Big pharma is drafted by ethical and fiscal responsibilities to collaborate on waste reduction effortsThe EPA defines green chemistry as “the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances.” This definition is taken to include the entire life cycle of the product from bench to bedside.
While such endpoints are easily expressed, even the experts find it a bit much to comprehend in practical terms. Thus the formation of the American Chemical Society’s Green Chemistry Institute (ACS GCI) and within that—and more to the medicinal point—the collaborative working group known as the ACS GCI Pharmaceutical Roundtable (GCIPR).
Green TeamIt could almost be said that that big pharma’s awareness of green chemistry and the roundtable’s creation in 2005 were prompted by a growing embarrassment. “A paper came out by Roger Sheldon that looked at a metric called e-factor,” explained Julie Manley, senior industrial coordinator with the ACS GCI and the GCIPR. “E-factor generally referred to the amount of waste generated per kilo of product produced, and he showed that, on that basis, pharma generated the most waste” as compared with other chemical-based industries.1
Because the waste comprises chemicals, it is rarely benign. Corporate reputations are at risk, liabilities accrue, and waste in this or any context can be measured in terms of resources squandered. “The roundtable looks to combine the ethical and fiscal objectives,” Manley explained. “This not only helps the bottom line of the company, but improves its environmental health and safety standards as well.”
But why and how do pharmaceutical companies collaborate on what should be a competitive issue? “There are, in fact, common challenges across the industry,” said Manley, “and while each company has a focus on their unique molecule, in general, much of the chemistry is very similar. Everyone uses certain solvents, certain reactants… .”
One company looking for green alternatives on its own cannot match the creativity of 16 companies—the current number of roundtable members—working together. “The key is to interact in a noncompetitive way, and that is how the roundtable is set up,” Manley said. Shared data sets are blinded to retain corporate privacy, and co-company authored papers are legally vetted by all contributors.
Further, the roundtable is able to encourage, and hopefully share in, green chemistry innovation beyond its membership by using a portion of membership dues, ranging from $10,000 to $25,000 a year, to fund research grants that have totaled more than $950,000.
“Right now the program is limited to academics,” said Manley. Part of the reason for this restriction is to focus on spreading the word, to influence academic curricula. “If people are doing the research, then green chemistry is being communicated internally within that institution.”
Available to non-GCIPR members are analytic tools that can be accessed through the ACS green chemistry website.2 For example, there is a tool for calculating the so-called process mass intensity (PMI), defined as the kilos of mass of all materials that go into producing an active pharmaceutical ingredient (API), normalized by the mass of the end product; this is taken as a measure of the “greenness” of a given process.3 “The benchmark of PMI has been a very useful tool so that companies can compare apples to apples,” of particular use when considering the greenness of third-party manufacturers that may be a part of your supply chain.
CASE STUDY: Green MeansThe 15th annual Green Chemistry and Engineering Conference—the premier green chemistry event—saw BioAmber Inc., win the Presidential Green Chemistry Challenge Award, bestowed by the Environmental Protection Agency and the American Chemical Society in Washington, D.C., in June.
BioAmber, a renewable chemistry company, received the honor for their innovation in the biosynthesis of succinic acid, which is normally produced with petrochemicals. BioAmber’s proprietary platform uses microbes that have been optimized for succinic acid production.
Last year’s co-winners, Merck and Codexis, were honored for their green chemistry approach in retooling the synthesis steps for making the diabetes drug sitagliptin. Along with numerous green optimizations, the critical alteration was finding an alternative to the catalytic use of rhodium, a rare metal that became prohibitively expensive during the scale-up of manufacture for sitagliptin; for this, scientists were able to substitute a transaminase enzyme for a rhodium-based hydrogenation catalyst.1
Another example of biocatalysis in green pharmaceutical chemistry is seen in the production of the neuroactive agent pregabalin. In this case, the initially developed API synthesis was highly wasteful, producing 86 kg of waste per one kilogram of product. In addressing this issue, the manufacturer, Pfizer, performed an enzymatic screen for a problematic cyanodiester. The resulting hit was a lipase derived from Thermomyces lanuginosus, resulting in a marked reduction of useless byproduct.2
A final example of green pharmaco-chemistry comes from the familiar class of drugs known as statins—specifically, rouvastatin. In this instance, an initially wasteful chemical reaction was replaced with an enzymatic step that uses deoxyribose phosphate aldolase (DERA) an innovation pioneered in an academic lab. Once the efficacy of this approach was established, a nagging problem remained involving the irreversible deactivation of the enzyme by a chloroacetaldehyde. This was solved with DERA 2.0, if you will, which was created using the biotech method of directed mutagenic evolution.3
For a review of these and other green chemistry options see: Dunn PJ. The importance of green chemistry in process research and development [published online ahead of print May 12, 2011]. Chem Soc Rev
- Grate J, Huisman G. A greener biocatalytic manufacturing route to sitagliptin. Paper presented at: 13th Annual Green Chemistry and Engineering Conference; June 23, 2009; College Park, Md.
- Martinez CA, Hu S, Dumond Y, et al. Development of a chemoenzymatic manufacturing process for pregabalin. Org Process Res Dev. March 18, 2008. Available at: http://pubs.acs.org/doi/abs/10.1021/ op7002248. Accessed August 1, 2011.
- Jennewein S, Schürmann M, Wolberg M, et al. Directed evolution of an industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase. Biotechnol J. 2006;1(5):537-548.
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This process mass intensity calculator is one of several analytic tools available at the ACS Green Chemistry Institute website: http://bit.ly/qb5buA
An engineer by training who has published on the subject, Dr. Jiménez-González is concerned with the production issues beyond the flask: “There are very common techniques outside of pharma that are not really as practiced within pharma, like life cycle assessment, process identification, or the use of continuous processes. We need to move away from emulating what happens in the lab when considering scale up.”4
For example, GSK has recently finalized a carbon footprint analysis for its global operations. “We wanted to identify the main contributors to the footprint—what we call ‘hotspots,’ ” Dr. Jiménez-González said. The chief suspect of un-greenness she identified overall is GSK’s use of solvents. “We did some case studies going from cradle to gate in manufacture, from the moment you extract raw materials to the moment you finish the API, and we found out that the impact of solvents is, on average, around 70% to 75% of all the overall environmental impact of the process.”5
So what to do? Recycling is one possibility, and it can be done is such a way that it does not affect good manufacturing practices. For instance, you can use recycled solvent to serve the same step in a synthesis. “The other option, when you are looking at the process from the life cycle standpoint, is [that] it really doesn’t matter if you recycle through the same process or you down-cycle, say, to a paint manufacturer,” Dr. Jiménez-González noted.
Or, you could simply use a more benign solvent. Though chemists may be loath to make changes to a set process, there are now references available to guide them in selecting alternative solvents; resources include advice from GSK, Pfizer, and the GCIPR.6-8
“In general, it makes life easier for us if we include those types of changes prior to filing the IND [investigational new drug application],” Dr. Jiménez-González said. Beyond that, a retooling of the process could cost you valuable patent expiration time.
Green ThinkRetooling, or even thinking de novo, can often be a challenge for creatures of habit. If you’re stuck in a circle of self-referencing ideas, you may want to bring someone in from outside—someone like John Warner, PhD, president and chief technology officer of the Warner Babcock Institute for Green Chemistry in Wilmington, Mass.
“The most amazing, most shocking thing is that a chemist can go through six years of higher education and never have a single course in toxicology. Never have a course in environmental mechanisms, never a course in anything at all to prepare them for understanding the regulatory consequences of chemistry.”“It happens all the time: a company has enormous resources working on a problem, they’re poring over the literature, the textbooks, people are scouring this material, pushing to get that incremental change to do something new, and they come up against a brick wall,” Dr. Warner explained. The problem is the starting point of having an outdated chemical methods perspective.
—John Warner, PhD, president and chief technology officer of the Warner Babcock Institute for Green Chemistry
To start fresh in green chemistry, you might want to first check out the bible of the field, Dr. Warner’s Green Chemistry: Theory and Practice, cowritten with Paul Anastos, PhD, of the Environmental Protection Agency.9 In it you will find the 12 guiding principles of practicing green chemistry, which are, though initially intended for use by the chemical industry, easily applied to medicinal chemistry. Not so surprising, given the fact that Dr. Warner’s career started by contributing to the synthesis of the anticancer agent Alimpta.
In Dr. Warner’s opinion, the impediments to green chemistry adoption are not merely intellectual but institutional as well. “There is a love-hate relationship between discovery and process,” he asserted. “The people in discovery are always very grumpy that the people in process don’t take their pearls of wisdom and bring them to amazing fruition, and the people downstream look at the discovery people and say, Why do you keep sending us stuff that can’t be scaled up? Why these solvents, and these toxic reagents? Green chemistry is the language they should both be speaking. If you think about it, the least changes that are made in a process from the bench to the bottle, the more profitable the company will be.”
Dr. Warner acknowledged that progress is being made. Great strides, for instance, have been made in biocatalysis (see case study). And he sees the possibility of one day attaining the holy grail of pharma manufacture: continuous-flow reactions, which would make for a much smaller footprint at greater cost savings. But he remains concerned about the generation of toxic byproducts.
Of particular note is the book’s green principle No. 4: Chemical products should be designed to preserve efficacy of function while reducing toxicity. “The most amazing, most shocking thing is that a chemist can go through six years of higher education and never have a single course in toxicology,” said Dr. Warner. “Never have a course in environmental mechanisms, never a course in anything at all to prepare them for understanding the regulatory consequences of chemistry.”
He is also concerned about competition: “India is mandating that all chemists in training take a yearlong course in green chemistry. China has opened up 15 national research centers dedicated to green chemistry.” These developing economies are going to become far more competitive and innovative because they are putting green chemistry into the front end of innovation and creativity, “and we are still scratching our heads about whether we should do it.”
- Sheldon RA. Catalysis: the key to waste minimization. J Chem Technol Biotechnol. 1997;68(4):381-388.
- American Chemistry Society. ACS GCI Pharmaceutical Roundtable. American Chemistry Society website. Available at: http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_TRANSITIONMAIN&node_id=1407&use_sec=false&sec_url_var=region1&__uuid=a628a938-683c-4c0d-8cac-2aba9f3f06ab. Accessed August 1, 2011.
- American Chemistry Society. PMI worksheet. Available at: http://portal.acs.org:80/portal/PublicWebSite/greenchemistry/industriainnovation/roundtable/CNBP_026644. Accessed August 1, 2011.
- Jiménez-González C, Poechlauer P, Broxterman QB, et al. Key green engineering research areas for sustainable manufacturing: a perspective from pharmaceutical and fine chemicals manufacturers. Org Process Res Dev. February 22, 2011. Available at: http://pubs.acs.org/doi/abs/10.1021/op100327d. Accessed August 1, 2011.
- Constable DJC, Jiménez-González C, Henderson RK. Perspective on solvent use in the pharmaceutical industry. Org Process Res Dev. December 14, 2006. Available at: http://pubs.acs.org/doi/abs/10.1021/op060170h. Accessed August 1, 2011.
- Jiménez-González C, Curzons AD, Constable DJC, et al. Expanding GSK’s Solvent Selection Guide—application of life cycle assessment to enhance solvent selections. Clean Technol Environ Policy. April 8, 2004. Available at: www.springerlink.com/content/bk59v8me1l6pv85q/. Accessed August 1, 2011.
- Alfonsi K, Colberg J, Dunn PJ, et al. Green chemistry tools to influence a medicinal chemistry and research chemistry based organisation. Green Chem. November 16, 2007. Available at: http://pubs.rsc.org/en/content/articlelanding/2008/gc/b711717e. Accessed August 1, 2011.
- Hargreaves CR. Collaboration to deliver a solvent selection guide for the pharmaceutical industry. Paper presented at: American Institute of Chemical Engineers Annual Meeting; November 17, 2008; Philadelphia.
- Anastas PT, Warner JC. Green Chemistry: Theory and Practice. New York: Oxford University Press; 1998.