Seven Important Elements for an Effective Green Chemistry Program

Concept Article pubs.acs.org/OPRD

Seven Important Elements for an Effective Green Chemistry Program: An IQ Consortium Perspective David K. Leahy,*,† John L. Tucker,‡ Ingrid Mergelsberg,§ Peter J. Dunn,∥ Michael E. Kopach,⊥ and Vikram C. Purohit# †

Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States Small Molecule Process R&D, Amgen, One Amgen Center Drive, Thousand Oaks, California 91320, United States § Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States ∥ Sandwich Laboratories, Pfizer Global Supply, Sandwich, Kent CT 13 9NJ, United Kingdom ⊥ Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States # Chemical Process Research and Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States ‡

ABSTRACT: The authors of this concept article are members of the IQ Green Chemistry working group, one of many subgroups of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) which has been officially chartered in April 2010. The IQ Green Chemistry Working Group seeks to drive innovation and the awareness of green chemistry in pharmaceutical development through the establishment and adoption of best practices, sharing of information within peer networks, and collaboration with regulatory agencies and other key stakeholders.

1. INTRODUCTION Sustainability has been defined as the ability to meet the needs of the present without compromising the ability of future generations to meet their own needs.1 In a world that is challenged by an increasing population with an ever decreasing supply of essential resources, such as petroleum, drinkable water, arable land, and raw materials, the need for sustainable development has never been more urgent. Green chemistry and engineering represent an important framework for the “design and application of chemical products and processes to reduce or to eliminate the use and generation of hazardous substances” that will help guide the development of such products and processes in a sustainable manner.2 The pharmaceutical industry has been criticised for being among those entities generating the highest amounts of waste per kilogram of product compared to the broader chemical industry.3 While this trend can be explained by the additional complexity and higherpurity requirements of pharmaceutical products, a significant challenge to the industry remains. For the past decade a vitalization of green chemistry efforts have encompassed the pharmaceutical industry as evidenced by a number of highly recognised success stories.4 Process chemists and chemical engineers are in a unique position to impact the environmental footprint of their respective companies by designing and developing the processes in which new pharmaceutical products are produced.5 As such, an effective green chemistry program is vital to any process research and development department wishing to embrace this important chemical philosophy. Hence, we report the seven elements required for an effective green chemistry program: 1. Empowered green chemistry teams with management support 2. Metrics and targets © 2013 American Chemical Society

3. 4. 5. 6. 7.

Resources and tools Education Awareness and recognition Investment in green technology External collaboration

2. EMPOWERED GREEN CHEMISTRY TEAMS WITH MANAGEMENT SUPPORT For a process research and development department to fully embrace green chemistry, a culture change may be required. Cultural change can more readily occur from the bottom up, rather than the top down: “culture eats strategy for lunch”. For this reason, a group of highly motivated green chemistry champions who are empowered to drive green chemistry change will be able to make great strides in achieving this goal. However, any green chemistry team needs full support of their management, sharing a vision, strategy, and goals to accomplish this transformation.6 A green chemistry team should promote green chemistry and engineering within their departments by finding and creating resources to enable green chemistry, by educating and advising, by improving green chemistry awareness and visibility, and by collecting green chemistry metrics and recommending green targets. Many process departments have established such teams, and while the specific formats vary from company to company, the overall vision and mission of these green teams are consistent. The following examples illustrate the composition and roles of green chemistry teams at various companies. Received: July 16, 2013 Published: September 5, 2013 1099

dx.doi.org/10.1021/op400192h | Org. Process Res. Dev. 2013, 17, 1099−1109

Organic Process Research & Development

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Figure 1. Green Chemistry Team Activities.

3. METRICS AND TARGETS The goals of most green chemistry programs in pharmaceutical development will typically include maximising efficiency, reducing waste, and minimising environmental footprints, while still delivering important medicines to patients. In order to measure progress and identify opportunities against these goals, a set of simple, clearly defined, and easily measurable green chemistry metrics should be employed. Additionally, collecting metrics will allow for the identification of baseline performance, whereupon targets can be set for further improvements. While the best metric to employ will vary from organization to organization, a few have become quite prominent. A number of mass-based green chemistry metrics have emerged to measure green performance, including process mass intensity (PMI), E-factor, mass efficiency, atom economy, and others. Of these, the pharmaceutical industry has recently gravitated towards PMI, which can be defined simply as the total mass of materials needed to produce a given amount of product (eq 1). PMI is favored over other mass-based and waste-based metrics due its focus on maximising value and efficiency, its being a leading (vs lagging) indicator, and its ease of measurement and comparison by scientists in a laboratory setting. As such, the ACS Green Chemistry Institute has endorsed it as the green yardstick of choice.7

Pfizer utilises a multidisciplinary green chemistry team at each synthetic chemistry research site. The program is coordinated by a global steering team which is made up of the site team leaders and representatives from manufacturing and Global EHS (environmental health and safety). Amgen’s green chemistry teams are organised by modality, including small molecule, biologics, and medicinal chemistry. The teams are guided by champions and are assembled for broad representation from multiple scientific disciplines of engineering, chemistry, analytical, drug product, and EHS. Each of the teams achieves cross pollination with the others by exchanging selected members and attending each others’ meetings. Likewise, Bristol-Myers Squibb uses cross-functional teams where members serve a 2-year rotation on the team with half of the team rotating off each year. This format serves to directly expose a large percentage of the organization to green chemistry over the years, while members rotating off are expected to retain and embrace the principles that they learned. Throughout the industry, green chemistry teams are expanding from the traditional small molecule space to include biologics within their scope. Some typical green chemistry team activities are summarised in Figure 1. Through these activities, green chemistry teams function as catalysts to drive awareness and improvements in sustainability. High-level, full-time, green chemistry leaders help accelerate progress, and several companies have embraced this philosophy. For example, in 2005 Pfizer became the first pharmaceutical company to appoint a full-time green chemistry leader, which led to a major acceleration of the green chemistry program at Pfizer. Likewise, at Janssen Pharmaceuticals, sustainability is led by a group of top management that includes representatives from research, marketing, finance, sourcing, and operations. This council sponsors and funds teams that are key to the company’s sustainability effort, including the Green Technology Team. Thus, the combination of empowered green chemistry teams with actively supportive leadership can serve as an effective foundation for any green chemistry and engineering program. This combination will help shape the broader green chemistry program and help drive activities to meet the company’s sustainability goals.

process mass intensity (PMI) =

total mass of inputs mass of product

(1)

Since PMI can be limited in scope, a more holistic, albeit labor-intensive, approach to greenness metrics is the use of life cycle assessment (LCA). A number of LCA metrics, including carbon dioxide equivalents, have been employed to characterise the cumulative impact of a product’s life from cradle-to-grave on the environment. GlaxoSmithKline has been working on integrating life cycle assessment (LCA) into product development and redesign with the ultimate aim to minimise the environmental impact across the entire value chain of material extraction, manufacturing, transport, product use, and disposal or recycling. Once appropriate metrics are chosen, their collection and tracking across projects and across a company’s portfolios will help establish a baseline performance. Collecting metrics for a given project or product over its development lifecycle helps track improvements to that process over time. Collection of 1100



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metrics for a single step or an entire process can also be advantageous. Steps with less than desirable greenness metrics will be obvious from the analysis, and additional effort can then focus on improving these problem areas. For example, at Bristol-Myers Squibb, PMI and other greenness metrics are collected at the completion of each campaign then reviewed by the green chemistry team and the project team to identify which aspects of each step contributes negatively to the overall ‘score’. Teams then discuss the issues and agree upon a development plan to focus on improved green performance. Alternatively, collecting metrics across an entire portfolio helps determine how well the organization is doing as a whole. Many companies choose to complete metric collection activities at various developmental milestones or at the completion of campaigns. This is useful to determine a baseline from which targets can be set. However, it is important to consider the stage of development of an asset when comparing metrics such as PMI, because they usually improve as projects proceed through development. Thus an apparent improvement (or decline) could actually result from a shift in the mix of development stages of assets in the overall portfolio over time. One way to overcome this issue is to group assets by development stage when performing analysis or setting targets. This strategy was employed by the ACS GCI Pharmaceutical Roundtable when collecting and publishing PMI metrics for the pharmaceutical industry. Their findings can be used for benchmarking purposes and show an industry median PMI for commercial products of 68 versus a median of 433 for a preclinical candidate (Figure 2).8

Figure 3. GlaxoSmithKline Process Mass Intensity (PMI) targets.

product lifecycle, but custom PMI targets are based upon projected volume and molecular complexity.9 The correlation of greenness metrics with cost of goods is an important consideration for industry. Gratifyingly, such analysis confirms the positive impact practicing green chemistry has to the ‘triple bottom line’.10 At Amgen, cost tracking software offers the ability for instantaneous calculation of the total raw material use required to manufacture any desired final quantity of drug substance (Figure 4). Thus, the cost versus E-factor11 can be instantly calculated and correlated over sequential campaigns.

Figure 4. Example correlation between E-factor and cost reduction.

4. RESOURCES AND TOOLS While the use of metrics and targets allow for measurement and setting of goals, they do not directly inform scientist on how the goal can be accomplished. Therefore, an important element of any green chemistry program is the selection and development of resources and tools for deployment across the organization to aid in green process design (Figure 5).

Figure 2. Industry median PMI per phase of development (2010 data).

Once appropriate metrics are selected and a baseline is established, many companies set targets to meet. While some companies affix discrete hard targets that must be achieved at a given point in development, others view the targets more as aspirational goals. Regardless of the approach, setting targets can enhance green performance in a measurable way. For example, the Green Technology Team at Janssen Pharmaceuticals has a goal of improving the average PMI of their scale-up processes by 20% over the next five years (2010 to 2015). Likewise, GlaxoSmithKline has consistently set more and more aggressive PMI targets over time as illustrated in Figure 3 and has reported progress in this area as the average PMI of new primary processes transferred to manufacturing in 2011 was 45. Lilly takes a similar approach where PMI is tracked over

Figure 5. Benefits of green chemistry tools. 1101



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Figure 6. Avenues to enhance green chemistry awareness.

Besides selection guides, tools for collecting metrics with minimal effort by scientists are also a necessary component to any green chemistry program. One such resource has been developed by the ACS GCI Pharmaceutical Roundtable: an easy-to-use PMI calculator. This Excel spreadsheet with embedded calculations requires only basic and readily available information to calculate PMI for linear sequences. In addition to calculating PMI for an overall process, it also reports separate PMI for solvents, water, and reagents, which may be of interest to some users. Like the solvent selection guide, the PMI calculator is free to all, available at www.acs.org/ gcipharmaroundtable. In addition to utilising this calculator for internal purposes, many companies have shared this tool with their suppliers in order to encourage green chemistry in their supply chain. Development scientists at Bristol-Myers Squibb make use of a process greenness scorecard to track metrics that help identify areas of a process that are not green and drive towards green solutions. This scorecard looks holistically at a process and scores it based upon fourteen criteria: solvent selection, solvent recovery, solvent waste, solid waste, emissions, byproducts, number of transformations, number of isolations, yield, listed reagents, dust explosion potential, process hazards, biopersistence and worker exposure. This tool is useful for assessing both individual steps as well as overall routes and is an integral part of the process development paradigm at Bristol-Myers Squibb. Merck has developed an analytical method volume intensity (AMVI) metric and corresponding tool to drive the development of green HPLC methods in its analytical areas. It is a simple method to measure the total solvent consumption of an HPLC method including sample preparation and supports informed decisions on how to design greener methods and lower their environmental impact. Realized solvent savings in Merck’s API laboratories is ∼30% by using fast LC and low AMVI methods, and the solvent usage in API supply Quality

Organizations such as the ACS GCI pharmaceutical roundtable have developed a number of selection guides, while a number of commercial products are available to provide guidance to scientists. Still other tools have been developed internally to meet specific companies’ unique needs. Members of the ACS GCI pharmaceutical roundtable have recently published the first collaboratively developed solvent selection guide, which is universally available to the public free of charge at www.acs.org/gcipharmaroundtable. This guide considers safety, health and environmental impact of solvents, and aids scientists in making informed decisions on solvent choices. Similarly, the roundtable is developing reagent selection guides that help scientists choose reaction conditions for commonly employed transformations. Well established reaction conditions are ranked by three criteria: greenness, scalability and wide utility and displayed in an easy to read Venn diagram. Useful information for key reactions is provided, including mechanism, references, examples and notes and general applicability. Many companies have developed internal custom resources, such as Bristol-Myers Squibb’s ‘green reactions’ internal Wiki site. While considerably more simple in scope than a selection guide, their list points researchers in the right direction when trying a transformation for the first time or looking for greener solutions to a given reaction. The list is organised by reaction class (searchable by key word) and contains a reaction scheme, basic synopsis, and link to the primary literature. Other, more complex resources include GSK’s Eco-Design Toolkit, which is composed of six modules: Green Chemistry/Technology Guide,12 FLASC (Fast Lifecycle Assessment for Synthetic Chemisty,13 Materials Selection Guides (Solvents14−16 and Bases), Green Packaging Guide, Chemicals Legislation Guide (CLG),17 and a Reagents Guide. Likewise, Pfizer provides its researches with an extensive suite of tools including a solvent guide, reagent guide, 18 metrics tool, acid/base guide, biocatalysis guide, and a simple carbon-footprinting tool. 1102



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Scheme 1. Green RCM approach to HCV drug candidate, BILN 2061

Operations laboratories is anticipated to be reduced by ∼2000 L annually.19 One essential component of a successful green chemistry program is the electronic laboratory notebook (ELN).20 The ELN offers an excellent opportunity to incorporate green chemistry into the scientist’s daily activities. Green metrics such as process mass intensity (PMI process input/process output), E-factor (process waste/process output), and atom economy can easily be calculated from the notebook materials table. Some notebook providers have already incorporated PMI for a multistep synthesis and are working toward providing a breakdown of PMI contributors by reagent, solvent, and aqueous streams. The ELN also has the capacity to warn users when a material is selected that is present on one of the many governmental environmental control lists such as the EPA’s TRI (toxics release inventory), OSHA’s regulated carcinogens, reproductive toxins, and highly toxic chemicals, or the European Commission’s substances of very high concern (REACH). As an example of potential utility, Amgen has embedded a solvent selection guide directly into its ELN.

Internal green chemistry award programs can also have a profound impact. These award programs serve multiple functions, the most obvious being recognition of superior science on the part of the winning submission. Perhaps most important, though, is the acknowledgement and value afforded to green chemistry by organizational leadership. This positive recognition and reward inspires greater staff involvement and achievement and communicates organizational desires and expectations for greater efficiency and environmental concern. External award programs provide a distinct opportunity to demonstrate green chemistry commitment and execution to peers and to the general public. One of the most visible awards, the EPA’s Presidential Green Chemistry Award, recognizes outstanding achievement in a number of industrial and academic categories including the pharmaceutical industry.4 Many outstanding pharmaceutical examples can be found by examining past award recipients, and the organizational recognition is significant. Such awards can have an extremely motivating effect towards the development of cutting-edge, green chemistry science.

5. AWARENESS AND RECOGNITION Beyond having a formalized green chemistry program in place, it is vitally important to ensure that green chemistry stays on the forefront of scientists’ minds by raising green chemistry awareness (Figure 6). One inspirational and effective practice is providing internal lectures and symposia on green chemistry that showcases award-winning scientists and recognized leaders in efficiency and sustainability. Many companies encourage participation in external green chemistry meetings such as the American Chemical Society Green Chemistry and Engineering Conference or contribute their work to focused green chemistry journals such as the Royal Chemistry Society’s Green Chemistry. Many pharmaceutical companies also raise awareness by creating and utilising Green Chemistry SharePoint sites, which serve as a primary location for tools and provide a forum to address questions of green chemistry philosophy and application. These sites also provide an opportunity to share metrics and best practices in real time throughout an organization, eliciting a greater concern and resultant improvement in green chemistry performance and efficiency. Another important tool to elevate awareness is the propagation of easily accessible visual reminders. Magnets and posters including the 12 principles of green chemistry and solvent selection guides have been created that can be placed upon fume hoods and on laboratory walls for quick reference. Some also publish newsletters highlighting in-house and literature examples of green chemistry that raise institutional awareness.

6. EDUCATION While the number of universities and colleges offering green chemistry and green engineering courses are increasing (a step in the right direction), we are still far away from having this important subject included in every chemistry or engineering degree curriculum. As a result, the majority of green chemistry education becomes the responsibility of the employer, should they desire a sustainability-minded scientific workforce. Not surprisingly, many pharmaceutical companies have developed their own green chemistry training programs, often to teach both fundamental principles as well as to raise awareness of departmental expectations and available resources. Merck, for example, has developed a Green Chemistry eLearning course with modules for Medicinal Chemistry, Chemical Development, Engineering, and Analytical Chemistry with many examples from the respective areas presenting the issues first, followed by green and sustainable solutions and improvements. Quarterly issued Green Chemistry Newsletters show successful examples of application of the 12 principles of Green Chemistry and Engineering across the company.2 At Lilly, one of the first activities for a new employee is training on the company electronic laboratory notebook (ELN). The builtin green chemistry functionality of the ELN, such as PMI, hazardous chemical designation, and solvent tier, helps educate scientists in this area at the start of their professional careers. As an alternative, various external organizations offer professional training courses for scientists and engineers that focus on green chemistry and sustainability. Regardless of the 1103



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Scheme 2. Green transamination approach to Januvia (sitagliptin)

Figure 7. Green plant cell fermentation approach to Taxol (paclitaxel).

factor of 370 kg/kg for just that one step. Their Catalysis Skill Center was able to identify the key parameters influencing the course of the reaction and developed a highly efficient, commercially viable process where the RCM was achieved in 93% yield using only 0.1 mol % Grela catalyst and 0.2 M substrate concentration in toluene. The E-factor dramatically decreased to 52 kg/kg (>85% reduction).22 Enzymes are the ultimate green catalysts; they are renewable, biodegradable, and generally believed to provide a more sustainable means of synthesis than more traditional chemistry approaches. Bioprocesses are transformative technologies widely practiced throughout the pharmaceutical industry. They benefit from often superb selectivity and minimal byproduct formation, and most importantly, they typically run in the greenest of reaction solventswater. Two important classes of bioprocesses include enzymatic chemical reactions and fermentations. Each has proven its value via commercialscale implementation in numerous award-winning pharmaceutical processes. Merck’s type 2 diabetes drug, Januvia (sitagliptin), represents an outstanding success story in the application of enzymatic chemical reactions to pharmaceutical manufacturing (Scheme 2). In order to address growing demand for the drug, a more

method, green chemistry education serves as an important cornerstone of a successful green chemistry program.

7. INVESTMENT IN GREEN TECHNOLOGIES To truly enable greenness, a company must be invested in green technologies, which can provide a step change in the greenness of chemical processes. Some examples include catalysis, biocatalysis, continuous processing, and solvent and catalyst recycling. It is vitally important for development organizations to embrace and exploit these transformative new technologies. Catalysis is a core technology that enables greener chemical processes. Investment in catalysis by industry is essential for developing highly efficient catalytic reactions for industrial scales, and most major pharmaceutical companies have developed significant in-house capacity for catalysis research. An excellent case study is Boehringer Ingelheim’s synthesis of a hepatitis C virus (HCV) drug candidate (BILN 2061; Scheme 1).21 The key challenge was the formation of the 15-membered macrocycle via a ring-closing metathesis (RCM) reaction. The initial RCM reaction required high dilution (0.01 M) and high catalyst loading (3−5 mol % Hoveyda first-generation catalyst) using dichloromethane as the solvent, resulting in a high E1104



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Scheme 3. Selected examples of continuous processing used to enable greenness

advantages.24 Due to superior mixing and heat transfer, reactions can often be run more highly concentrated, thus minimising waste and reducing PMI. Process safety is also enhanced as only small quantities of reagents are reacting at a given time. Quality can often be more consistently controlled as processes are run under steady state, minimising batch-to-batch variation associated with the dynamic nature of batch processes. Finally, lower production costs can often be realized due to smaller footprints, waste and emission, and energy use, especially when using cryogenic conditions. Over the past few years Eli Lilly and Company has shifted its Process Research R&D strategy from primarily batch processing to continuous flow. Some recent examples of continuous processes from Eli Lilly and Company include the following: (a) Schotten−Bauman acylation in three disposable continuously stirring tank reactors to minimize cleaning requirements for a cytotoxic API,25 (b) a continuous Barbier reaction to mitigate risks from the highly exothermic metal activation step,26 (c) a fully continuous asymmetric hydrogenation reaction operating at 70 bar hydrogen in a plug flow reactor for process safety as well as reductions in catalyst and capital cost,27 (d) a high-pressure cyclization (70 bar) of a ketoamide to form a 1H-4-substituted imidazole followed by a thermal Boc deprotection using supercritical conditions, with both in a plug flow reactor,28 (e) an Ireland Claisen rearrangement in a thermal tube reactor to improve process safety, yield, and purity relative to those in batch processing,29

efficient, less environmentally impactful process was required. The first-generation manufacturing process for sitagliptin was energy intensive and required a rare metal, rhodium, as a catalyst that needed to be removed at the end of the process. The second-generation process utilized a reductive amination catalysed by a custom-tailored transaminase, which was rapidly developed using directed evolution technology in close partnership with Codexis. This enzymatic process demonstrated potential to double productivity, increase yield by about 10%, and significantly reduce overall waste generation; as a result it won the EPA’s Presidential Green Chemistry Award. Plant cell fermentation is another important bioprocess technology that is extremely effective for the large-scale production of certain naturally occurring phytochemicals. This technique capitalizes on a plant culture’s ability to synthesize complex organic molecules from simple feedstocks. Bristol-Myers Squibb made use of this technology to replace their semisynthetic approach to Taxol (paclitaxel). This was an especially challenging application of plant cell fermentation technology as paclitaxel is a secondary metabolite (Figure 7).23 As a result of this effort, Taxol could be prepared on commercial scale, eliminating an estimated 32,000 kg of hazardous chemicals in its first 5 years of production alone. For this achievement, Bristol-Myers Squibb also won the EPA’s Presidential Green Chemistry Award. Continuous processing is an enabling green technology that has numerous environmental, safety, quality, and economic 1105



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Scheme 4. Green lipase-based approach to Lyrica (pregabalin)

Figure 8. Example solvent recovery strategy for commerical phamaceutical production.

manufacturing.34 For large-volume APIs it is important to consider recovering and recycling process solvents. Significant efficiency gains and cost saving can be realized by reusing recovered solvents in API manufacturing processes when the recovered solvents meet the appropriate specifications.35 It is often technically feasible and economical to recover solvents from API processes by atmospheric or reduced pressure fractional distillation.36 Solvents that cannot be recovered economically are often downcycled for other industrial applications or heat recovery. Likewise, valuable and rare precious metals are conserved by retaining heterogeneous precious metal catalysts after use and returning them to suppliers and catalyst recovery businesses for recovery and reuse as new catalytic products. An example provided by Abbot illustrates the value of a solvent recovery strategy (Figure 8). Two discrete organic wastes are generated in the process: the wet distillate of solvent A containing 2−4% of water and the crystallization mother liquors consisting of solvents A and B. A portion of the “wet distillate” A is directly recycled in the first step of the synthesis since the reaction takes place in a binary mixture of solvent A and water. The remaining wet distillate of solvent A is purified by fractional distillation to remove water and other solvent impurities, making the recovered dried solvent suitable for the water-sensitive reactions in the syntheses. Fractional distillation of the mother liquors gives an A-and-B azeotrope (mainly A) followed by pure B. This allowed for a modified crystallization process replacing pure A with the recovered A-and-B azeotrope.

(f) an azide displacement using a continuous-flow channel reactor to mitigate the toxicity and explosion risks associated with hydrazoic acid produced from sodium azide (Scheme 3).30 Often the use of multiple new technologies is required to achieve the highest standards of green chemistry efficiency, and an example of this is the Pfizer synthesis of Lyrica (pregabalin) which uses both biocatalysis and continuous processing.31 The process is shown in Scheme 4, the desired stereochemical center is introduced by a lipase catalysed hydrolysis but this produces an equal amount of the unwanted (R)-enantiomer. Recycling the wrong enantiomer is made difficult as the hydrogen atom center to be epimerized is not the most acidic hydrogen atom in the molecule. The problem is solved by performing the base-catalysed epimerization in a continuous reactor. The new synthesis has numerous environmental benefits including the following: • Water is used as the reaction solvent in every chemical step. • An 8-fold reduction in the use of Raney nickel catalyst. • The E-factor of the new process is 10 vs 86 for the previous synthesis.31,32 • By using this process over 3 million metric tons of CO2 emissions will be eliminated between 2007 and 2020.33 The pharmaceutical industry consumes large quantities of organic solvents for carrying out chemical transformations, extractions, and purifications for starting materials, chemical intermediates, and APIs. Indeed, it has been estimated that solvents make up as much as 80% of the material usage for API 1106



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Figure 9. Continuous flow tubular reactor designed of homogeneous palladium-catalysed aerobic oxidations.

The small amount of solvent B at the start of crystallization acts as a portion of antisolvent B prior to the onset of crystallization. Recovered B is then used to complete the crystallization. At full production, over 5 million liters of solvent are recovered and reused annually, greatly reducing the environmental impact for this product.

green chemistry IQ working group promotes Green Chemistry in the Pharmaceutical Industry by focusing on opportunities for cooperative efforts between the FDA and the pharmaceutical industry. A first meeting with the FDA in February 2012 resulted in a tentative plan to detail challenges and opportunities for the FDA to further promote and encourage the use of green chemistry within the highly regulated pharmaceutical industry. Many European pharmaceutical companies are partnering with European public sector researchers to solve sustainable manufacturing challenges through the Innovative Medicines Initiative (IMI).38 One project within IMI is CHEM21, which is devoting €6.4 million on green chemistry challenges. Key areas of focus include improved catalytic and flow chemistry methods, novel biocatalysts, synthetic biology approaches to enable useful cascade reactions in cells, and improvements in sustainable chemistry education. Another successful collaboration can be seen with the Singapore Economic Development Board and GlaxoSmithKline. They have made a joint commitment to improve manufacturing efficiency in pharmaceutical and fine chemical manufacture in Singapore with the “GSK-Singapore Partnership for Green and Sustainable Manufacturing”,39 a public-private partnership. Through this program, GSK proposes industry problems in sustainability for study, and the academic community prepares research proposals to solve these problems. Many focused green chemistry research projects and collaborations exist between industry and academia. Eli Lilly and company and Professor Shannon S. Stahl from the University of Wisconsin, Madison, are an excellent example of academia and industry leveraging strengths in a strategic collaboration. Together, they have developed safe and scalable palladium-catalysed aerobic oxidations, using the greenest possible oxidantmolecular oxygen (Figure 9).40 Safety limitations were addressed by the development of a continuous-flow tube reactor for the aerobic oxidation of alcohols. Importantly, the use of a dilute oxygen gas source (8% O2 in N2), and further dilution to 4% oxygen in the reactor, ensures that the oxygen/organic mixture never enters the explosive regime. Efficient gas−liquid mixing in the reactor

8. EXTERNAL COLLABORATION External collaboration is an important element for any effective green chemistry program as it allows for the cross-pollination of ideas, the sharing of best practices, and the pooling of resources to accomplish mutually beneficial objectives. There exists a number of collaborative groups with a focus on green chemistry within the pharmaceutical industry, as well as a number of fruitful collaborative efforts between pharmaceutical companies and academic researchers, that aims to develop new green technologies. The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) is one of the more established collaborative organizations with a focus on green chemistry within the pharmaceutical industry.37 Started in 2005, it currently has 15 member companies representing a diverse cross section of the global pharmaceutical industry. The ACS GCIPR focuses on four strategic priorities: • Inform and influence the research agenda • Develop tools for innovation • Provide education resources • Enable global collaboration This group has awarded over a million dollars in research grants, developed a number of useful tools (PMI calculator, solvent selection guide), and publishes position papers, green articles of interest, and numerous other activities in alignment with its mission to catalyse the implementation of green chemistry and green engineering in the global pharmaceutical industry. Similarly, a formulators’ roundtable and chemical manufacture’s roundtable exist to serve these specific industries. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) was officially chartered in April 2010 andas of nowhas 32 member companies. A 1107



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(6) Tucker, J. L. Org. Process Res. Dev. 2010, 14, 328−331. (7) For a further discussion on the advantages and limitations of the PMI metric, see: Jiménez-González, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912−917. (8) Broxterman, Q. B.; Hughes, D. L. Chim. Oggi 2011, 29, 58−61. (9) Kjell, D. P.; Watson, I. A.; Wolfe, C. N.; Spitler, J. T. Org. Process Res. Dev. 2013, 17, 169−174. (10) Elkington, J. Cannibals with Forks: The Triple Bottom Line of 21st Century Business; New Society Publishers: Stony Creek, CT, 1998. (11) E-factor = total waste (kg)/product (kg) (12) Jiménez-González, C.; Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Clean Technol. Environ. Policy 2002, 4, 44−53. (13) Curzons, A.; Jiménez-González, C.; Duncan, A.; Constable, D. J. C.; Cunningham, V. Int. J. LCA 2007, 12, 272−280. (14) Jiménez-González, C.; Curzons, A. D.; Constable, D. J. C.; Cunningham, V. L. Clean Technol. Environ. Policy 2005, 7, 42−50. (15) Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. P.; Fisher, G.; Sherwood, J.; Binks, S.; Curzons, A. Green Chem. 2011, 13, 854−862. (16) Curzons, A. D.; Constable, D. J. C.; Cunningham, V. L. Clean Prod. Processes 1999, 1, 82−90. (17) Jiménez-González, C.; Constable, D. J. C.; Henderson, R. K.; De Leeuwe, R.; Cardo, L. In Design for Energy and the Environment; ElHalwagi, M. M., Linninger, A. A., Eds; CRC Press: Boca Raton, 2010; pp 27−38. (18) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A. Green Chem. 2008, 10, 31−36. (19) Hartman, R.; Helmy, R.; Al-Sayah, M.; Welch, C. J. Green Chem. 2011, 13, 934−939. (20) Kopach, M. E.; Reiff, E. A. Future Med. Chem. 2012, 11, 1395− 1398. (21) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Boes, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagacé, L.; LaPlante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; St. George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llinàs-Brunet, M. Nature 2003, 426, 186−189. (22) Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanyake, C. H. Org. Process Res. Dev. 2009, 13, 250−254. (23) Mountford, P. G. In Green Chemistry in the Pharmaceutical Industry; Dunn, P. J., Wells, A. S., Williams, M. T., Eds; Wiley-VCH: Weinheim, Germany, 2010; pp 145−160. (24) Jiménez-González, C.; Poechlauer, P.; Broxterman, Q. B.; Yang, B.; Ende, D. A.; Baird, J.; Bertsch, C.; Hannah, R. E.; Dell’Orco, P.; Noorman, H.; Yee, S.; Reintjens, R.; Wells, A.; Massonneau, V.; Manley, J. Org. Process Res. Dev. 2011, 15, 900−911. (25) White, T. D.; Berglund, K. D.; Groh, J. M.; Johnson, M. D.; Miller, R. D.; Yates, M. H. Org. Process Res. Dev. 2012, 16, 939−957. (26) Kopach, M. E.; Roberts, D. J.; Johnson, M. D.; Groh, J. M.; Adler, J. J.; Schafer, J. P.; Kobierski, M. E.; Trankle, W. G. Green Chem. 2012, 14, 1524−1536. (27) Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.; Miller, M. T.; Brennan, J. Org. Process Res. Dev. 2012, 16, 1017−1038. (28) May, S. A.; Johnson, M. D.; Braden, T. M.; Calvin, J. R.; Haeberle, B. D.; Jines, A. R.; Miller, R. D.; Plocharczyk, E. F.; Rener, G. A.; Richey, R. N.; Schmid, C. R.; Vaid, R. K.; Yu, H. Org. Process Res. Dev. 2012, 16, 982−1002. (29) Rincon, J. A.; Barberis, M.; Gonzalez- Esguevillas, M.; Johnson, M. D.; Niemeier, J. K.; Sun, W. Org. Process Res. Dev. 2011, 15, 1428− 1432. (30) Kopach, M. E.; Murray, M. M.; Braden, T. M.; Kobierski, M. E.; Williams, O. L. Org. Process Res. Dev. 2009, 13, 152−160. (31) (a) Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org. Process Res. Dev. 2008, 12, 392−398. (b) Dunn, P. J.; Hettenbach, K.; Kelleher, P.; Martinez, C. A. In Green Chemistry in the

minimizes decomposition of the homogeneous catalyst into inactive Pd metal, providing the basis for large-scale implementation of this and related green processes. The National Science Foundation also is highly supportive of industry−university collaboration and makes research money available via the Grant Opportunities for Academic Liaison with Industry (GOALI) program. This program has been used to support green chemistry research, which is becoming an increasingly higher priority at NSF. An excellent example can be seen in the GOALI supported collaboration between Michigan State University (Prof. Maleczka) and Merck “on “C−H Bond Activation and Functionalization Methods for Medicinal and Process Chemistry”. The work is focused on the development of catalytic borylations, owing in part to the Suzuki reaction’s prominence in the pharmaceutical industry. This work is also cosupported by the ACS Green Chemistry Institute’s Pharmaceutical Roundtable, as CH-activation of aromatics tops their list of key green chemistry research areas.41

9. CONCLUSIONS The pharmaceutical industry has largely embraced the corporate sustainability movement, a key element of which is the environmentally responsible manufacture of pharmaceutical products. It is here that green chemistry can make an enormous impact on a company’s triple bottom line, as it is more costeffective, safer for employees, and better for the environment.10 A focused green chemistry program that includes empowered green chemistry teams with management support, metrics and targets, resources and tools, education, awareness and recognition, investment in green technology, and external collaboration can pay measurable and significant dividends to a company’s sustainability efforts.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) for providing a forum that allowed this work to come together. We also acknowledge Concepción Jiménez-González, Philip Dell’orco, Howard Morton, Emily Reiff, Sandy Yee, Jeff Song, Steven Pfeiffer, and Jaan Pesti for pertinent industry examples and helpful discussions. IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science-based and scientifically driven standards and regulations for pharmaceutical and biotechnology products worldwide. Please visit www.iqconsortium.org for more information.

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REFERENCES

(1) World Commission on Environment and Development Our Common Future; Oxford University Press: Oxford, 1987. (2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (3) Sheldon, R. CHEMTECH 1994, 24, 38−47. (4) A summary of winners of the EPA Presidential Green Challenge Awards can be found at: http://www.epa.gov/greenchemistry/pubs/ pgcc/past.html (5) Tucker, J. L. Org. Process Res. Dev. 2006, 10, 315−319. 1108



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Pharmaceutical Industry; Dunn, P. J.; Wells, A. S.; and Williams, M. T., Eds; Wiley-VCH, 2010, pp 161−177. (32) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Gote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklyn, L. C.; Granger, E. J.; Karrick, G. L. Org. Process Res. Dev. 1997, 1, 26−38. (33) Savelski, M.; Slater, C. S.; Dunn, P.; Knochel, D.; Visnic, C. “Use of Life Cycle Assessment to Evaluate the Sustainable Manufacture of the Active Pharmaceutical Ingredient Pregabalin” AIChE Annual Meeting, Minneapolis, October 2011, Paper 124c. (34) Constable, D. J. C.; Jiminez-Gonzalez, C.; Henderson, R. K. Org. Process Res. Dev. 2007, 11, 133−137. (35) Dunn, P. J.; Galvin, S.; Hettenbach, K. Green Chem. 2004, 6, 43−48. (36) Ramzan, N.; Degenkolbe, S.; Witt, W. Chem Eng. J. 2008, 140, 201−213. (37) The ACS CGI Pharmaceutical Roundtable website can be found at: www.acs.org/gcipharmaroundtable (38) The Innovative Medicines Initiative website can be found at: www.imi.europa.eu (39) The GSK-EDB Partnership for Green and Sustainable Manufacturing website can be found at: www.ace.gsk.com/GSM/ Home.aspx (40) Ye, X.; Johnson, M. D; Diao, T.; Yates, M. H.; Stahl, S. S. Green Chem. 2010, 12, 1180−1186. (41) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420.

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