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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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September 16, 2010

Six Sigma in Drug Discovery? Part One - Are Chemists Too Individual?

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Posted by Derek

I had an interesting email about a 2009 paper in Drug Discovery Today that has some bearing on the "how much compound to submit" question, as well as several other areas. It's from a team at AstraZeneca, and covers their application of "Lean Six Sigma" to the drug discovery process. I didn't see it at the time, but The title probably made me skip over it even if I had.

I'll admit my biases up front: outside of its possible uses in sheer widget-production-line settings, I've tended to regard Six Sigma and its variants as a buzzword-driven cult. From what I've been able to see of it, it generates a huge number of meetings and exhortations from management, along with a blizzard of posters, slogans, and other detritus. On the other hand, it gives everyone responsible a feeling that they've Really Accomplished Something, which is what most of these managerial overhauls seem to deliver before - or in place of - anything concrete. There, I feel better already.

On the other hand, I am presumably a scientist, so I should be willing to be persuaded by evidence. And if sensible recommendations emerge, I probably shouldn't be so steamed up about the process used to arrive at them. So, what are the changes that the AZ team says that they made?

Well, first off is a realization that too much time was being spent early on in resynthesis. The group ended up recommending that every lead-optimization compound be submitted in at least a 30 to 35 mg batch. From my experience, that's definitely on the high side; a lot of people don't seem to produce that much. But according to the AZ people, it really does save you time in the long run.

A more controversial shift was in the way that chemistry teams work. Reflecting on the relationship between overall speed and the amount of work in progress, they came up with this:

Traditionally, chemists have worked alongside each other, each working on multiple target compounds independently from the other members in the team. Unless managed very carefully by the team leader, this model results in a large, and relatively invisible, amount of work in progress across a team of chemists. In order to reduce the lead time for each target, it was decided to introduce more cooperative team working, combined with actively restricting the work in progress. The key driver to achieve and sustain these two goals was the introduction of a visual planning system that enables control of work in progress and also facil-
itates work sharing across the team. Such a visual planning system also allows the team to keep track of ideas, arrival of starting materials, ongoing synthesis and compounds being purified. It also makes problems more readily recognizable when they do occur.

We have reflected on why chemistry teams have always been organized in such an individual-based way. We believe that a major factor lies in the education and training of chemists at universities, in particular at the doctoral and postdoctoral level, which is always focused on delivery of separate pieces of work by the students. This habit has then been maintained in the pharmaceutical industry even though team working, with chemists supporting each other in the delivery of compounds, would be beneficial and reduce synthesis lead times.

OK, that by itself is enough to run a big discussion here, so I think I'll split off the rest of the AZ ideas into another post or two. So, what do you think? Is the "You do your compounds and I'll do mine" style hurting productivity in drug research? Is the switch to something else desirable, or even possible? And if it is, has AstraZeneca really accomplished it, or do they just say that they have? (Nothing personal intended there - it's just that I've seen a lot of "Now we do everything differently!" presentations over the years. . .) After all, this paper is over a year old now, and presumably covers things that happened well before that. Is this how things really work at AZ? Let the discussion commence!

Comments (50) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs | Who Discovers and Why


COMMENTS

1. NYSpursFan on September 16, 2010 9:23 AM writes...

Exceedingly interesting hyppothesis. It's certainly true in any PhD program that you're trained to think and act and produce and write as an individual. Then you get a job in industry and are thrown into a "team" environment, which isn't really a team, per se, but a group of individuals. The group is being managed by an "individualist" with no experience or training in group oversight or management. As I think out loud here, there may be quite a bit of truth in this. I also see this in the financial and consulting communities. Perhaps the answer lies in "team" PhDs?

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2. Bob on September 16, 2010 9:36 AM writes...

If this was true, then surely "german model" organisations (Novartis, Merck-Serono, Roche et al.) would have gone out of business years ago or have been demonstrably less productive than the competition.

In addition to an over-abundance of six sigma black belt crapola, AZs real problem is evidently (and by their own admission) a lack of careful med chem managers.

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3. Cellbio on September 16, 2010 9:43 AM writes...

Nothing here specific to Lean or Six Sigma. I worked in a great team culture in my first company, and had to learn that my productivity was in the team and not my lab. The culture was built by the founders, long before six sigma became popular, and without meetings and with no requirement to laminate anything. it was all supported by the way the leadership acted.

Also, nothing particular to chemists way of working. In fact, I found the biologist, or target champion, to be much worse than the chemists. Each wanted to screen their teams compounds at the dose they chose, against the related targets they thought reasonable and in assays they built, even if closely replicating an existing assay. This meant chemists compounds were decorated with non-overlapping data sets from similar but importantly different assays that made cross-team comparisons difficult.

I fixed all this with common sense, and occasionally a bit of insistence, but never had to invoke Lean or SiX sigma. In fact, my best allies for change were the chemists, who wanted a better system of assuring rapid and meaningful turn-around of data that informed the next round of synthesis. I found that most every chemist had the experience of working in a team with assay 'blinders' which resulted in months to years of work that would have been redirected if only a simple assay had been run early in the program. Easy fix with sound rationale, no need to bring in the black belts.

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4. Hap on September 16, 2010 9:44 AM writes...

1)...and credited as an individual. From grad school, part of what potential employers want to know is what the capacities of each person are, and an education that makes it hard for employers to disentangle the contributions of each person will probably make it (more) difficult for those people to get jobs afterwards.

2) I don't know the day-to-day operations in drug research, but I had assumed that people mostly made separate and discrete things, or interacted on separate steps in a synthesis (though even that means that unless you have lots of things going at once, one person's difficulties hinder everyone else in the sequence). Even in a team environment, people do discrete tasks, and anything that lumps lots of things together makes their output dependent on multiple people in concert and makes the contributions of individuals difficult to disentangle. How do you change this?

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5. Calvin on September 16, 2010 9:48 AM writes...

Hmmmm. I've seen the AZ Six Sigma folks in action. It's a cult for sure. It's a career badge thing on their journey up that career ladder. However, I'd agree that the combative nature of many PhD groups does not lend itself well to teamwork and there is scope to do things better (Chris Lipinski used to talk about this too). In fact, we use the tracking board idea but not nearly as rigidly as AZ and it does work pretty well. Certainly, it's helped the group that I work in share information and intermediates more readily to such an extent that specific chemists will do a step, pass it on, and then maybe get the batch back later on. Everybody can see where everybody is (roughly) with a target or intermediate. So it definitely helps but only because it's a simple tool that aids communication. I have to admit I was VERY skeptical and we certainly don't use it as AZ do (we don't date when a compound goes into synthesis and when it gets submitted and log the overall time) but it's something that's worth trying out

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6. SixSigmaSkeptic on September 16, 2010 9:50 AM writes...

Hi Derek,
Having worked at GSK for some years where some groups were very keen on SixSigma etc, I think you've summed it up perfectly in your second paragraph. SixSigma was the perfect vehicle for ambitious but scientifically/technically limited managers to climb the career ladder. It was a Godsend for them, lots of pointless meetings, full of meaningless buzzwords that produced nothing tangible except promotions for said managers. Me personally, I wouldn't hire anyone with SixSigma tendencies, for the same reasons, I'm also very suspicious of such titles as "project managers" and "business analysts", "IT strategy managers" etc. These types of roles appear to have proliferated in "Big Pharma" in recent years and are I believe major factors in its current decline! That's my very strong personal bias born of witnessing the rise and rise of these "empty suits"!

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7. Cloud on September 16, 2010 10:38 AM writes...

Like @cellbio, my perspective is more on the overall industry than just on chemists. I think the switch from focusing purely on your own project to thinking more broadly about the good of the organization is one of the hardest things about the academia to industry transition for some scientists. I'm in biotech, where projects are often competing for limited resources. I've seen too many project leads who are so focused on the success of their projects that they kill/maim other important projects. I just want to shake the project lead and say "Yes, your project will succeed. But what good is that if the entire company is out of business?"

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8. dearieme on September 16, 2010 10:49 AM writes...

Those engineers who do PhDs also do them as individuals. Yet afterwards they tend to work in well-integrated teams.

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9. LeeH on September 16, 2010 11:04 AM writes...

As a cheminformatics guy I'm usually in favor of slick ways to organize information and make things easier for project teams. That being said, my experience is that you can't get people to use any system unless you can demonstrate that the tool will make life easier for them, and not just add another accounting burden. My sense is that if people at AZ (or elsewhere) are actually using this kind of system then it is really making their life easier in some tangible way (or they've been threatened with consequences if the system isn't used - also possible).

You could imagine of how a formal system to show people where they are in terms of the synthesis of compounds with respect to others in the project if:

1. They're physically separated. (Most likely)
2. They don't like to talk amongst themselves but don't mind interacting with a computer system or bulletin board. (i.e. the company tends to hire bright but otherwise socially inept)
3. The manager is very hands off and the troops have decided to organize on their own. (not so unlikely given the lack of management skill by scientists in general)
4. Combinations of the above.

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10. Petros on September 16, 2010 11:22 AM writes...

I've seen them present the virtues of this at 2 or 3 med chem meetings and expound how it had been widely adopted throughout AZ

Of course AZ is now much leaner than before having shuttered Charnwoood, Lund and various other sites

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11. cynical1 on September 16, 2010 12:07 PM writes...

The only way to encourage true team efforts in drug discovery is through team rewards. After 25 years in the industry, I can say that it just doesn't happen, particularly in larger organizations. Individuals are rewarded even when there was a true team effort that produced the accomplishments. Typically the project leader receives a disproportionate amount of the accolades even if their main contribution was making nice Power Point presentations for upper management or worse, an active impediment to progress. You don't have to have an MBA or a Lean Sigma Six black belt to understand that you have to incentivize teamwork. "Team pride", as they put it, doesn't pay the bills or bring job security and while I don't work at AZ, I'll bet that this little exercise has done little to address those two critical issues.

One other observation: there are 25 authors from AZ on that paper. That's just so wrong on so many levels.

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12. victory pilsner on September 16, 2010 12:16 PM writes...

It may be fine for development and manufacturing although I doubt it. Six sigma stuff is garbage for research and the epitome of what's wrong with big pharma. It is a lowest common denominator approach that is more bureaucracy, chaff, and stifling of creativity - no wonder innovation comes predominantly out of small business. I'm with Dilbert - http://adamdeane.wordpress.com/2010/05/19/six-sigma-friend-or-foe/

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13. DLIB on September 16, 2010 12:42 PM writes...

Sounds alot like the work in process issues in a Semiconductor Fab being translated into the chem lab.

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14. processchemist on September 16, 2010 12:47 PM writes...

@12

if for "development" you mean chemical development, six sigma is deleterious. In the past I've seen more than a chemical development project managed with "productivity improvement" strategies, with the poorest results. You can use parallel systems, but parallel/automated chemistry increases productictivy only if there's a chemist who really knows what he is doing (single parameter variations, fancy parallel systems with non scalable results can be a total waste of time). Same for DOE: cool software can be a solid waste of time, or a wonderful way to demonstrate the obvious, if stuffed with meaningless parameters or used for the search of third order effects that approximate zero.
And I've seen ALL of this kind of useless combinations (great - often hyped - tools and poor process chemistry).

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15. Khaki Mango on September 16, 2010 1:00 PM writes...

Lean process improvements work very well for repetitive, infrequently-changing, and quantifiable processes. I've seen it work very well in compound management and/or HTS screening environments. It can also work well in specific areas of the lead optimization process that are done routinely, as noted above, like in compound submission, standardized assays, etc; however, by the nature of the beast, the discovery/lead optimization process has too many variables that must change many times in order to be successful including assay development on the fly, changing SAR/focus on the chemistry side, changes to the screening trees, etc. Some of the best work I've seen and done has been outside of the "standard" process or thinking. Creativity and six sigma just don't go together; we're all too different.

With regards to compound submission amounts, years ago I mandated 30 mg as the target amount (a goal, not a hard rule) for lead op work to the whole group, and was met with complaints and grumbles; but, it greatly paid off on the back in by always having enough to do all in vitro work and pk/other in vivo expts. Of course, then there was trying to actually get a pk slot or animal study in a timely manner.

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16. Dave L on September 16, 2010 1:18 PM writes...

I'm a PhD Chemist and was very skeptical of SixSigma when I was "forced" to take the 3 week course several years ago. I worked in a manufacturing area that was adopting the SixSigma methodology and we were all encouraged to take the training. I have to say that I've successfully used the SixSigma process a few times in my career. If you know how to use the tools, are good at them, and are not distracted by management wanting to rush it along, the process can really help in bringing a wide group of people together with very different skills and abilities and maintain their focus on solving a problem. I do find it better suited for manufacturing problems such as decreasing defects in a process. I haven't seen any great examples of enabling innovation and those sorts of things. The biggest problem is half-hearted adoption of SixSigma by managment only wanting to look like they are "on board". They roll out the training, establish some projects, and then quickly claim accomplishement with liberal use of "buzz words" to demonstrate they are "on board". But there's no real commitment. Few things succeed with no commitment.

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17. Skeptics on September 16, 2010 1:28 PM writes...

Re: Are Chemists Too Individual?

Ha! Its obvious none of them can think for themselves at all.

Definition of a Med Chem: Design of small-molecule drugs to target proteins and inhibit their biological function.

Reality: Not a single med chem has an expert understanding of protein-ligand associations. Therefore target specificity and efficacy is never improved upon. This simple fact does not appear to bother a single med chem.

There is no bedrock to even call this a profession. So it is this investors opinion that the med chems and the six sigma kooks deserve one another.

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18. Mutatis Mutandis on September 16, 2010 1:58 PM writes...

The problem with this type of optimization strategy is that it tends to split up tasks in sub-tasks and sub-sub-tasks, so that each little job can be executed by a dedicated specialist who presumably excels at it; rather than the whole being accomplished by an all-round scientist who is supposedly "good enough" at any of the sub-sub-tasks.

That often sounds more efficient on paper, but the reasoning often ignores the communication overhead, the loss of motivation and creativity if people don't have a feeling of ownership of the project, and last but not least the difficulties it creates in cooperating across disciplines. At some level chemists, cheminformaticians, assay biologists, and people with clinical and commercial insights will have to sit together. If these are all going to be teams rather than individuals, the sum of them is going to look like a parliament instead of a drug discovery team.

Nevertheless, up to a given level, it can work. It is just important to keep an eye on the cost/benefit curve, and not overdo it. I think that e.g. if you have 20 chemists, it is better to make 3 to 5 teams out of them, rather than one big team.

As for six sigma, it has its value and its downsides. The real problem may be that most people in pharmaceutical R&D know shockingly little about statistics, and therefore tend towards uncritical acceptance of such tools.

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19. Kay on September 16, 2010 2:16 PM writes...

I switched from a large pharma company, where everything was done individually, to a small biotech where synthesis was done as a group. There were good and bad points to both approaches. The problem with working on a "group" project is that the person who makes the final compound often gets the credit for the work, since their name is on the compound. If you are a lower level chemist, you may get shuttled off to do scale-up, and if you stay there long enough, it can derail your career. You may be doing work that is crucial for the team, but it tends to be invisible work that may not be recognized when it comes to raises and promotions. At the small company where I worked, it led to a lot of competition and infighting among the chemists.

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20. Anonymous on September 16, 2010 2:28 PM writes...

@Skeptics

You'll probably get flamed enough by the rest of the med chemists, so I'll avoid the Molotov cocktails.

Though you state an inflammatory generalization, there is some truth in the fact that we do not understand protein-ligand interactions at the expert level. That is because only now are very crude tools to model those become available with the computational speed to assess even small molecule interactions statically, much less dynamically.

It is helping the field to have much more structure-based design going on and it is becoming a good tool in the toolbox (cliche alert!) to use. However, it is still crude, has its limitations, and many of us have seen it sometimes work but often not, so we still use traditional empirical SAR techniques and experience to drive the programs.

Reality: Target specificity and efficacy are constantly being improved upon at least around here and throughout the industry, so I don't know where you're getting your info from. We're just not as good at this drug thing as we wish we were.

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21. Jack Vinson on September 16, 2010 2:28 PM writes...

I don't know directly about AZ and this particular implementation, but if you remove the buzzwords that get in people's way, the paragraph you clipped is a reasonable approach.

Most organizations have far too many things going on at one time. Businesses and managers have no gating process: if they have a good idea, they just go ahead and start it under the assumption that the sooner you get started, the sooner it will finish. The problem is that with so many projects, there are just too many moving pieces, and no one can determine what is the next right thing to move the projects forward. Or it becomes too easy to jump to the next interesting thing, rather than the next thing that needs to happen.

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22. CYTIRPS on September 16, 2010 2:37 PM writes...

Six Sigma is just another excuse used by the R&D air heads to pretend that they are doing something. Six Sigma is only a QC strategy for manufactoring a product. We do not know which compound is the final product in discovery research! If the project managers can predict the final product, they can skip research and go to manufacturing directly. No one is that good yet. It is a good thing for individual chemist to explore in different direction. There is no road map leading to the final product. The important thing is to look at the data at the end of the day and determine whether it is the right direction. A common mistake is that many chemists attach to their own ideas and ignore the data. IMHO, the only useful tool in Six Sigma for discovery is the PICK chart. However, even that is just common sense.

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23. partial agonist on September 16, 2010 3:35 PM writes...

Skeptics:

"Not a single med chem has an expert understanding of protein-ligand associations."


That hinges on your interpretation of the word "expert". I think we certainly have a far better grasp on fundamental concepts like productive ligand-protein van der Waals interactions, H-bonding, dipole-dipole interactions, pi-pi,cation-pi interactions, implications of ligand desolvation penalties, etc than we ever did before, and can often apply such concepts in a rational way to improve ligands.

"Therefore target specificity and efficacy is never improved upon."

Well, the biologists told us forever that kinases, for example, were poor drug targets because we could never get selective within the ATP-binding pocket. Do you want to see the data for a kinase inhibitor that has subnanomolar affinity for the two kinases it was designed to hit and >1 uM afinity for 300 other kinases looked at, and also no activity vs. 100 other GPCRs and enzymes? Chemists can make amazingly target-selective compounds. The issue, I admit, is knowing what are the off-targets to avoid, and curiously what off targets actually help you when you take our precious molecules in vivo. If anything, molecules often get ruined due to too much target selectivity, so in vivo a single mutation wipes away all efficacy. We all know the "dirty" lead that works in vivo, then we polish it up against the "target" and improve potency & selectivity, then it goes back to animals and fails. Well... duh... the initial "dirty" lead was hitting multiple targets of value.

"This simple fact does not appear to bother a single med chem."

Just a load of crap: Target selectivity is something we think about every day and in every structure we make. We stay up night thinking whether the structural changes I want to make will affect CYP profiles, hERG channel, half-life, or 100 other things.

"There is no bedrock to even call this a profession"

How are those gene patents and pathway patents working out? What matters is the molecule you can put in a bottle. You need chemists for that, yesterday, today, and as far as I can tell, always.

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24. Chris on September 16, 2010 4:41 PM writes...

My feeling is that basic research changes too frequently for it to be useful. On one project we had to make a candidate quickly to access an unexpectedly available safety slot, we had the whole team working on the route using a flow chart to monitor progress on multiple parallel strategies. Chemists switched from one route to another to help address problems.
On many occasions we had individuals making large amounts of intermediates that were used by the whole group.
I didn't think of it as anything unusual, perhaps we needed to think of a catchy title?

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25. cliffintokyo on September 16, 2010 8:27 PM writes...

#5
Nice balancing act, Calvin.
"Communication" says it all, for me anyway.

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26. Don Corleone on September 16, 2010 9:04 PM writes...

In the latest issue of Fortune magazine, there is an article about 3M. It talks about how innovative culture at 3M was negatively impacted during the Jim McNerney era, an MBA (one of GE "wonder" boys). One of scientists in the article said something which is so true "you can't schedule innovation". Drug discovery and six sigma do not mix.

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27. Peter Ellis on September 17, 2010 1:58 AM writes...

"chemists supporting each other in the delivery of compounds"

I'm no chemist, but this feels to me like putting nine women in a room and telling them to produce a baby in one month.

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28. SandwichMan on September 17, 2010 2:51 AM writes...

I largely agree with Derek's opening piece and the comments. I've seen SS zealously pursued at Pfizer. We had our share of "green belts" and "black belts" etc, that sort of terminology is enough to put anyone off for starters. To me it just seemed like commonsense wrapped up in jargon. Many of the ideas may be good but, as many have pointed out here already, it's not really conducive to original thinking and goes down very badly with scientists generally. That might be down to the personality types who ram it down unwilling throats. And yes, SS green/black belts are just one type gasbag that has managed to thrive in the pharmaceutical industry, there are many more and the mega-mergers of the past 15 years or so have allowed them to thrive. Sadly, in the current shakedowns, the gasbags seem to do rather better than the scientists.

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29. DrSnowboard on September 17, 2010 4:17 AM writes...

I'm no sixsigma apostle, but I sort of agree that time can be wasted in a 'conventional' chemistry team. You have a couple of important hypothesis compounds to make and the chemist involved goes on holiday for 3 weeks, do you wait till they get back? No. So why shouldn't you flip intermediates around the group normally, as long as the group has a major say in who does what, when - hence the visual tracking system of what is where. It does require senior chemists to pull their weight in making intermediates though..And the group to also be looking at results as they come through.
Too utopian for you?

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30. processchemist on September 17, 2010 4:52 AM writes...

@29

This is common sense, not ss.

A real life example in chemical development:
300 g of product needed, 4 months timeline, six step synthesis, procedure available for 100 mg of final product.
The Gannt diagram was saying 3 weeks for test/familiarization with the transimetted procedure, 5 weeks for screening/optimization, 2 months for production. The first scale up was scheduled as soon as one step was confirmed with isolated yelds > 60%, the kilolab/pilot plant operations were scheduled immediately after the first scale up. This intensive, beautiful diagram heavily conflicted with the harsh reality: the non reproducibility of the results of the last 2 steps with a batch size larger than 1 g.
When the insane machine was stopped I was crystallizing 3 Kg of the fourth intermediate, and a five Kg batch of the first was just released. The first 10 g of target were produced 10 months later, with different chemistry for steps 2-6 not involving intermediate 4.
The genius that planned this crash: no background in this specific field, but 10 years of project management experience.

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31. DrSnowboard on September 17, 2010 5:34 AM writes...

@30
I agree, common sense but that is often short on the ground in big pharma depts/silos/ hierarchies? I suppose my point was, the best people to improve teamwork is the people doing the work and give them the ability to do that, that is more useful than a guru cult culture of external careerist manipulation.

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32. Chemjobber on September 17, 2010 7:10 AM writes...

I agree with and expand on Kay's point about group approaches to chemistry (and credit-sharing) in the post linked in my handle.

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33. mikeymedchem on September 17, 2010 8:01 AM writes...

I've read the italicized text in the post a couple times, and am having trouble visualizing what this actually LOOKS like on the ground. Can someone from AZ give us a sense, as a chemist operating under this process, how this works, perhaps using a fictitious project with two or three chemical series being pursued?

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34. sepisp on September 17, 2010 8:01 AM writes...

#28: I imagine this company has a "SS officer".

Jokes aside, I like the practice of asking the right questions, but the mentality that SS is going to be applicable to anything is a bit too evangelical. It's the classical "when you have a hammer, everything looks like a nail" effect.

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35. CMCguy on September 17, 2010 10:40 AM writes...

#30 processchemist what you describe seems to be the customary project cycle experienced in chemical development which has existed long before Six Sigma or other Quality initiatives were introduced to Pharma. There may be new terms thrown around now with prettier charts for tracking but the disconnect between what is promised by managers/sales and what can be done in the lab/plant is often frustratingly wide. The basic problem is that there is a tendency towards defining projects in One Size Fits All mentality, with the baseline Size being a small straightforward successful example rather than realistic model.

Although I agree application of strict Six Sigma type principles do not fit well with R&D operations I wish people would not be so dismissive of such efforts out of hand. Having endured many variants most stuff does come across as repacked MBA BS but typically there are certain points, often really commonsense reminders, that can be adapted for improvements even by people in the labs. As others have indicated at the very least can enhance communications which can be a root cause for many problems. Relative to the statements about scientists, chemists in particular, being educated to be independent units whereas in industry must merge into teams is very true. Unfortunately because rewards can be not aligned with actual contributions Sibling rivalries are commonplace that inhibit practical functioning as teams. Drug development requires multitude of disciplines working together so must establish connections and collaborations. Probably the most difficult thing for innovation is creating and maintaining a balance between individualism and collectivism and this ties to leadership.

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36. RM on September 17, 2010 11:08 AM writes...

My gut impression of the Six Sigma-type program management systems is that most of the gains are due solely to stepping back and actually thinking about what you want to accomplish. All the other stuff is just embellishments. With product amounts - how often do we actually think through the cost/benefits of the different amounts? Rarely - most of the time we just go with old rule-of-thumbs, or change amounts due to bad experiences.

It's relatively straightforward to calculate how much you really need. If the extra cost of doing the amount bump divided by the probability that you'll actually need it is less than the cost incurred in doing a re-synthesis, do it. If not, don't. The issue, though, is that this calculation changes based on different compounds (e.g. shorter or longer synthesis, or material costs), the likeliness of a "hit" in this compound class, and which "cost" you're trying to optimize (time, money, facilities usage, etc.). The difficulty is because these figures are hard to come by a priori. Unfortunately, the takehome message is usually not "*think* about what *you* are doing", but is instead castrated to "Lean Six Sigma says to produce 30-35 mg".

Regarding teamwork, it also depends on your environment. If you're all doing very similar things and you're not coordinated, you'll probably waste time&money with resynthesis of intermediates, or half-used reagent bottles. Maybe not deliberately, but "oh, if I knew you were going to need it, I could have scaled up my synthesis last week." Even if you're doing dissimilar things, it might make sense to have task specialization, especially on tricky things, to reduce waste from failed reactions. That said, there's no reason to throw multiple people on a synthesis just to say it was a team effort.

They are no one-size-fits-all answers.

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37. processchemist on September 17, 2010 11:56 AM writes...

@ CMCguy

Few years before, in the same place, I was in charge for the ISO certification process (for the production activities). Togheter with the consultant we fought to keep R&D out of the scheme (with a good success). I must say that ISO was a good tool to grant continuous levels of quality for the products, and I remember some occasional problems coming not from the plant guys, but from the management itself, tempted by shortcuts on the logistics/sourcing side.

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38. Blob on September 17, 2010 12:52 PM writes...

@2 Bob,
AZ Mölndal (Sweden) doesn't follow the german model as you call it, because e.g. in Sweden you do not find CTAs (chemistry technical assistant) - Sweden is in many ways abit different and this makes a huge difference.

Lean Sigma is as said before pure common sense and maybe useful for production processes with automatisation. This is were they saved most of the time e.g. how to see if a compound can be tested, how to register, a simple board on which is marked who is when on holidays/sick ...

I think it works fine for them (not working there though), new experience to have replacment if one is sick.Furthermore the team decides who is doing what so better use of experience and personal preferences. Common sense.

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39. Toluene on September 17, 2010 7:27 PM writes...

I have also worked at a large multinational pharma company which espoused the virtues of Six/Lean Sigma. I was "volunteered" by my VP to be the SS rep for our division which entailed a week's training in the UK, closely followed by another week in a major US city. We learned the jargon, role-played production scenarios and calculated idle time on our expensive equipment that is not getting enough use to justify it's existance (automated synthesis equipment is a great example!).

The truth of the matter is that drug discovery is a process that cannot be formulated or run by timelines. Granted, there are certain parts of this process which are amenable to SS optimization, such as compound management and screening mentioned earlier.

Chemists are individualists, and the reward system at many companies has done little to change this. Rather than trying to get chemists to cooperate on synthesis, it is better to have the whole project team agree on the compounds which should be made, then have these made by individual chemists. Patent issues make this tough sometimes as the person who had the idea contributes the IP as opposed to the person who actually makes the compound (unless a non-obvious synthesis).

I think that Pharma would have been more productive had it stuck with the "classical" empirical approach, rather than being distracted by combinatorial chemistry, systems biology, virtual screening etc. But I digress......

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40. AZ Guy on September 18, 2010 7:59 AM writes...

I worked at AZ in Wilmington, DE (until being downsized in March) and much of the LSS program originated in Wilmington. LSS had some good effects, but in the haste and enthusiasm to implement it, it wasted a huge amount of time. LSS teams were formed to improve everything in the chemistry dept from equipment problems, to purchasing to synthesis to shipping to the prep lab. It will come as no surprise that the prep lab was in the process of making changes prior to the LSS investigation but were told to wait until the LSS was complete so that it would be credited with the change. Our dept head was really pushing LSS so if you wanted to get ahead, you had to push his agenda.

To address exactly what the article says, I have no idea what they are speaking of. A push for new tools to visualize proposed and active targets was implemented about the same time and it resulted in many new programs that were used by the projects. I do not know if that correlation in time was related to LSS but they were almost certainly not. The actual work for the bench chemist did not change: a chemist was assigned a group of targets and then worked independently upon them. Often some chemists would prepare intermediates, but that was going on long before LSS was implemented.

The synthesis, equipment, and many other LSS groups returned nothing of use that could not have been observed prior to sinking the time in (and it was a huge time sink). The main utility in LSS came from cross functional teams where the process mapping caused the various functions to speak to one another and it fostered an understanding of what problems were caused when a submitted compound was out of the ordinary (such as an oil or too little sample were submitted). Or from a chemistry perspective what delaying assays such as PGP, binding and functional data did to the medicinal chemists attempting to incorporate new learnings into target compounds. Was LSS required for this - obviously not, but it did provide an excuse for the various departments to speak to one-another. We had a silo mentality and LSS helped to bridge that.

AZ always had a great spirit of team work and cooperation. People did share intermediates and really helped out others in accomplishing their targets. This is in direct contrast to my experience with another large pharma company in which people compete actively against each other and will lend no help even when asked.

With all that said, the article was from a different AZ site and may have impacted them differently. The various AZ sites had very different cultures and LSS may have impacted the Swedes more than the US, but every AZ Swede (an admittedly small sample space) that I interacted with had a negative impression of LSS so I think it is just management-speak for them as well.

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41. Ron on September 18, 2010 1:39 PM writes...

Phony management + LSS = Phony LSS
Substantive management + LSS = Successful LSS

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42. Rich V. on September 18, 2010 4:55 PM writes...

Six sigma statistically means 99.9997% success in manufacturing. This would mean you would need to do something 1,000,000 time for 3 failures or 333,333 times for 1 failure. If anybody is running this many experiments in Pharma on one process I would like to meet them and shake their hand. The only possible place this may be of usefulness in Pharma would be in the production of tablets or possibly blister packs.

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43. ole ginger on September 20, 2010 3:33 AM writes...

It seems a bit cheep to me to claim all positive results from systematic process improvement projects to "common sense" and all the bad to the methodology, its jargon and its proponents. I guess some of the good these methodologies can contribute is providing a stage or framework for taking a fresh look at a situation and then try to fix or improve it, and a leaver to get management support for the change. After all, all the methodologies demand that those in the process fix it. If the fix is just imposed from above the project is a failure even in the sense of the methodology itself.

Finally, any claim about what is or who is the beholder of "common sense" invokes deep suspicion in me; a bit like any reference to "common sense of justice".

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44. abos on September 20, 2010 10:06 PM writes...

Sounds like a pile of BS. Exactly the wrong thing for pharma to be doing. Pharma needs to stress creativity and novel research and discourage anything related to assembly-line-optimization. Who actually believes that increasing the # of compounds each chemist makes by 5% is going to save the industry?

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45. anonynous on September 21, 2010 7:53 AM writes...

Goodness gracious me, what an apalling level of ignorance on display here....

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46. DrSnowboard on September 22, 2010 2:46 AM writes...

@45

Er, ignorant maybe, literate yes, or is 'appalling' too negative a word to feature on your course?

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47. Flat Eric on September 27, 2010 4:53 AM writes...

Having been subjected to the Lean Sigma ‘initiatives’ mentioned in the above string I would like to give my own reflections.
Firstly, rather than being a cult as described by Calvin I’d have to say it felt more like a dictatorship where any challenge was viewed as being merely negative and dealt with accordingly. Not quite the corporate message Astrazeneca wishes to portray. This led to a situation reminiscent of the Emperor’s New Clothes where the obvious drawbacks of over processing an environment where innovation is key were widely commented on in private discussion but never mentioned in public. Perhaps more damaging was the resulting reluctance to openly evaluate the claimed level of improvement which resulted from the project. But let’s be fair, there have been improvements to the testing cascade which is now run in parallel and certain aspects of DMPK. The local lab environment has also been standardised to make re-stocking more efficient. Hardly an earth shattering breakthrough. The real issues, however, relate to exaggerated improvement claims within the chemistry department and the impact of Lean Sigma on innovation.
The initial phase of the Lean Sigma project claimed to have achieved the remarkable improvement in productivity of 40% by limiting the chemists to working on less targets at one time and chemists sharing targets within a project group with this centred around the Work in Progress (WIP) board. In reality the way in which a target was viewed had changed with intermediates being a target and all derivatives from that also viewed as individual targets. Perhaps a good comparison would be if Toyota decided they needed to improve their productivity so instead of measuring the time it takes to build a car in total they decided to individually measure the time it takes to build firstly an engine then a chassis and finally how long it takes to put the engine in the chassis. Instant progress, high fives all round and a big bonus for the bosses while the workers look on in disbelief.
The impact on lab staff depended on their level of involvement with the Lean project. Inevitably those who viewed the success of the project as a means of personal advancement carried on with the high fives. Note the number of authors on the published paper. Most galling of all were the hypocrites who expounded the virtues of the project while not practicing what they preached. Of course the Emperor’s New Clothes mentality ensured that this behaviour was never picked up with the result that those who were not actively involved in the project felt even more disenfranchised. Perhaps a follow up publication from the group could be titled ‘Lies, Damn Lies and Statistics.
As you might expect, a regimented approach to Discovery has had an inevitable impact on free thought and innovation. The key author of the published paper recently gave a presentation at an ACS conference in which the negative impact of Lean Sigma on innovation was highlighted. It should be noted that as yet noone has had the decency to give this presentation to the individuals who have suffered at the hands of Lean Sigma and were used as an example to expound the benefits of a ‘new way of working’. What really saddens me is that along with the previous initiative to improve productivity (metrics) managers were warned of the potential negative impact but chose to ignore the concerns. The result? A few individuals have done nicely thank you and moved on to better things leaving the vestigial remains to rot away. Meanwhile we are now undergoing a new initiative to restore innovation in the workplace!! A key part of this new ‘process’ will be the use of WIP boards which seem to serve little purpose in this particular area other than accommodating the apparent herding instinct of sycophants.
In conclusion I’d have to say that if a group is considering going down the Lean Sigma route then they should think very carefully about what they stand to lose as well as what they hope to gain. A key part of Lean Sigma is to reduce variability and waste but one of the key variables in any creative environment is the people. This, however, should be a strength rather than a weakness if one wishes to generate a genuinely innovative environment. Last of all, if the project is going to impact a group of educated people then at least be honest and encourage honesty. One person standing at a podium waxing lyrical about flawed statistics doesn’t make a process work. The Emperor was, after all, standing there stark naked all the time.

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48. isobar on December 12, 2010 12:08 PM writes...

I am a newcomer to this and have no direct pharma experience. However, the medicinal chemist and the chemistry are the seeds of the pharma universe. I wonder the damage where the marketers are the heros and the chemistry the dorks of the pharma world (my view from listening).

Strong management is the key to success of even a very mediocre idea (not MBA trained management?). Is pharma suffering from lack of high level, integrated managerial oversight that can take the long view? From stir bar to shareholder? Are there enough super clinical pharmacologists? The M.D. PhD? who is a scientist first.

And what is the this manic emphasis on time? It looks like a race to the bottom?

I can't help but being provocative, but that comes easy being on the outside.

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49. Deepthroat on March 11, 2011 3:22 PM writes...

When reading "Creativity, innovation and lean sigma: a controversial combination?" (http://dx.doi.org/10.1016/j.drudis.2010.11.005) I couldn't help thinking of "Flat Eric" and his comments above (#47)...

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50. anonymous on August 30, 2011 4:19 PM writes...

One question, why wasn't all the common sense being implemented before the Lean Six Sigma initiative? Seems like if everything was perfect we would have more drugs, and if everything discovered by Lean Six Sigma was common sense we would have already been doing them.....

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