If chemists are like chefs, then green chemistry is a style of cooking. Even chefs who studied at the same culinary school, though, will use tools and ingredients differently to create a variety of dishes.
That’s what Will Watson, technical director at the U.K. consulting firm Scientific Update, found in surveying 21 pharmaceutical and fine chemicals producers about their green chemistry practices. “There are a lot of common things that people do, but once you get into the detail you find that a lot of things are different,” he says.
The concept of green chemistry has been simmering since 1998, when champions of the field Paul T. Anastas and John C. Warner published 12 guiding principles. But it took several years for companies to translate those principles into measurable goals for environmentally sound pharmaceutical research, development, and production. Today, a single recipe for success seems unlikely and maybe even unnecessary. But enough guidelines have emerged from companies, consultants, and industry groups to create a cookbook of sorts for the practice of green chemistry.
Watson undertook his survey to learn the extent to which the 21 companies have enacted green chemistry policies, adopted green technologies, and installed green performance metrics. Although some firms have been slow to introduce green principles, most are making progress and three or four clearly are leaders, he concludes in a paper published late last year (Green Chem., DOI: 10.1039/c1gc15904f). Still, only about half have introduced formal policies, and many did so only within the past five years.
Persuading chemists to embrace the concept has been a mission of the seven-year-old Pharmaceutical Roundtable at the American Chemical Society’s Green Chemistry Institute. The roundtable is a forum for sharing best practices and for benchmarking performance. The members include 13 global pharma companies, one Indian generic drug firm, and three contract manufacturers. Thirteen companies overlap between the roundtable and Watson’s survey group.
Even the roundtable members are at various stages of implementing green chemistry concepts and use different tools and terminology, says Concepción Jiménez-González, director for operational sustainability at GlaxoSmithKline and a recent cochair of the group. Complete consensus on details isn’t the goal of the collaboration, she explains, but the members need to support the big-picture messages it puts out.
Last year, to help scientists make informed choices, the group released a selection guide comparing the environmental, health, and safety characteristics of more than 60 solvents. It also talked with suppliers about incorporating green chemistry tools in electronic laboratory notebooks. The group has endorsed the process mass intensity (PMI) metric (Org. Process Res. Dev., DOI: 10.1021/op200097d) and launched a calculator to facilitate its use. PMI is the total mass of materials used per mass of product made.
To bring attention to solvent selection, green metrics, and environmental assessments, the roundtable has also worked to influence journals to include these concepts in their publishing policies (C&EN, Jan. 30, page 49).
Among 10 or more metrics that companies can use, Watson found that the two most popular are PMI and the E-factor, which measures the amount of waste generated per kilogram of product. Most big pharma firms use PMI, Watson discovered, and many also collect and combine multiple metrics.
The numbers generated by these metrics for pharmaceuticals are decreasing, “but they could drop further,” says Berkeley W. Cue Jr., a former Pfizer R&D executive who is a private consultant and who chairs the Green Chemistry Institute Governing Board.
However, the metrics by their nature are quantitative. “We need qualitative metrics as well,” Cue says. “You could have an E-factor of 20, which would be low by pharmaceutical standards, but if the solvent in every single step in the process is benzene, it’s not a green process.”
The drug industry has ample opportunity to improve its greenness, both qualitatively and quantitatively. Its E-factor ranges up to about 100, orders of magnitude higher than those of the chemical industry. Using PMI, Cue says, roundtable members benchmarked their performance in 2006, 2008, and 2010. Recent numbers show that solvents make up 54% of the mass of materials used, and water contributes about 35%. Reactants and other materials make up the rest.
Although solvent usage has declined a bit in recent years, unfortunately, PMI figures haven’t changed significantly overall, according to Jiménez-González. Reducing solvent use is still a priority, she says.
Solvent use rose to the top of the list of areas that companies are embracing to improve their green performance, Watson found, with all 21 surveyed encouraging the use of greener ones. All the firms have stopped using chloroform and carbon tetrachloride, and they avoid using dichloromethane unless absolutely necessary, he says.
After solvent considerations, the areas of process metrics, route design, and energy usage ranked high, followed by choices of reagents, raw materials, and reactions. Many firms try to avoid reactions that involve highly toxic materials or produce a lot of waste, such as chlorosulfonations and Mitsunobu and Wittig reactions, Watson says. They may, however, leave it to outside suppliers to run their hazardous reactions.
Among what are considered green technologies, catalysis is widely embraced, and biocatalysis to a lesser extent. Continuous chemistry generates a lot of interest among companies, but technologies such as microwave heating, photochemistry, and electrochemistry do not, Watson says.
The roundtable has surveyed its members on their use of continuous processing and expects to publish an analysis this year. It is considering a similar review of bioprocessing and biocatalysis methods, Jiménez-González says. Biocatalysis, for example, “has promise to really drive sustainable pharmaceutical processes, but at the same time it is a field that might be unevenly applied across companies,” she points out (see page 13).
The roundtable has been working to fill gaps in technology. In 2011, the group published “Key Green Engineering Research Areas for Sustainable Manufacturing,” Jiménez-González says, to show which engineering research fields have the greatest potential to advance green principles (Org. Process Res. Dev., DOI: 10.1021/op100327d). The article is a companion to one from 2007 that highlights chemistry research needs, including 12 classes of reactions that could be improved (Green Chem., DOI: 10.1039/b703488c).
“These are areas that we feel from the pharma and fine chemicals manufacturing perspective could be explored further both in academia and industry,” Jiménez-González says.
The group intends to follow up the 2007 article with a progress report on improvements in reactions. It is also working on a reagent selection guide for about 20 leading reactions to help chemists find environmentally benign combinations and conditions. After the roundtable held discussions with lab chemical suppliers, many began providing organometallic reagents in solvents other than tetrahydrofuran or diethyl ether.
To advance green chemistry, the roundtable is also seeking research proposals. Since its inception, it has independently funded nine research grants totaling more than $1 million. This year, it launched a $50,000, one-year grant to support academic work on optimizing widely used coupling reactions. The group also acts as a partner for some government grants and has been talking with funding agencies about including green chemistry among the criteria for evaluating grant proposals.
Although progress in developing green techniques is occurring, the rate of change has been incremental, Cue says. “We need more tools in the green chemistry toolbox, and that is true for manufacturing, process, and medicinal chemists.”
Particularly in the discovery and early development stages, chemists faced with having to make many molecules by a deadline may resort to whatever is on hand “because they don’t have time to invent something new,” he says. “So somebody, and that is largely academia, has to invent the new chemistry tools that will allow the drug discovery people to do chemistry in a greener way.”
Similarly, trade-offs occur in chemical development and production as companies balance goals, timing, and resources, Watson found out. For about half the companies surveyed, project timing usually takes precedence over green considerations during early development, he says. For another third, the “big picture” or “green concerns” win out.
Companies often set green targets as a drug synthesis moves toward production, although at which stage they become important varies. Some do it throughout their activities, Jiménez-González says, which include the full development process and even later-generation manufacturing processes after a drug is on the market.
In 12 of the 21 companies, Watson found, the emphasis changes as projects progress. Whether their emphases evolve or not, 13 companies start discussing green issues when they reach the hundreds-of-grams scale, or when a compound enters development, but before clinical trials. Five consider these issues even earlier, when making just gram-scale quantities.
In 2011, to encourage companies to consider green chemistry at the early stages of drug discovery, the roundtable developed a medicinal chemistry focus group. The group has compiled a list of activities at member companies and plans to summarize greener methods for medicinal chemistry in a review article.
Some industry observers say medicinal chemists making tiny quantities under great time constraints shouldn’t concern themselves with green chemistry. Although the quantities involved are very small, they add up, Cue points out. “Even at the lab-scale stages, they are generating millions of pounds of waste a year across the industry.” And disposing of this often mixed and poorly characterized waste can be expensive.
At the very least, if medicinal chemists change solvents, the impact on the amount of waste generated can be significant, Cue explains. A good solvent choice at the outset can reduce the need for later process changes if the compound advances in development, he adds.
However, because of high attrition rates for compounds in development, some firms won’t spend the time and money to optimize a synthesis until later, maybe after Phase II clinical trials. “Some companies will basically take the medicinal chemistry route and scale that up until they have proof of concept,” Watson says.
Every company has its own approach to synthetic route design, Watson points out. And even within a company, “each project can be different,” he adds. “It depends on the target molecule and the best way to make it.”
Along with the work they do internally, drug companies use outside partners for process development and manufacturing. Watson found that 17 of the 21 firms he surveyed apply the same standards they use internally when they outsource. They also expect the price of green raw materials to be low, he says. Simply put, “less waste means less cost.”
This handoff can be straightforward if a contract manufacturer is implementing the drug company’s route. Whether or not green concerns are contractually obligated depends on the relationship, Jiménez-González says. “It also comes down to how well green chemistry, green engineering, and sustainability principles are integrated into procurement.”
Another roundtable project is looking at how to engage contract manufacturing organizations (CMOs) in green chemistry and green engineering, Jiménez-González says. The PMI calculator should allow suppliers to measure and communicate their own successes in going green.
Some drug firms commented to Watson that CMOs vary in their levels of awareness or training and that it can be difficult to audit their performance. “The bigger CMOs are in some ways almost ahead of the pharma companies in terms of green chemistry,” Watson says. “Quite a few are looking to develop a technology that will give them an edge to get business from the big pharma companies.”
Two-thirds or more of prescription drugs sold in the world are made by companies that practice green chemistry to some extent, according to Cue. But a huge sector may be absent from the table. “I struggle to find any evidence of green chemistry going on in some of the biggest generics companies in the world,” he says. “Generic drug production is a huge opportunity.”
Meanwhile, Cue believes that small drug and biotech companies are getting more involved, although green metrics for biologics are not as well established as they are for small molecules (Green Chem., DOI: 10.1039/b927443j). The roundtable is creating a team on biopharmaceuticals, Jiménez-González notes, and she sees “good potential to engage additional smaller pharma companies that are mostly in the biotech area.”
Greater engagement will require more awareness, a learning curve, and company managers who set high expectations. “Even the big pharma companies that are now advocates of green chemistry all went through this metamorphosis, some faster than others,” Cue says.