This month we have dedicated The Nexus to green chemistry and public health, and at the nexus of these issues is the pharmaceutical industry and their innovation processes. As an industry dedicated to developing products that can save people’s lives, typically the primary priority in the innovation process has been ensuring that the drug works rather than guaranteeing that the synthesis will lead to the most efficient or safest possible manufacturing process. Therefore what often goes unrecognized in the drug discovery phase is that huge amounts of waste can be generated in pharmaceutical production processes, and that waste (including volatile organic solvents) can be toxic or difficult to manage. With nearly 25-100 kg of waste being produced for each kilogram of drug in a pharmaceutical plant’s optimized process (a metric known as process mass intensity), there is much room to reduce the impact of the manufacturing process on public health and the environment.
Greener chemistry and engineering is an upstream approach to addressing waste, pollution, and resource issues through toxicity reduction, biodegradability, energy efficiency, and more. For 20 years, the U.S. Environmental Protection Agency (EPA) has sponsored the Presidential Green Chemistry Challenge Awards (PGCCA), in partnership with the American Chemical Society, and it is the premier recognition for sustainable innovation in chemistry. Five awards are given every year to highlight greener groundbreaking science in the chemical enterprise. Winners are chosen if their developments reduce waste, improve efficiency, are commercially viable, and are equally or more cost effective. Over the past two decades the pharmaceutical science has been one of the more active sectors in this sphere, having received 11 awards thus far.
At the time of the inception of the award some companies were beginning to green their pharmaceutical processes, but there was no comprehensive strategy across the industry to understand their relative waste footprint or incorporate greener practices. Most improvements were driven by Manufacturing or Environmental Health & Safety departments, rather than Research & Development. While there many instances of more sustainable processes prior to the mid-1990s, one of the most widely cited examples of greener chemistry is the first pharmaceutical PGCCA recipient in 1997—BHC Company (now BASF Corporation) and their virtually waste free synthesis of Ibuprofen (an active ingredient in many over-the-counter pain relievers). The original process required six stoichiometric steps and wasted more than half of the material introduced in the process. The greener innovation generated the same active ingredient but required only three catalytic steps, doubled the utilization of the inputs, and introduced a byproduct recovery step.
By 2005, after 10 years of the PGCCA, four more awards had been given in the pharmaceutical industry. Lilly Research Laboratories (1999) eliminated huge amounts of chromium and solvent waste from an epilepsy drug process, and in 2000 Roche Colorado Corporation (now CordenPharma Colorado) removed two hazardous waste streams and 11 materials from their process for an antiviral agent (Cytovene) for immune-compromised patients (including those with AIDS). Pfizer (2002) transformed their process for the active ingredient in Zoloft (a depression treatment) that dramatically reduced waste and solvent use, and doubled their yield, and Bristol-Myers Squibb (2004) created an alternative synthetic approach to Paclitaxel (active ingredient in the cancer drug, Taxol) so that it no longer needed to be harvested from the ecologically sensitive Pacific yew tree.
Beyond the awards, green chemistry activity was continuing to build in the industry. Pfizer had developed an in-house and cross-departmental green chemistry program and this model began to be replicated by other major players in the industry. Furthermore, it was at this time that the ACS Green Chemistry Institute founded the Pharmaceutical Roundtable. Eli Lilly, Merck & Co., Inc., and Pfizer were the initial members and the mission of the group was to catalyze the implementation of green chemistry and engineering in the global pharmaceutical industry. They came together to identify critical challenges faced by the industry and created strategic priorities to address them (informing and influencing the research agenda, creating tools for innovation, engaging as an education resource and collaborating globally).
Now, after 20 years of PGCCA, most major pharmaceutical companies are adopting green chemistry in some fashion and are incorporating greener practices in their drug discovery stage so that their processes are safer and the final products can be scaled more efficiently. The ACS GCI Pharmaceutical Roundtable has 15 members (and growing), and these are the companies that are dominating the PGCCA. Three more industrial pharmaceutical awards have been given; two exclusively to Merck & Co., Inc. (in 2005 and 2006), one to Codexis, Inc. (2006), and one to both companies for a collaborative innovation (2010)—both companies are Roundtable members. As academic-industrial partnerships became even more of a goal in the industry, we have started to see notable academic developments with commercial potential. In 2012, Codexis, Inc. collaborated with Professor Yi Tang from University of California, Los Angeles to create a single-step biocatalytic process to synthesize simvastatin (a cholesterol drug). And just last year, Professor Shannon Stahl of the University of Wisconsin-Madison won for his aerobic oxidation developments for pharmaceutical synthesis, which utilize oxygen from air to oxidize through a new catalytic, mild condition, and highly selective method (replacing the need for hazardous inputs such as chlorinated solvents).
There has been dramatic growth in green innovation in the pharmaceutical industry, and from discovery to scale, it is clear to see that the chemistry done at every phase of drug development has huge implications for public health and the sustainability of the industry. There have been many successes and increased adoption throughout all aspects of companies’ processes, but there are still huge gains to be made. Improvements to process mass intensity are still needed, the dominance of batch processes over flow chemistry holds strong, and the inclusion of generic companies in this green paradigm has yet to fully blossom. There are some companies who are starting to work with suppliers to integrate green chemistry throughout their supply chain, but it is not yet the norm. Outsourcing of the drug discovery phase is growing in the industry, so increasingly a company strategy focused on green and sustainable innovation is needed, as well as continued partnerships with academia to further the research agenda. With these needs, we can surely expect the continuation of green developments in the pharmaceutical industry and we can count on the PGCCA to keep recognizing the top innovators who can deliver on these needs—keep an eye out this summer, when the 2015 PGCCA awards are announced in July to see the next wave of innovation and learn how their science can change the world.
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