When Does Process Intensification Just Become Too Complex to Control?

Just filing a few more notes on the Yale Green Processing conference from last week.  Afternoon sessions during the first day focused on the "hot" topic of continuous processing and use of process intensification to improve reaction chemistry. The question above came up; supporters for the concept of using multiple microreactors in series or parallel appeared to outnumber the other side, but a dissenting view was expressed by Lee Proctor, technical director at Phoenix Chemical, U.K., who looked more like a rock star than the stereotypical chem lab nerd.  Furnishing some of the more colorful quotes of the day (an example: "Chemistry is one of the most widely published disciplines on the planet, yet the way we run reactions hasn’t really changed in 500 years….we always default to round bottom flasks….and carry out reactions using 500-year-old technology….There has to be a better way." He is reportedly an avid rock climber, too. First presentation in this "applied" vein was made by RouteScout (love that title) Rinus Broxterman, Corporate Scientist for RouteScouting and Selection, and Program Manager, Advanced Synthetic Methods, DSM, Netherlands. He talked a bit about DSM, which started as a coal mining company and whose green motto is "people planet and profit," and which has scored high on the Dow sustainbility index for three years running...the talk focused on using catalytic technologies to develop greener, more sustainable and lower cost process routes to pharma ingredients.


He went on to talk about routescouting, which follows a basic pattern:  first, assign chemist as project leader, do initial lit search, perform multicompetence integrated brainstorms, do first evaluation, then do cost comparison estimates for new vs. established route, then fine tuning....then repeat steps 3 on...

He is a fairly soft-spoken man who didn't use the microphone too often, so I confess that I lost quite a bit in transmission

But, he said, DSM has defined its core competencies as follows: Process development, Organic synthesis biocatalysis, homogeneous catalysis, chiral technology, unnatural amino aceids and peptides, oxidation, fermentation….


Mr. Broxterman then discussed how the company developed a way to synthesize Pharma PLE, a version of pig liver esterase enzyme, PLE, made from non-animal sources, which is used to resolve chiral mixtures. The DSM team isolated the specific form responsible for the desired activity in a project that reportedly took four months to move from lab to full industrial scale and won a 2007 corporate prize for innovation. 

He  then went on to discuss green process development for a generic version of the semisynthetic antibiotic, cephalexin.

Sustainability parameters were used to judge various process generations , he explained, and the team studied consumption of raw material, waste….organic solvents, high variable costs, high salt load, as well as the complex process equipment needed…

The company decided to use micro-process technology and process intensification.  "It may seem like the 'new kid on the block' in pharma," Mr. Broxterman explained, "but in reality, process intensification has been around for a long time in the chemical industry."  DSM's team selected it to  reduce cost of manufacturing, quickly respond to market changes, increase manufacturing flexibility, and speed up scaleup from lab.  It was actually a double process intensification, designed to improve a process that was exothermic, dangerous and had low productivity. The team wanted to perform key process steps continuously and minimize inventory level.  Since this project, DSM has scaled up the microreactor set up which is now making over 900 m.t. of product, and has improved chemical yield by over 20%. Mr. Procter from Phoenix them discussed continuous manufacturing, noting that it could be an effective way to reduce waste generation, improve process efficiency by using less raw material and recycling or reusing solvents, and to deliver cleaner processes. Currently, he said, the regulatory drivers for green process development are much stronger in Europe, with REACH and IPPC, but increasing competition from low-cost centers in India and China were also playing a part.  He noted that continuous processing requires less inventory, facilitates remote control, reduces occupational exposure and emissions level, improves energy efficiencies.  However, he noted, there is a regulatory understanding and gap in knowledge of appropriate tool base.  "Education is needed, in the process development knowhow, technical skill base, competency and route selection.  Chemists know how to scale up the traditional ways." Another problem is that batch users have no experience against which to compare continuous procesing.  In general, he says, companies are hard pressed to manage the change they already have to handle, and prefer to use tools they've always used. FDA has supported efforts to move to continuous manufacturing, he noted, "but they won't tell you how to do it."

Developing a continuous process requires lateral, outside the box thinking, he said, and consideration of all the process elements (holistic design), ensuring that PAT is inerent to the process design, combining good chemistry with good engineering


"The industry needs to employ people who embrace failure.  Because, after all, it's an iterative process: understand why something has failed, then improve it….fundamental science is the intrinsic property you need.


The much praised concept of "Right First Time" may make people worry too much about getting a process right the first time and not finding out what works and what doesn’t, he said.  

Mr. Proctor emphasized the fact that continuous processing needn't use esoteric technology or focus on reaction. "One should instead look at such things as feed tanks, reaction, workup, waste management….off-the-shelf technology exists that can be retrofit into existing processes," he said.


People focus on the "sexy" stage (reaction), he said, but thinking about whole process when starting out and including workup and waste management stage in the designis important.  One also needs to ensure that process analytical technologies (PAT) are correctly used, he said. Noting DSM's commercial success with process intensification using combinations of microreactors, Mr. Procter said that the practice can also be difficult to control and that Phoenix's team decided not to use it. .


He went on to discuss how Phoenix used continuous processing to manufacture the hydroxynitrile used in Lipitor.  Using the traditional process, the highest reported yield had been  50-55% and maximum purity was around 60%.  The company developed some changes, and also developed a plug-flow continuous process. "If you can't spend hundreds of thousands on microreactor technology you can use what you have---for example, even such things as HPLC pumps, capillary tubing and a heat-transfer bath, you can develop very good, highly automated systems that work well.


He went on to discuss results seen in various process systems (more of this will be covered in our next issue).  Following Mr. Proctor, Ph.D. engineer Philippe Caze of Corning SAS (who pointed out that he was NOT a chemist) discussed microreactors and how they can otpimize mas and heat ransfer. Most batch process development involves compromises, he said. "Then you end up in commercial production….we’ve tried to move from optimized chemistry to reactor through mass and heat transfer design, designing the right reactor for the process involved."  More on this, soon.


Basically, the Green Process Industry Symposium is an excellent program for anyone with interest in green industrial chemistry----not only its pure side but its applied side.  Despite their common goals, scientists in atendance were not unanimous in their opinions, so there was a lot of interesting discussion. Keep an eye on any announcements for next year's program.



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  • <p>Life has to change. A Wise man said "if there is will there is way." It is not hard for "chick" to come out of its egg-shell. Open space does have its risks for the chick but there is lot of fun. Reward/risk has to be considered and the reward in continuous process is significantly higher than the risk of living in a batch process.</p> <p>Continuous processing "gospel" has been recited, practiced and admired by many in specialty chemical [API are specialty chemicals with a disease curing value.] but pharmaceuticals have been insular as the thinking has been "it cant be done."</p> <p>Change is coming and the question is do we want to swim with the current or against the current. Choice is ours to make.</p> <p>Bon voyage!</p>


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