing any good?" zone, and not all of them emerge, no matter how much they might cost.

That's the first criterion: does the new equipment do anything useful? You'd think that this would have been worked out by, say, the team that developed the product in the first place, but hope does spring eternal. Companies do sometimes get some funny ideas about what their intended markets are clamoring for.

The second test is whether it does its thing in a way that doesn't mess up what you're already doing. "Useful but annoying" is an all-too-well populated category, and if the balance tips too far toward the latter, people will gradually find reasons to stop using the equipment. With some equipment, you start to feel as if you're paying twenty dollars for $20.03 in pennies, putting the whole process into the "not worth the trouble" bin.

Automation is often a factor here. Poorly engineering automation will drive people away like a skunk, of course. Lack of automation won't drive them away, but it won't give them an incentive to come back, either. But do it right, and you lower the perceived cost of using the equipment. Microwave reactors for chemical reactions are a good example of this. The first buckaroos who did these things used kitchen microwave ovens and homebrew reaction vessels. Then there was a generation of reaction carousels that fit into the oven compartment, but that fell into the "annoying" category. The more recent crops of dedicated machines, though, have caught on. They don't look like microwave ovens at all (for example), since the reaction chamber is much smaller (built, in fact, to fit the reaction vials). And they run from a software interface, allowing you to put your tube in the rack, set up your conditions, and walk away.

That phrase "and walk away" is the key idea behind good lab automation. You shouldn't have to stand in front of a machine to make sure that it's going to do what it's supposed to. You can walk away from NMRs, from LC/MS machines, from fraction collectors and many other devices. But if you can't, because the machine hasn't evolved to the point where automation is possible - or worse, if it has automation you can't trust - then the benefit of using the thing had better be substantial.

Lab-scale flow reactors are a good example of equipment that hasn't quite reached the walk-away stage yet (although I have hopes). I know that there are several machines out there that have some ability to do multiple unattended runs, but I'd be interested to know how many users actually manage to leave the things alone while they're doing them. I'm a fan of flow chemistry, but until the machines are more like the microwave reactors, their user base will be confined more to hairy, wild-eyed types like me. The companies in the business seem to realize, though, that my phenotype will not allow them to earn an honest living, and are taking steps.

Comments (23) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. gyges on July 14, 2009 10:34 AM writes...

At the top of my wish list would be continuous flow apparatus which would include a higee distillation apparatus.

As for your link above ... "I'm a fan of flow chemistry" the fluidised bed MnO2 reactor was a cracking tale. Well done to you and the contributor.

Has anyone done anything similar with homebrew? Sort of like, yeast suspended in calcium alginate and mash slowly pumped through producing a pint of five-percent beer per hour? (Not in an industrial capacity, just in the garage?).

Lastly, this passed me by the first time around Drugs made abroad. It's almost but not quite a rant from a lawyer (most probably looking for work) from earlier this year. It could generate sensible comments if anyone is interested in discussing the points he raises.

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2. AR on July 14, 2009 10:46 AM writes...

Ha! This strikes a chord. I am not a chemist, but biologist who has spent a lot of time using liquid handlers to pipette small volumes into 96, 384 and 1576 well plates. I never met a robot liquid handler you could turn your back on once the ink was dry on the invoice check. People who say otherwise must be the senior managers who approved the order and stand to look good to VP’s because of improved worker efficiency.

That said, precision is improved with liquid handlers, just do not walk away.

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3. azmanam on July 14, 2009 11:49 AM writes...

Is that a Karel Capek reference? (wikipedia)

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4. processchemist on July 14, 2009 12:26 PM writes...

I'm in theory a fan of flow chemistry... in my university days I projected a continuous fixed bed reactor for phosgene production...
#1 correctly focused on the huge downstream workup volumes. Another problem is that you turn from stirrable mixtures to pumpable mixtures and this can be a serious issue with microreactors (clogging!).
In our line of work recently flow chemistry has been used at DSM to produce a nitrate (naproxicinod) (if I remember correctly they used microreactors), but this is the only case study that hit the news, as far as I know (apart from the "we implemented this great stuff" declarations)
So my opinion about microreactors is: cool technology, pretty much hyped, with important but limited real life applications. Exactly the opposite of DOE applied to process chemistry - most chemists does not fancy DOE beacause it involves mathemathics, so it's not so sexy; not hyped at all; virtually unlimited applications, with great results from well designed experiments.

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5. Derek Lowe on July 14, 2009 12:56 PM writes...

#3 - yep, that's the title, all right. I probably should have put periods after each letter.

#4 - I really need to do a blog entry on DOE. I haven't had a chance to use it myself, but I like what I've seen.

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6. MikeyMedchem on July 14, 2009 1:09 PM writes...

Re: #1 and #4 - you can couple a flow reactor to the Vapourtec V-10 evaporator and evaporate the solvent as the reaction flows out. Nifty stuff.

I agree with Derek's assertion: "until the (flow chemistry) machines are more like the microwave reactors, their user base will be confined more to hairy, wild-eyed types like me." I've told this to the vendors a zillion times:

"Me dumb chemist. Me want big green button to start machine and big red button to stop machine."

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7. David P on July 14, 2009 1:58 PM writes...

Actually I don't think you should just walk away from a microwave reactor either. Well, not till you are sure it is not going to take off. Even though those things are built like a bomb shelter, it tends to be bad for instrument use when you keep having to clean bits of glass out of it.

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8. Chemjobber on July 14, 2009 2:08 PM writes...

I have yet to really shatter one of those Biotage/Personal Chemistry microwave vials. However, I did once load compound and straight MnO2 (don't ask -- it was an ARKIVOC procedure) into one and it really tore the hell out of the seal.

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9. milkshake on July 14, 2009 2:24 PM writes...

I think what sold the microwave reactors is that the whole package is useful - the Biotage-ready disposable tubes (with a fitting inexpensive stirrbar) that can hold up to 22 atm - they replaced small regular pressure tubes in our lab.

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10. Theotocopulos on July 14, 2009 2:44 PM writes...

Imagine this:
The Automated Lab Device is built. It works well, and everyone jumps on the bandwagon to make it more "efficient". It is networked to other Automated Lab Devices. After some period of time, every Automated Lab Device in the world is networked to every other. This is done in the name of "efficiency and or time/money savings, and/or increased capacity" or whatever. Then this network is connected to computers which do automated analysis. Now we have a gigantic network that is the equivalent of a Lab Chemist Borg.

Derek's second point is important. "Messing up what you are doing" can be taken to extremes.

Maybe the Luddites had a point.

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11. Lily Kim on July 14, 2009 7:59 PM writes...

In the past I developed microfluidic technologies intended for use in labs (for drug discovery, basic biology, etc.). Because our work was academic, the goal was proof-of-concept, never mind what the end user might want. Still, I think it would have been valuable to learn the types of things you describe in this post--what would make a technology actually useful?

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12. CMC guy on July 14, 2009 9:54 PM writes...

#11 Lily Kim states "Because our work was academic, the goal was proof-of-concept, never mind what the end user might want." Unfortunately this is an apt description and attitude of a vast majority of academic work which makes me cringe every time I hear talk of government and universities "doing drug discovery". It takes a different mindset that usually takes a while working in industry to break away from that perspective.

In terms of what would make a technology useful I think Derek provides good start and fundamentally like most types of innovation (except perhaps novel drugs it seems) would want maximally flexible, faster, simpler and cheaper than alternatives.

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13. Device dabbler on July 14, 2009 10:25 PM writes...

We occasionally build instrumentation (academic lab), but it is not our focus. By chance, the last few times, the construction of the device started in late spring. Trying out a new machine is a great summer undergraduate project because they tend to be enthusiastic about (rather than dread) homebuilt kit. If the machine works out well, they have a decent shot at a paper. If it doesn't, they had the same level of productivity as the other summers.

Because of this, we've delegated testing to summers. This has led to a design philosophy of "sufficiently fail-proof for a green (but bright) summer undergraduate to operate successfully."

A year or two down the line, once you've forgotten how the circuit works or the graduate student who built it has gone off to do other things, you thank yourself.

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14. Mutatis Mutandis on July 15, 2009 4:37 AM writes...

A key to making new technology useful -- pardon me for sounding like a cynic -- is not to overestimate its users. Too many new platforms work happily in the hands of someone who gives them a lot of attention and TLC, but can't cope with routine use in an industrial environment. Life sciences labs usually have about a third of the engineering and IT support that the designer of the instrument would regard as the absolute minimum, and most routine users have very little affinity for hardware. Instruments have to be able to survive torture.

It is also important to get the software right. The typical first-generation laboratory software has awkward, poor quality and unstable software. (The typical seconds generation software is merely awkward and poor quality.) Too often it is the limiting factor for what could have been a very useful instrument or automation.

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15. RB Woodweird on July 15, 2009 6:48 AM writes...

We got a CombiFlash from Isco last year, and now I don't know how I ever got any chemistry done without one. I am right now sitting at my desk in an office area watching the separation in a browser tab, with the ability to change any parameter I want without getting up. If this unit ever breaks down and is not replaced, I will have to quit chemistry, as I would never be able to run a regular column again without paralyzing remorse. It would be like having your backhoe quit and having to go back to digging that ditch with a shovel.

Historical anecdote actually on topic: A German general once said that after he had been captured and was being taken to the back of the Allied lines, he passed an important intersection of roads, a target that both sides shelled and bombed when the other held it. He said that when the Germans had the position, they used to send out a couple of platoons with shovels to fill in the holes. In the American's hands, the holes were being filled - many times faster - by one black GI driving a bulldozer. It wasn't until that moment, the general said, that he realized Germany was going to lose the war.

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16. Anonymous on July 15, 2009 8:35 AM writes...

Yes, our CombiFlash is a wonder.... It has it's limitations - mostly related to compounds lacking a chromophore, you'll likely be doing lots of TLC spotting even with DCM/Acetone or something.

But it still runs a column - setup to finish - 20 minutes.... I love it.

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17. Tok on July 15, 2009 8:54 AM writes...

+1 for Combiflash goodness.
#16 anon - Isco has new software out for the machines that includes the ability to monitor all wavelengths the DAD can detect. Seems to work well even with things that lack a good chromophore.

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18. anon the II on July 15, 2009 9:05 AM writes...

The CombiFlash is an excellent example of what Mutatis is saying. ISCO (now Teledyne) has been working on such a beast for over 30 years. I was watching. They had most of the pieces back in the late '70's. They finally got it to work (competitively with manual flash) around 2003. Biotage may have figured it out a couple of years later. By comparison, given only a few years to 'solve' the parallel synthesis problem, it's no wonder that so much of that equipment was not very useful and relegated to storage.

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19. JC on July 15, 2009 4:08 PM writes...

I dug a rather large hole in my yard last year, myself & a few fellows I paid $250 a piece. A plumber came over & asked me how much I thought he would have charged for it. I said $1800 & he said 'more'.

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20. doctor doom on July 16, 2009 10:43 AM writes...

I used to be really into the technology side of our business, and we had all the toys - ACTs, Tecans and indeed we still have the ISCOs and Biotages. But it turns out that a contractor in India or China is much more versatile and cheaper to run than these shiny toys. So the toys gather dust and our labs are going silent.

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21. AlchemX on July 24, 2009 2:40 AM writes...

Hey, I'm good with those toys actually. I'm a grad student that knows a lot about electronics and fixing those things (especially ISCOs!!) So if anyone is trying to save space, feel free to give me some of those toys.

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22. Brewer on July 30, 2009 3:06 PM writes...

I don't know if anyone is using the yeast bioreactors in home-brew operations, but they never really left the lab settings in the beer industry.

It would have to be one clean freak of a homebrewer (most brewers are) to get it to work before it's infected.

There are some small scale continuous fermentation using non-brewers yeast and other microbes to create sour ales. Some brewers keep a culture going in the barrel and draw off finished beer and add fresh beer regularly. It's not truly a bioreactor, but it's close.

Actually, after having just looked at a lab-setup, mayby I will give it a shot...

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23. ABC on August 23, 2009 5:16 AM writes...

This thread has focussed on the merits of flow reactors from the perspective of lab productivity. On that measure, automation achieves a high score.

When a chemical process is transferred to manufacturing however, the commercial driver switches to yield/quality. Several years ago one of the flow reactor manufacturers published a comparison between batch and flow for about 25 different reactions. The average yield uplift from using flow was about 12.5%. Given that the COGs within the pharma industry in 2008 was around $200 billion, the commercial significance of yield uplifts of this order are huge.

One of the reasons that flow experiments are difficult to ’leave alone’ is linked to the level of automation currently available. The other is ease of set up and reliability. On this score many of the flow reactors currently on the market score badly because they rely on static mixing. As a result, they have a tendency to block/foul and users have to tinker with them to find the sweet spot in terms of pressure drop/mixing/flow/ length/residence time/plug flow. Although micro reactors are more tolerant (because they use diffusion for mixing and conduction for heat transfer) they have their own set of problems. Several companies in the UK have sought to tackle the problem of reactor tuning by developing variable length reactors.

The alternative is to adopt reactor types which are inherently more flexible and less prone to blockage. The two main examples of these include oscillatory baffled reactors and multi stage CSTRs.

The flow reactor market is still in its infancy but it is here to stay, of that we can be sure. The commercial advantages of flow for some types of process are too great to ignore.

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