Wednesday, April 3, 2013

Process Wednesday: how to choose a scale-up partner?

From a respected reader, a very interesting set of questions about kilo-scale chemistry:
  • How should I go about vetting the capabilities of a process chemist vs a regular bench scale chemist?
  • Are they actually as different as I imagine?
  • Where might I find toll manufacturers that have good reputations with small-mid size batches (1-10 kg at first)?
I'm a relatively new process chemist, but I have some ideas, naturally. (I invite readers with more experience than I to chime in.) I confess that after my very short stint in a large pharma environment, I've spent my time working on the other side of this question, i.e. we're the people trying to get the business of people like my respected reader. So that colors my thoughts about these questions (I'm just trying to air my biases here.) 

I've sat here for 30 minutes trying to come up with a good definition, but I should just rely on our mentor-by-literature, Dr. Neal Anderson, who says that "[t]he role of process R&D is to ensure that high-quality material is produced in a timely fashion to fill the needs of developing a compound." 

Perhaps I reveal my cognitive biases, but I don't think it's a coincidence that "high quality" is first in Dr. Anderson's definition. I believe that "process chemists" spend much more time as analytical chemists, worrying about quality and specifications than typical bench-scale chemists. While we spend most of our time thinking about the how and the how much, it is the question of how good? that I feel I worry most about. (...because if it's not good enough, you can't sell it!) 

All of this to say that there are a variety of means to judge process chemists and contract manufacturing organizations: by their experience levels, by their publication records, patents, etc. It's nice when they've performed large-scale chemistry before (their answer to "What's the largest reaction you've routinely run?"), or had their processes scaled past the kilo laboratory into a plant. On 1 kilogram scale, you can pull off a variety of kludgey tricks (column chromatography, etc.) that you can't really perform on 100 kilogram scale. Questions about their largest reactor size or batch size (and when they used it last!) and their drying capabilities might be helpful in determining whether or not they are used to handling kilogram quantities of material.  

But while all of the above is helpful, I believe the question "What are your specifications?" and "What assays do you use?" will come much sooner from an experienced process chemist.* **

(As for finding good toll manufacturers for 1-10 kilogram scale, that's a difficult question. Naturally, I'm going to encourage you to look in the Western world (though I don't doubt there are bargains to be had overseas!). There are, of course, the larger companies -- the AMRIs and the Cambridge Majors. Informex and other similar fine chemical manufacturing conferences are good places to talk to representatives from smaller companies. There are some relevant publications -- I'm thinking of Contract Pharma in particular, here. Here's that recent thread at In the Pipeline about small-scale API manufacture, with a lot of good recommendations.) 

Readers, I've blathered on quite a bit. I'm doubtlessly wrong -- please tell me where. 

*Naturally, "how much do you need?", "when do you want it?" and "how much can you pay?" are questions that you'll get asked, too. 

**We haven't talked about the essential need for a dedicated, well-resourced analytical/quality control department. Another post, maybe. 


  1. While I agree a strong sense of quality and analytical details is important for process chemist there are many other attributes that can differentiate good process chemists. I always put Safety mindset at the top as although we chemists can sometime be caviler in the lab such unawareness at large scale can be true recipe for disaster (this may be nebulous to determine but also believe can be learned if willing). And even though I never liked PChem it comes in very handy in many aspects of scale-up, again some tied to safety such as thermodynamics but the ability to understand and see alternate reaction mechanisms is vital. The ability to be flexible and adaptable are useful traits, especially under pressure, as is being able to work with diverse teams across many levels and disciplines since for a period of time in development they can play a central role in advancement of projects. A few more I could suggest as well but interested to see others input. CMCguy

  2. Colleagues were in Freiburg transferring our (somewhat tricky) procedure to a German CRO that was scaling it for us under GMP. The guys there were Teutonic-thorough and asked a lot of questions about every damned detail - questions just like those that you mentioned. They made sure to get the same columns as we had for GPC analysis and the same NMR pulse sequence for their NMR like we use (our stuff was polymeric so one needs long acquisition time even for simple proton NMR)

  3. I agree with the first comment – competence with process safety is crucial.
    I found that the easiest way to learn the ropes is a continuous interaction with process engineers (and it helps to take some engineering courses in college). Getting calorimetry data on chemistry that you develop puts you in the right frame of mind. You have to think about heat transfer and mass transfer on scale (which is a huge field in itself, but I’ll just mention a couple of seemingly trivial issues that stumped people – would your slurry flow, or can it be pumped? Is it possible to filter it, or will the mother liquor evaporate, because the filtering cloth is silted?) You have to balance your equations (your protecting groups do not just “fall off”) and really track the fate of your chemical inputs. You’d be surprised at how many truly bright chemists get themselves painted into a corner when they realize that they generated a gaseous byproduct that makes the reaction mixture erupt on large scale, that their workup conditions result in a highly hazardous byproduct, or that an innocuous quench reagent left as a residue from previous step reacts in the next step.
    Which bring to mind the next point: I agree with Chemjobber – you have to be very thorough with your analytical methods. In fact, I think process chemist is the last line of defense when it comes to having an adequate set of sound analytical methods for the process.
    You have to learn about crystallizations (and get at least an inkling of how to develop one).
    Bottom line, a process chemist needs to think like a/n (organic) chemist, an analytical chemist, a process engineer and a plant operator (you always have to see yourself next to a large reactor performing – with your own two hands - all the steps that you have performed on a small scale, which means you have to have familiarity with large scale equipment).
    I’m sure I’ve missed some important points – I feel rather strongly about the subject and wanted to give my 2 cents - but it’s time to get to work. :-)