The Green Movement: Rethinking Chemistry

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Denise Myshko

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BY DENISE MYSHKO

Major pharmaceutical companies are working together to minimize the environmental impact of how they make their products.

The GREEN MOVEMENT

Rethinking Chemistry GREEN IS THE NEW BLACK. The push to make prescription drugs more efficient, cleaner, and safer is gaining momentum amid growing awareness that the manufacturing process is where the industry leaves its biggest mark on the environment. In the last few years,several large pharmaceutical companies have made significant strides in the area of green chemistry, also known as sustainable chemistry, especially with regard to minimizing the waste created by current manufacturing processes and modifying processes to use less raw material. They also have identified the environmental impact of solvents and reagents and are working to reduce and even eliminate their use. Green chemistry refers to environmentally friendly chemicals and processes that result in reduced waste, safer products, and reduced use of energy and resources, according to the Environmental Protection Agency (EPA). The EPA created a green chemistry program following the passage of the Pollution Prevention Act of 1990. The agency’s program aims to work with industry for the prevention of pollution, and it recognizes advances in the area through the Presidential Green Chemistry Challenge Program. PV0908LayoutFINAL 8/20/08 11:39 AM Page 30 The green chemistry movement is gain ing traction in Congress as well. In September 2007, the House passed the Green Chemistry Research and Develop ment Act of 2007. This bill, introduced by Rep. Phil Gingrey of Georgia, directs the president to establish a program to pro mote and coordinate federal green chem istry research, development, education, and technology transfer activities. Within the scope of the pharma indus try, green chemistry entails a rethink about its manufacturing processes. David Constable, Ph.D., director of environmental product and process stew ardship at GlaxoSmithKline, says there needs to be a change in industry perspec tive regarding chemical processes. “When people focus on waste, they focus on recycling and reuse,” he says. “That’s very important but it isn’t the only consideration, and it certainly isn’t going to get us to more sustainable processes. We need to address why we are buying and paying for more resources than we need, and then paying to manage, use, and throw it out. Why don’t we just use what we need? This slightly different focus gets peo ple to start thinking about different chemistries and different technologies.” Green chemistry is really a mindset and a way of working, says Andrew Wells, Ph.D., senior principal scientist at AstraZeneca. “There is a perception that green chem istry means more work and more expensive equipment,” he says. “But it’s really about getting all of the chemists and engineers to understand the cost chemistry has on the environment and the impact of waste.” Good chemistry and good science will lead the way to sustainable and scalable processes as well as the best economic and green results, says R.P. “Skip” Volante, Ph.D., VP and global head of process research at Merck Research Laboratories (MRL), Merck & Co. Inc. “Being green doesn’t necessarily mean increased costs; we think green processes will end up being more economical,” he says. Through the American Chemical Soci ety’s Green Chemistry Institute (GCI), eight pharmaceutical companies are working together to implement green chemistry and engineering. The GCI Pharmaceutical Roundtable was formed in 2005 and aims to address the chal lenges of the pharmaceutical industry and to develop tools, as well as be a forum for cooper ation between the member companies. (For more information, see box on page 34.) The roundtable has resulted in a number of green environmental chemistry collaborations between pharma companies. For example, last year AstraZeneca and Pfizer entered into an agreement to share green chemistry tools, and in 2008 AstraZeneca and Glaxo SmithKline agreed to work together in the area of solvent lifecycle impact. “Through our consortium efforts and our individual efforts we are advancing stateoftheart chemistry that could be useful to other finechemical industries,” says John Kindervater, environmental con sultant for Eli Lilly & Co. “We are also working on organic chemistry advances and on engineering changes. Traditionally, pharmaceutical products have been made by batch process. We’re working on con tinuous processing, which can be more efficient.” NewProcesses Lilly has set a goal to cut hazardous material purchases by onethird by 2010. To drive progress toward this goal, Lilly has established specific materialuse efficiency standards for the critical steps in the prod uct development process. The Efactor (a ratio of material used per unit of active pharmaceutical ingredient) of the proposed manufacturing process is evaluated at key development milestones. If the standard is not met at the checkpoint, management review is triggered. These standards are driving improvements in efficiency. For example, Lilly estimates that the improved process identified for one pharmaceutical product will cut material use by 13 million pounds per year at fullscale production. “We use a numeric system to rate the solvents,” Mr. Kindervater says. “We look at the flammability of a solvent and its car cinogenic toxicity. Then we use empirical data from our own experiences, as well as information and literature from the field. We consider potential alternatives; in some solvent classes there are many alternatives that work.” In just two years, Lilly has exceeded its goal to reduce hazardous material purchas es by 37.6% as a result of efficiency increas es, solvent recovery, changes in product mix, and supplychain actions. Similar to Lilly, the educational push at other companies toward improving green chemistry efforts is directed at scientists. “Initially, we realized we needed to go out side the box to encourage our people to think about innovative chemistry,” says Elizabeth Kang, senior manager, environmental techni cal services in ScheringPlough’s Global Safety and Environmental Affairs Group. “Through education and continuous communications, we’ve overcome this obstacle.” Ingrid Mergelsberg, Ph.D., director of syn GREEN chemistry ACADEMICALLY,CHEMISTS ARENOT REWARDED FORGREENCHEMISTRY. Until we start putting green chemistry as a science deliverable in academia, there is a perception that it’s neither good science nor innovative. DR.DAVID CONSTABLE GlaxoSmithKline THERECANBEAPERCEPTIONTHAT GREENCHEMISTRYTAKESMORE WORKANDNEEDSMORE EXPENSIVE EQUIPMENT,but it’s really a mindset and a way of working. DR.ANDREWWELLS AstraZeneca 31 PharmaVOICE S e p t e mb e r 20 08 PV0908LayoutFINAL 8/20/08 11:40 AM Page 31 thetic chemistry at ScheringPlough, says some in the organization considered the green chem istry effort in the beginning as an extra burden. “As we do with quality, we developed our vision to build in green chemistry principals right from the beginning of development; this way we didn’t add to already heavy workloads,” she says. “We started to involve discovery regarding green chemistry principals so that we increase awareness very early on.” ScheringPlough has established a cross functional team comprised of chemists from chemical and physical sciences in the Schering Plough Research Institute, as well as the com pany’s safety and environmental affairs group. “We start with a process notification form that lists all of the materials used in the pro cess, and the chemists crossreference all of the materials against a chemical selection guide,” Ms. Kang says. “The guide classifies each chemical as red, yellow, or green. Green means it’s good from an environmental perspective. We have regular meetings to talk about ways we can improve and apply green chemistry.” At AstraZeneca, the green chemistry net work links environmental specialists with chemistry and engineering organizations with in process development to help promote the principles of green chemistry and engineering. Every two years, all of the scientists in the Global Process Research and Development function in Europe have the opportunity to attend training on how they can minimize the environmental impact of the manufacturing processes they are developing. Dr. Wells says the green chemistry group at AstraZeneca is a multinational, crosscountry function and has representation from process chemistry and engineering, environmental, and SHE (social aspects, health, and environment) specialists in the United States, the United Kingdom, and Sweden. And more medicinal chemistry people are also becoming involved. “We provide software tools, guides, and advice for our synthetic chemists and chemical engineers so they can make the correct choice of solvents on environmental grounds,” he says. “We have a tool called the substance avoidance strategy, and this alerts chemists to reagents and solvents that have environmental issues. We also have an API (active pharmaceutical ingredient) removal tool, which guides engi neers to the most appropriate technologies to take API out of the water stream. “Apart from the positive impact on the envi ronment, it’s good for the company,” Dr. Wells says. “The cost of goods is lower, there is better throughput for pilot plants, we buy fewer sol vents, and we dispose of fewer solvents.” GSK’s Dr. Constable says typically 80% to 90% of the total mass that goes into the pro cess is composed of solvents. Of that, only about 30% to 40% gets recycled. GSK has a set of tools that provides infor mation that can guide chemists in making decisions. It includes: a summary of the most used chemistries; a review of issues encoun tered during process design and development; a summary of common technology alternatives for chemical processing; and guidance on materials, process alternatives, synthetic route strategies, and metrics for evaluating chemistries, technologies, and processes. The company has also developed a materials guide for solvent selection, which compares and ranks 45 solvents according to an environ mental waste profile, environmental impact, a safety profile, and a health impact. “Our desire is to reduce the lifecycle envi ronmental impact associated with using sol vents; burning a solvent as fuel in an incinerator comes with a much larger lifecycle impact than burning kerosene,” Dr. Constable says. “Our longterm goal is to get people to use different chemistries that aren’t as solventdependent.” NewTechnologies Green chemistry at Merck focuses on the development and application of technology for GREEN chemistry 32 S e p t e mb e r 2008 PharmaVOICE PREVENTWASTE Design chemical syntheses to prevent waste, leaving no waste to treat or clean up. DESIGN SAFER CHEMICALS AND PRODUCTS Design chemical products to be fully effective, yet have little or no toxicity. DESIGN LESS HAZARDOUSCHEMICAL SYNTHESES Design syntheses to use and generate substances with little or no toxicity to humans and the environment. USE RENEWABLE FEEDSTOCKS Use raw materials and feedstocks that are renewable rather than depleting.Renewable feedstocks are often made from agricultural products or are the wastes of other processes; depleting feedstocks are made from fossil fuels (petroleum,natural gas, or coal) or are mined. USE CATALYSTS,NOT STOICHIOMETRIC REAGENTS Minimize waste by using catalytic reactions. Catalysts are used in small amounts and can carry out a single reaction many times.They are preferable to stoichiometric reagents, which are used in excess and work only once. AVOID CHEMICAL DERIVATIVES Avoid using blocking or protecting groups or any temporary modifications if possible. Derivatives use additional reagents and generate waste. MAXIMIZE ATOM ECONOMY Design syntheses so that the final product contains the maximum proportion of the starting materials.There should be few, if any, wasted atoms. USE SAFER SOLVENTS AND REACTION CONDITIONS Avoid using solvents, separation agents,or other auxiliary chemicals. If these chemicals are necessary, use innocuous chemicals. INCREASE ENERGY EFFICIENCY Run chemical reactions at ambient temperature and pressure whenever possible. DESIGN CHEMICALS AND PRODUCTS TODEGRADEAFTERUSE Design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment. ANALYZE IN REALTIMETO PREVENT POLLUTION Include inprocess realtime monitoring and control during syntheses to minimize or eliminate the formation of byproducts. MINIMIZETHE POTENTIAL FORACCIDENTS Design chemicals and their forms (solid, liquid, or gas) to minimize the potential for chemical accidents including explosions, fires, and releases to the environment. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 12 Principles of Green Chemistry Source:Originally published by Paul Anastas and John Warner in Green Chemistry:Theory and Practice (Oxford University Press). LILLY’S GREEN CHEMISTRY EFFORTS include implementing new process technologies,such as these coiled tube reactors being used by members of the Alternative Reactor Technology (ART) team to produce drug candidate material for clinical trials. PV0908LayoutFINAL 8/20/08 11:40 AM Page 32 In PostApproval, knowing what looms around every corner is critical to your success. You need an experienced partner who can empower you with a thorough understanding to make informed decisions. For over a decade, our PostApproval teams have been comprised of medical professionals. Our experts work passionately alongside your teams to rapidly identify actionable safety data, putting you in control of your product’s lifecycle. To learn more, please call Craig Eslinger at +1 919 456 4200 x4325 or visit www.postapproval.ppdi.com.

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