Benchmarking Green Chemistry Adoption by the Global

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Benchmarking green chemistry adoption by the global pharmaceutical supply chain Vesela Veleva, Berkeley Cue, Jr., and Svetlana Todorova ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02277 • Publication Date (Web): 08 Nov 2017 Downloaded from http://pubs.acs.org on November 10, 2017

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ACS Sustainable Chemistry & Engineering

Benchmarking green chemistry adoption by the global pharmaceutical supply chain Vesela R. Veleva, ScD* University of Massachusetts Boston, College of Management, 100 Morrissey Blvd., Boston, MA 02125, USA, phone: 617-287-6293, email: [email protected] Berkeley W. Cue, Jr., PhD BWC Pharma, LLC, P.O. Box 280, 135 Highland Avenue, Nottingham, NH 03290, USA, email: [email protected] Svetlana Todorova, PhD Northeastern University, D'Amore-McKim School of Business, 360 Huntington Avenue, Boston, MA 02115, USA, email: [email protected] Abstract The pharmaceutical industry was among the first to embrace green chemistry (GC) with many “big pharma” companies creating GC teams, adopting metrics, tools and training to “green” drug design and manufacturing. Yet, little is known about GC adoption by generic drug companies and active pharmaceutical ingredient (API) manufacturers who manufacture the majority of drugs sold presently. The primary goal of this paper is to benchmark the adoption of GC by the entire pharmaceutical supply chain based on information from industry representatives leading such efforts. Data was obtained from a survey of 34 global companies, including 13 “big pharma”, 5 smaller R&D pharma, 4 generic pharma companies, and 12 API manufacturers (their classification is based on each company’s primary activity). Results demonstrate that time pressures to deliver new drugs and regulatory risk are the top two barriers to greater GC adoption, while costs savings and environmental regulations are the top two drivers. The study also demonstrates that despite a lack of public disclosure, generic drug companies, API manufacturers and smaller R&D pharma exhibit significant interest and some advances in using GC principles (e.g., 35% have cross-functional team to lead these efforts and 25% use E-factor, PMI and number of steps to track progress). Yet, 81% of these companies have no publicly stated commitment to GC, 43% do not use any GC metrics, 24% do not invest in green technology and 58% are not involved in any external collaborations. The study concludes that wider adoption of green chemistry by the entire supply chain requires more effective and globally harmonized environmental regulations, use of life cycle assessment metrics, expanding GC education, and establishing effective supplier management programs. Keywords Green chemistry, sustainability, pharmaceutical industry, pharma supply chain, green chemistry metrics, drivers, barriers Introduction Introduced in the 1990s green chemistry (GC) has achieved significant growth driven by stakeholder pressures to reduce environmental impacts of manufacturing as well as cost savings and other business benefits such as improved reputation, market positioning, customer relations and ability to attract and retain talent. Green chemistry is defined as “the design of chemical products and processes that reduce or eliminate the generation of hazardous substances”1 and its 1 ACS Paragon Plus Environment


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implementation is guided by the 12 Principles of Green Chemistry2. The pharmaceutical industry was among the first sectors to embrace green chemistry with many “big pharma” creating green chemistry teams, adopting metrics, tools and training, to advance “greener” drug design and manufacturing. Many pharmaceutical companies were nominated for the prestigious Environmental Protection Agency (EPA) Presidential Green Chemistry Challenge Award3. In 2005 the American Chemical Society (ACS) established the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) to advance greater adoption of green chemistry by the entire sector through developing tools, sharing best practices, supporting research and education, and engaging with policy makers. The roundtable has grown from the three founding members (Pfizer, Merck and Eli Lilly) to 14 members and four associate members as of 2017 (including some companies outside the R&D-based pharmaceuticals). Research has demonstrated that most “big pharma” have adopted green chemistry to some extent 4-5and numerous studies have reported the significant environmental and business benefits of GC 5, 6-8. Despite the strong business case for green chemistry, research has raised concerns that generic drug companies and Active Pharmaceutical Ingredient (API) manufacturers have not embraced it to the extent that large R&D companies have5. With the adoption of the Hatch Waxman Act, which promoted generic drugs, and the increasing pressures globally to reduce healthcare costs, the percent of drugs coming from generics is growing and projected to reach 92% of all drugs globally by 2022 9. Furthermore, many “big pharma” are outsourcing drug discovery and manufacturing to low cost countries such as India and China in order to reduce costs10. Thus the real impact of GC on the environment will come from incorporating GC practices throughout the entire supply chain, including API suppliers and generic drug companies. In 2006 a group of pharmaceutical and healthcare companies launched the Pharmaceutical Industry Supply Chain Initiative (PSCI) to promote better environmental, health and safety practices by the entire supply chain11. Yet, to date little research has been done to benchmark progress and identify exiting barriers and future opportunities for the entire supply chain. This paper aims to address this gap and has three main objectives: 1) benchmark current adoption of green chemistry practices by the global pharmaceutical industry (large R&D pharma, smaller R&D pharma, generic manufacturers and API manufacturers); 2) examine the drivers and barriers to greater adoption of green chemistry by the pharmaceutical industry, and 3) identify opportunities to advance wider adoption of green chemistry by the entire pharmaceutical supply chain. The main contribution of the paper is that it is the first effort to benchmark GC adoption by the pharmaceutical supply chain based on information from industry representatives leading such efforts. Data was obtained from an online survey which involved 34 companies from the U.S., European Union, China, and India, and included 13 “big pharma”, 5 smaller R&D pharma, 4 generic pharma companies and 12 API manufacturers. The paper begins with an overview of the industry, environmental impacts and regulations, current initiatives, barriers, opportunities and metrics for advancing GC in the pharmaceutical supply chain. Next, the authors present the study goals and methods, followed by survey results and discussion. The paper concludes with a summary of key findings and implications for future research, policy, and practice. Literature review 2 ACS Paragon Plus Environment

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Green chemistry traces its origin to the works by Anastas, Clarke, Sheldon, Trost, Warner and others in the 1990s who reported the large amounts of waste generated during discovery and synthesis of new processes and products12. The term “green chemistry” was first introduced by Anastas in the early 90’s with Anastas and Warner (1998) publishing a book on the subject2 and defining the 12 Principles of Green Chemistry (see Text Box 1). Over the years these principles have become an important “road map” for chemists and scientists interested in designing safer chemicals and products. While some studies have implied that green chemistry and sustainable chemistry are synonymous1,4,13, Cannon et. al. (2012)14 demonstrate that green chemistry is a subset of sustainable chemistry, which is one of the tools used to advance sustainability. Green chemistry has been adopted by many sectors, including bulk chemicals, consumer products, electronics, furniture, and personal care products; this paper, however, focuses specifically on the pharmaceutical industry and its supply chain. Text Box 1. The 12 Principles of Green Chemistry2 1.Prevent waste 7. Use renewable feedstocks 2.Maximize atom economy 8. Reduce derivatives reagents 3.Use less hazardous chemical syntheses 4.Design safer chemicals 5.Use safer solvents and auxiliary substances 6.Design for energy efficiency

9. Use catalysts over stoichiometric reagents 10.Design for degradation 11.Use real-time analysis to prevent pollution 12.Use safer chemical to minimize accidents

Pharmaceutical industry overview The global pharmaceutical industry exceeded $1 trillion in sales in 2014 and is projected to reach $1.2 trillion by 2020 9. Sales of pharmaceutical drugs are projected to grow at an annual rate of 4.4% driven by aging population and increasing healthcare spending globally. The United States remains the world’s largest market for prescription medicines with sales of $310 billion in 2015 and projections to reach $400 billion by 2020 15. The industry is under increasing pressure from regulators and other stakeholders in terms of pricing, marketing, lack of transparency and increasing concerns about its environmental impacts. The sector comprises four main segments1: a) Innovative pharmaceutical industry (large multinational companies such as Pfizer, Novartis, and Merck, which typically produce chemically derived drugs that undergo in-vitro and in-vivo testing and human clinical trials); b) Biopharmaceutical industry (companies which produce medical drugs from life forms (biologics) that include proteins, and nucleic acids used for therapeutic or in-vivo diagnostic); c) Biologics (companies focused on making products such as vaccines, therapeutic proteins, blood and blood components, and tissues); d) Generic pharmaceutical industry (companies involved in making copies of drugs upon expiration of their patents, which have the same API and are identical in strength, dosage form and route of administration).16

1

While some companies include subsidiaries with some or all of the above forms, their classification is based on their primary activity.

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Generic drug sales have experienced significant growth and in 2015 reached $79 billion globally with projections of increasing to $112 billion by 20209. According to IMS Health in 2014 generic drugs dispensed represented 88% of all drugs in the U.S., saving health care payers $254 billion, and projected to grow further to 92% by 2020 17. While innovative pharma companies are under increasing pressure to reduce drug costs, the cost to bring a new drug to market continues to grow, increasing from $1.188 billion on average in 2010 to $1.539 billion in 2016. In 2016 more than 7,000 drugs and treatments were reported in development globally, yet just 22 were approved by the U.S. Food and Drug Administration (FDA), down from 45 in 2015 and 56 in 2014 18. Environmental impacts and regulations Sheldon (1994) was the first to report that the pharmaceutical industry generated the most waste per unit of product compared to other chemical industry sectors - between 25 kg and 100 kg of waste per kilogram of API compared to bulk chemicals which generated less than 15 kg of waste per kg of product and fine chemicals which generated between 5 kg and 50 kg of waste per kg of product18. This metric called E-factor (or environmental factor), has since become a key indicator for tracking environmental and efficiency improvements by the pharmaceutical industry. Recent research has found that on average pharmaceutical companies use about 120 kg of material for making 1 kg of API and the majority of waste generated (~80%) is solvent6, 19-20. In addition to manufacturing waste, concerns are rising globally about the environmental impacts of pharmaceuticals themselves21-24. A 2002 study by the U.S. Geological Survey (USGS) found organic wastewater contaminants, including many pharmaceutical and personal care product contaminants, in 80% of 139 streams sampled in 30 states25. Such contaminants are result of not just manufacturing release but even more from the daily use and excretion of APIs, some of which are classified as endocrine disruptors22-23. While there is strong evidence of the environmental impacts of such micro pollutants on a range of species, there are still uncertainties regarding the potential human health impacts.21-25, 82-83 Globally there is increasing focus on this problem and potential solutions26, 34, 85. The issue of post-use APIs accumulating in the environmental media, however, is outside the scope of this study. The global pharmaceutical industry is subject to various environmental regulations. The U.S. FDA, for example, is required under the 1969 National Environmental Policy Act (NEPA) to evaluate the potential risks for “significant environmental impacts of proposed drugs or additives using fate, exposure, and effect data”27. Similarly, in the European Medicines Agency (EMA) requires through Article 8(3) of Directive 2001/83/EC the evaluation of the potential environmental risks posed by medicinal products to be submitted, their environmental impact to be assessed and, on a case-by-case basis, to consider specific arrangements to limit the potential impacts28. Other global drug regulatory agencies are developing similar protocols. Manufacturing APIs is covered under chemical manufacturing regulations such as the Toxics Substances Control Act (TSCA) in the U.S.29, and the Registration, Evaluation and Authorization of Chemicals (REACH) in the EU30. Recent studies have reported a steady decline in Toxics Release Inventory (TRI) releases from the pharmaceutical industry that correlates with the adoption of green chemistry by the U.S. pharmaceutical industry8,31. For instance, during the period 2001 – 2009, the pharmaceutical industry in the U.S. showed a 79% reduction in TRI 4 ACS Paragon Plus Environment

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normalized emissions and 73% reduction in total waste, compared to 27% and 15% reductions, respectively, for the manufacturing industry8. Other factors such as the FDA and EMA guidance on residual solvents, may also be responsible for some of the observed TRI reductions32. Despite such declines in the U.S., environmental releases in India and China continue to be a major issue as outsourcing of drug development and manufacturing to these low cost countries accelerates. A 2007 study of the effluent from a wastewater treatment plant serving 90 bulk drug manufacturers near Hyderabad, India, found concentrations of antibiotics such as ciprofloxacin exceeding levels toxic to some bacteria by over 1000-fold33. Researchers, NGOs, and policy makers have called for action by the pharma industry to address the environmental performance of their entire API supply chain34-36. In 2011 the Swedish Medical Products Agency proposed a new EU Regulation to set ceilings for emissions from the manufacturing of pharmaceutical substances that present environmental risks and incorporating these in the EU’s Good Manufacturing Practices (GMP) guidelines. The agency is working with its counterparts in China, India and the U.S. to encourage global actions37. Pharmaceutical industry and green chemistry Tucker (2006) offers a definition for pharmaceutical green chemistry – “the quest for benign synthetic processes that reduce the environmental burden… within the context of enabling the delivery of our current standard of living”38. He believes GC is driven by efficiency coupled with environmental responsibility and “requires a new priority and intent” and “a higher level of environmental stewardship”. Green chemistry calls for the use of renewable chemicals as building blocks and reagents (Principles 7 and 9; see Text Box 1). A recent practice becoming increasingly popular among big companies is biocatalysis, or the process of using enzymes as catalysts in chemical reactions. Enzymes are naturally occurring living organisms often referred to as “nature’s catalysts.” In a recent study 52% of participating companies and 68% of “big pharma” reported high interest in this area4, which also helps reduce costs and risks2. Furthermore, enzymes can help reduce the number of steps and increase reaction throughput leading to a significant reduction in the time to manufacture –in some cases by 80% 39-40. Catalysts derived from rare earth metals are becoming increasingly expensive and hard to obtain78-79, so a move to biocatalysis is a logical way to address the shrinking availability of metal catalysis. GC calls for using safer chemicals to minimize accidents (Principle 12) and a common practice in the pharmaceutical industry is the shift to less toxic solvents, which make up more than 80% of the material used for API manufacture and are associated with about 60% of the overall energy use and 50% of greenhouse gas (GHG) emissions12. Green chemistry also requires energy-efficient design (Principle 6, Text Box 1) and a growing number of pharmaceutical companies have begun to use their carbon footprint as a new green chemistry indicator. While all 12 GC principles have been used by many sectors to guide development of safer and more efficient processes, some of these principles do not work well for the pharmaceutical industry. Pinto and Silvestre (2014) argue that Principle 4 (design safer chemicals and products) is not applicable to the pharmaceutical industry since “medicinal products are precisely characterized by their pharmacological activity”41. One example is cancer drugs which are 2

Typical catalysis often includes rare earth metals such as palladium which are not only costly but present a range of sociopolitical risks as supply is controlled South Africa, Russia and China.



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designed to be toxic to tumors. Principle 10 (design for degradation) is also challenging for the pharmaceutical industry since to pass FDA approval drugs must show that they are stable in under manufacturing, storage and patient use conditions38,41. Principle 7 (use of renewable raw materials) cannot always be applied as in most cases synthetic routes have been designed using available building blocks typically from non-renewable sources41. To encourage integration of green chemistry and engineering principles into the pharmaceutical industry, the ACS GCIPR has supported the development of tools such as Reagent Selection Guide, Solvent Selection Guide, Process Mass Intensity Calculation Tool, and Product Mass Intensity-Life Cycle Analysis Tool. The Roundtable provides grants to universities and research centers for green chemistry research and is actively involved in policy discussions in the U.S. and the EU. Its four strategic priorities are: a) to inform and influence the research agenda, b) to provide tools for innovation, c) to provide educational resources, and d) to promote collaborations42. Another group focused on advancing green chemistry in the pharmaceutical industry is the Green Chemistry Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) which was established in 2010 and includes 32 members43. IQ analyzed the factors behind establishing an effective GC program and developed a framework of seven key elements required for implementing such a program: 1) Empowered green chemistry teams with management support; 2) Metrics and targets; 3) Resources and tools; 4) Education; 5) Awareness and recognition; 6) Investment in green technology; and 7) External collaborations. This framework has been used to establish effective GC programs as well as benchmark industry practices using publicly available data5. The ACS GCIPR and some of its members are also actively involved in the EU Innovative Medicine Initiative (IMI) and the recent CHEM 21 initiative (Chemical Manufacturing Methods for the 21st century pharmaceutical industries) which has committed €26.4 million to the development of “a range of methods to make the drug development process more environmentally friendly,” which would not only be good for the environment but “also help the pharmaceutical industry to cut costs, resulting in cheaper medicines for patients”44. Most large pharmaceutical companies are members of the Pharmaceutical Industry Supply Chain Initiative (PSCI) which has the mission “to provide members with a forum to establish industry principles that guide ethics, labor, health and safety, environmental sustainability, and management systems practices to support continuous improvement of suppliers’ capabilities“11. As of 2017 PSCI had 24 members including most “big pharma” companies such as Pfizer, Allergan, Novartis, Bristol-Myers Squibb, and Sanofi. Green chemistry drivers Research has found that both internal (top management commitment, cost savings) and external (regulatory requirements, stakeholder pressures) are driving greater adoption of GC by the pharmaceutical industry40. With the pressures to reduce prices cost savings from GC are becoming increasingly important6-7. Such savings stem from more efficient production, reduced energy and material costs, waste disposal fees, improved employee health and safety, and lower


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insurance premiums. For instance, Merck reported an estimated annual savings of $14 million from the improved process for Primaxin® 6. The increasing environmental legislation globally has been reported as an important driver for the adoption of GC by the pharmaceutical industry5,41. As discussed earlier these include European Union REACH directive, U.S. TSCA and NEPA, and incentive schemes such as the Swedish National Pharmaceutical Strategy (NPS). The latter directly calls for reducing the environmental impacts of pharmaceuticals and reporting materiality analysis, carbon footprint and other environmental metrics45. Sustainable, responsible and impact (SRI) investors have become a major driver for changing corporate behavior. In the U.S., assets under SRI management increased from $3.74 trillion in 2012 to $8.72 trillion in 2016, representing more than 1 in 5 dollars under professional management46. These investors continue to demand improved corporate sustainability performance and to file shareholder resolutions at public companies for environmental, social and governance issues. Large customers such as government and hospital associations are increasingly requesting more information on sustainable practices. In the United States, Practice Greenhealth is leading its member organizations to adopt sustainability in the healthcare sector with a focus on preventing waste, reducing energy and water, and promoting green procurement47. In 2012 it launched the Healthier Hospitals Initiative, a U.S.-wide effort to help healthcare organizations commit to sustainability goals and track their environmental efforts in six areas: engaged leadership, healthier food, leaner energy, less waste, safer chemicals and smarter purchasing48. The pharmaceutical industry continues to have poor reputation among key stakeholders. Research has shown that only 26% of young people approve the industry which has major implications for attracting and retaining talent38, 49. Good reputation is associated with many business benefits; for instance research has found that a one-point increase in the reputation of a pharmaceutical company would lead to: a) additional 28,000 patients asking their doctors about the company’s drugs; b) 3.33% increase in the company sales; c) 0.23% increase in the company’s market capitalization; d) 0.5% increase in policy-makers supporting favorable industry policies; and e) more than 5.7 million people likely to support the industry in a crisis50. Green chemistry metrics To measure progress in advancing green chemistry, the pharmaceutical industry has developed and implemented several metrics, including effective mass yield, E-factor, atom economy, mass intensity, carbon footprint and reaction mass efficiency51-53. In 2012 Pfizer became the first pharmaceutical company to publicly disclose its green chemistry metrics54 and since then other companies have followed suit. One of the most cited and widely-used metric for demonstrating the business case for green chemistry is the E-factor18, which despite its wide use has several limitations. First, it can be calculated with or without including the process water which creates issues with comparability and effectiveness. (A recent study found that solvents and water represent 58% and 28% of process waste, respectively, thus presenting a significant source of waste in pharmaceutical 7 ACS Paragon Plus Environment


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manufacturing55.) Second, E-factor has been associated with the end-of-pipe processes and focus on waste generated rather than the more preferred approach of waste prevention56. Another commonly used metric is Process Mass Intensity (PMI), which measures the ratio between the mass of all materials used to make a product and the mass of the product. An ideal process would have a PMI of 1; PMI is also related to E-factor since E-factor = PMI – 1. PMI is a leading indicator (compared to E-factor which is lagging); it is easy to generate and compare, and easy to apply by chemists and engineers56. It does not however, address concerns over environmental, health and safety of used materials. Another green chemistry metric is atom economy which was first proposed by Trost in 1991. It is defined as the ratio of the molecular weight of the desired product and the molecular weight of all products, converted into percent57. While simple this metric has some limitations - it does not take into consideration reaction yield or stoichiometry, and does not count the amount of solvents or other reagents in the reaction. Additional green chemistry metrics used by the industry and reported in the literature include: number of steps, carbon efficiency (CE), and reaction mass efficiency (RME)51. A more recent GC metric used by increasing number of companies is carbon footprint, which measures the carbon emissions for APIs over their entire life-cycle including manufacturing, transport and distribution, formulation and packaging, retail and use phase, and final disposal of packaging.58 For example, to better understand the most significant impacts of its blockbuster drug Lyrica® over its life cycle, Pfizer initiated such assessment and found that 90% of the environmental impacts were during manufacturing (including transportation of raw materials), 5% during formulation, 5% during packaging and less than 1% a result of distribution and endof-life management. Measuring the carbon footprint of the redesigned drug showed significant improvements, including 92% reduction in solvent use, 100% reduction of mandelic acid, 82% reduction in energy use (equivalent to taking 500,000 U.S. cars of the road for a year), 81% reduction in water use, and E-factor reduction from 86 to 97. Two limitations of this metric include its complexity and the data gaps in life cycle inventory information on complex organic materials56. Despite the number of GC metrics adopted by the industry there is still a need to develop a set of metrics that address all 12 Principles of Green Chemistry and remain simple enough to cater to decision-makers56. Roschangar et. al. (2015) recently proposed a new aggregate green chemistry metric called the Green Aspiration LevelTM concept and recommended introducing government regulations that mandate reporting of GC metrics55. Green chemistry in China and India China and India have emerged as the leading markets for manufacturing API and R&D outsourcing due to their cost advantage and highly educated workforce. In addition, as sales of pharmaceutical drugs slow in developed countries, they are projected to increase in many emerging markets. Between 2005 and 2015 China moved from the ninth largest national pharmaceutical market to the third largest. Its pharmaceutical industry is highly fragmented with more than 5,000 companies of which 98% make generic drugs10. China is the world’s number one exporter of APIs and in 2010 had 1,200 API manufacturers able to make more than 1,500 8 ACS Paragon Plus Environment

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categories of APIs. The Chinese government is expected to invest $761 million by 2020 to increase the country’s export value of APIs by $4 billion annually10. Green chemistry and engineering have grown rapidly in China and India over the past decade6061 . Chinese companies are increasingly embracing GC driven mostly by government energy efficiency policy, stricter enforcement of environmental standards, and national focus on cleaner production and circular economy60. A review of the state-of-the-art green chemistry research in China reported a range of innovations in the fields of catalysis, alternative solvents, biopolymers, green flame retardants and biomass utilization62. The main challenges facing Chinese pharmaceutical companies involve improving quality standards and operating procedures, improving efficiency in manufacturing and reducing environmental impacts. These are all critical issues for these companies as failure to comply with existing standards would prevent them from manufacturing and selling drugs63. Research has reported seven main barriers to development of GC and engineering in China: a) the competing agenda between economic growth and environmental protection, b) regulatory and bureaucratic barriers, c) lack of research funding, d) technical barriers, e) lack of sufficient expertise, f) lack of industrial engineering capacity, and g) economic and financial barriers62. India has also become increasingly important market for making API and generic drugs and the country is aiming to surpass China as the top supplier for “big pharma”. Its pharmaceutical industry is also highly fragmented with about 1,300 companies where the top 10 represent approximately 34% of the market share64. Environmental pollution from drug manufacturing, however, remains a significant problem and current efforts are focused on end-of-pipe treatment and considered inadequate to address the issues64. According to Kidwai (2001) government must introduce and enforce stricter environmental standards and increase funding for green chemistry research and education65. Mehta (2014) reports six main barriers to implementation of GC in India61: a) lack of available green technologies, b) scale-up and commercialization, c) lack of connection between GC solutions providers and industry, d) limited knowledge of the basic principles of GC and engineering, e) the myths that GC is difficult and complex and thus not viable for small and medium size companies, and f) regulatory hurdles, or the time and cost involved in filing a new Drug Master File (DMF) application when a change in the manufacturing process is made. Barriers and future opportunities Research has identified several main types of barriers to greater adoption of green chemistry such as economic, financial, regulatory, technical, organizational, and cultural55, 66. Among these, the pressures to deliver drugs faster have been reported as a major barrier to greater adoption of GC by the industry4,55. According to Juan Colberg at Pfizer, “Generally, researchers used to have two to three years to invent a synthesis; now the industry average is closer to six months”7. Several studies have outlined regulatory risk as a major barrier to greater adoption of GC5,38,40,67. In 2012, the IQ Consortium identified two “perceived” regulatory hurdles: second generation manufacturing route development, and manufacturing route development pre-NDA filing (New Drug Application). In the first case, if a company decides to redesign a drug that is already on the market, it must re-file for FDA approval, which the study found “could 9 ACS Paragon Plus Environment


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theoretically lead to the loss of already approved status on a marketed medicine”. In the second case, a company files for FDA approval, which can take years. If any innovative techniques are developed while the filing is pending, companies must forego the innovation as they are “locked” into the filing process. Any changes in the manufacturing process are perceived as risky and amendment of the filing may lead to longer approval time67. Besides the perceived risks of regulatory approval, the process of redesigning an existing drug can be burdensome and costly5,40,56. The time for regulatory approval, for instance, varies widely globally and can take anywhere from a few months to a few years53. This means that while approval of a redesigned drug is pending, a company must keep track of multiple inventories for two to three years. This creates substantial financial and operational impediments for the development of second-generation programs. As reported by Tucker (2006) “scientists are currently rewarded on API delivery or quantity as opposed to relative quality or efficiency” 40,68. Addressing this challenge requires top management education and understanding the business benefits of GC so new award systems for scientists are put in place. While green chemistry has been shown to reduce costs, there is still the challenge of upfront investment in green technology that can be a barrier to many pharmaceutical companies, especially the smaller ones. The cost of new solvents, reagents and instruments could be higher than for conventional technologies69. According to Cui et. al. (2011)62 and Sheldon (2017)70 future advances in GC require simultaneous application of all GC principles and better tools and metrics that measure the impacts over the entire lifecycle of a drug or API in order to avoid tradeoffs between different impacts such as energy efficiency and use of hazardous chemicals. Tucker (2010)68 summarizes three opportunities for greater adoption of GC by the industry: a) improving engagement and support of business and academic leaders, b) enhancing education and technical guidance, and c) adopting “proactive and pragmatic regulatory policies. Anastas and Allen (2016)71 report on the main achievements of GC over the past 25 years and believe the next 25 years must focus on greater integration of GC in chemistry and engineering education, increasing government investment, and capital and operational investments by companies. There is a need for a “fast track” in regulatory approval of process changes involving GC to help overcome one of the greatest barriers faced by the pharmaceutical industry61,68. Study design and method To conduct the study the researchers designed a 22-question survey to benchmark current practices, main barriers and future opportunities for greater adoption of GC by the pharmaceutical supply chain. Most benchmarking categories were based on the IQ Green Chemistry working group framework for effective green chemistry (GC) program43, and included questions about publicly stated commitment to GC, sustainability goals and targets, GC principles, use of metrics, system of governance, use of resources and tools, education and training, investing in green technology, external collaborations and measures of success. Additional questions were added to gauge the main barriers and drivers for GC adoption as well as current supply chain practices. The research team used a non-probability convenience sample 10 ACS Paragon Plus Environment

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survey. All survey questions allowed for quantitative analysis (% of sample population) to be used for actionable recommendations. The sample was developed to include sufficient number of companies in each of the four pharma segments and included 76 companies of which 16 “big pharma” (companies with 2015 sales greater than $10 billion), 13 smaller R&D pharma (companies with 2015 sales of less than $10 billion), 18 generic drug manufacturers and 29 API manufacturers. The online survey was conducted between October 2016 and January 2017. Email invitation and two reminders were sent to directors and senior executives in charge of Manufacturing, Research and Development (R&D), and Environmental, Health and Safety (EHS), known to be involved or leading green chemistry initiatives. A total of 34 companies completed the survey (45% response rate), including 13 “big pharma” (81% response rate), 5 smaller R&D pharma (38% response rate), 4 generic pharma companies (22% response rate) and 12 API manufacturers (41% response rate) (see Text Box 2). Text Box 2. Companies participating in the green chemistry survey, January 5, 2017

As incentive for participation in the survey respondents were offered a copy of the study report. Results were analyzed with SPSS Version 20. In addition to analyzing aggregate results for each question, the authors created two categories for additional analysis: a) “big pharma” companies, and b) “other” pharma, including small R&D pharma, generic drug manufacturers and API manufacturers. Such grouping was chosen for several reasons: a) previous research has found that “big pharma” companies at large have adopted GC practices while no such indication exists for other pharma companies5 which have also been absent from GC conferences and publications; b) combining API manufacturers with generic pharma is based on existing reports about environmental waste problems faced by both groups, primarily in India and China, and c) given the lower number of responses from generic pharma and small R&D pharma, combining several segments ensured results validity.



Results and discussion Only 11% of the survey respondents were not familiar with their company’s GC efforts (4 companies) and 8.8% were a little familiar; the rest of the respondents reported either leading such efforts (29.3%), very familiar (23.5%) or familiar (26.5%) with their company’s GC activities. Fifteen of the companies in the study were based in the U.S., seven in the EU, six in India, three in China, and two in the UK. Results revealed that 41% of companies in the study had publicly stated commitment to GC; however this number is much higher for “big pharma” at 77%, compared to 19% for the rest (small R&D pharma, generics and API manufacturers; 14% of companies did not know), confirming previously reported lack of public disclosure by some segments5. The most common sustainability goal reported by participating companies is on energy use/reduction (77%), followed by GHG emissions, water use and waste water reductions (each at 59%) (see Figure 1). Over half (53%) of respondents have sustainability goals related to toxics use reduction. Among large R&D companies, 93% have goals related to GHG emission reduction, 79% for energy use reduction and 71% for water use reduction, compared to “other pharma” where 75% of companies have energy reduction goals, 60% waste water reduction goals and 50% have toxics use reduction goals (e.g., reducing solvent use). Figure 1. Environmental/sustainability goals Does your company have environmental/sustainability goals or targets? (34 responses) 77% 59%

53%

59%

59% 38% 21%

Other (please specify)

We have goals/targets related to renewables/alternativ…

We have goals/targets related to energy use reduction

We have goals/targets related to waste water reduction/zero liquid…

We have goals/targets related to water use reduction

We have goals/targets related to toxics use reduction (e.g.,…

9% We have goals/targets related to Greenhouse Gas (GHG)…

90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

We do NOT have any environmental/sustain ability goals or targets

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Information about sustainability goals is most often captured at Phase 1, Phase 2 and drug discovery stages (see Figure 2), with 64% of “big pharma” reporting data collection at Phase 1 and 57% at Phase 2, compared to the rest of companies where 35% collect such sustainability information during drug discovery and 15% at Pre-clinical/IND.


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Figure 2. Drug development stages where sustainability information is gathered If you have environmental/sustainability goals at which stage of R&D or goals? commercial sales do you capture information related to these goals (31 responses) 36% 29%

26% 13%

13%


19%

Post-ANDA annual updates

NDA approval/product…

NDA preparation

Phase 3

Phase 2

Phase 1

16%

ANDA preparation

29% 23%

Post-NDA annual updates

36%

32%

Pre-clinical/IND preparation

40% 35% 30% 25% 20% 15% 10% 5% 0%

Drug discovery

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All participating companies report using the GC principles most in chemical development (93% of “big pharma” and 60% of others), followed by manufacturing (57% of “big pharma” and 55% of others), and synthetic API (43% of “big pharma” and 30% of other pharma). The study revealed that majority of the companies use cross-functional team to lead their GC initiatives (71% of large R&D companies and 35% of others). Fourteen percent of large R&D companies reported having a full-time GC leader. This demonstrates the growing importance of establishing a formal governance structure as a 2012 study found that 55% of “big pharma” had a designated person or a committee leading GC initiatives4. R&D is most often in charge of leading the GC initiatives as reported by 61% of all companies (79% of “big pharma” and 45% of others), followed by Environmental Health and Safety (EHS) reported by 49% of companies (43% of “big pharma” and 50% of others) and Manufacturing, reported by 30% of respondents (21% of “big pharma” versus 35% of others), which confirms previous research and demonstrates that GC is often integrated with the core business strategy4. While metrics are crucial for tracking progress and improving GC implementation over time, the study revealed that 27% of participating companies do not use any GC metrics (see Fig. 3) The top three metrics used by large R&D companies include: PMI (71% of respondents), GHG emissions (50%) and LCA and carbon footprint (36%). Among “other pharma”, the top metrics reported include PMI, E-factor and number of steps (each reported by 25% of companies), followed by GHG emissions and carbon footprint (each at 20%). These findings demonstrate that PMI has emerged as the preferred metric by all segments and that GHG emissions and carbon footprint are becoming increasingly important metrics for the entire supply chain as result of global policy actions and regulations to reduce energy use and related climate change impacts. Figure 3. Use of green chemistry metrics by study participants 13 ACS Paragon Plus Environment


Do you use metrics to track the "greenness" of your manufacturing process? (34 companies) 44% 32% 27%

27%

27%

27%

21% 12%


We use GHG emissions

We use number of steps per…

We use carbon footprint

We use lifecycle analysis…

We use atom economy

We use Process Mass…

6%

We use Efactor

50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0%

We do NOT use any metrics

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The most widely used GC tools as reported by participants include: Solvent Selection Guide (100% of “big pharma” and 57% of others), Reagent Guide (85% of “big pharma” and 38% of others) and PMI tool (77% of “big pharma” and 38% of others). These results confirm previous findings that “big pharma” companies are using to a larger extent GC tools in design and manufacturing 4-5, 72-77. The results, also demonstrate that while small R&D pharma, API manufacturers and generic drug companies have not provided public information about their efforts, many have invested in a range of tools and metrics, a hypothesis suggested by Veleva and Cue (2017)5. The extent of their investment presently is lower, most likely due to resource limitations and lack of external pressures. Providing GC education and investing in green technology are critical for getting chemists and engineers to implement such practices. Yet one in five respondents (21%) reported that their company does not educate employees about GC (see Fig. 4). Among the educational offerings, internal lectures on GC are offered by 64% of “big pharma” companies in the study and 40% of other pharma. Forty three percent of “big pharma” and 30% of other pharma segments report supporting GC training of scientists and researchers such as taking courses at local colleges or attending conferences. Fifty-seven percent of “big pharma” and 20% of other pharma report including GC updates in their company’s newsletter. While all “big pharma” report investing in green technology to some extent, 24% of “others” report not investing in green technology at all (see Table 1). Figure 4. Support for GC education


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50% 35%

35%

29%

24%

21%


We have an internal GC award/recognition program

We support scientists/researcher s training in GC (e.g., at local…

We include GC highlights/updates in our company newsletter

We offer eLearning opportunities in GC

15%

We offer internal lectures on GC

60% 50% 40% 30% 20% 10% 0%

Does your company support GC education and awareness? (34 companies)

We do NOT educate our employees about GC

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Table 1. Investing in green technology, Large R&D pharma vs. Others Q1: What is your company business type: Large R&D Pharma Q11: To what extent does your company invest in green technology? (e.g., biocatalysis, solvents and catalyst recycling)

Total

Not at all

Others

Total

23.8%

14.7%

Small

30.8%

23.8%

26.5%

Moderate

46.2%

33.3%

38.2%

Large

15.4%

14.3%

14.7%

Very Large

7.7%

4.8%

5.9%

100.0%

100.0%

100.0%

More than half (60%) of the companies in the survey reported having some external collaborations, such as participation in the ACS GCIPR, PSCI, IQ Consortium, research projects with universities or other companies. Analysis of publicly available data revealed that 14 of the companies in the study are members of ACS GCIPR and 14 are members of PSCI (see Text Box 2). All “big pharma” in the study report involvement in external collaborations compared to 32% of other pharma (58% of “others” report no external collaborations).



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While 36% of study participants manufacture their own drugs, the rest either buy them or both manufacture and buy from suppliers. Slightly over half (51%) of all companies in the study have some requirements for suppliers such as: a) criteria/guidelines for selecting supplier based on their environmental performance (57% of large pharma vs. 20% of others); b) voluntary environmental reporting for suppliers (21% for “big pharma” vs. 40% for others), and c) rate suppliers for their environmental performance (29% of “big pharma” vs. 15% of others) (see Fig. 5). This finding confirms the growing importance of supply chain management and the efforts by the industry to implement supplier guidelines, reporting and rating similar to other sectors. Figure 5. Supplier requirements – “big pharma” versus “other” pharma Supplier requirements - "big pharma" vs. other pharma (23 companies) 57%

60% 50% 40% 40% 29%

30% 21%

20%

20%

15%

10% 0% We have voluntary environmental reporting for suppliers

We rate suppliers for their environmental performance

Big pharma

We have criteria/guidelines for selecting supplier based on their environmental performance

Others

Both large R&D pharma and other pharma seem in agreement when it comes to the greatest barrier to wider adoption of GC being the time pressures to deliver new drugs (see Fig. 6), cited as #1 barrier by 43% of “big pharma” and 25% of other pharma. Additional barriers for “big pharma” include the upfront costs of implementing GC and lack of mandates/pressures (each at 29%). Other pharma reports regulatory risk (30%) as the #1 barrier, followed up by the time pressures to deliver new drugs (25%) and the lack of customer demand, pressures and expertise in GC (each at 15%). This finding confirms previous studies which have reported the time pressures and regulatory risks (either real or perceived) as key barriers to greater adoption of GC4-5. They also demonstrate that availability of green technology is not a top barrier for Indian companies as previously reported61. Only two “big pharma” and two other pharma reported the lack of available green technology among the top 3 barriers facing their companies.


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Figure 6. Barriers to greater adoption of GC by the pharmaceutical supply chain

Top 1 Top 2

Lack of expertise in GC

Lack of customer demand for green…

Lack of mandates/pressur…

Lack of proven GC technology at…

The lack of available GC…

Lack of awareness of GC…

Time pressures for delivering new…

The upfront cost of implementing GC

Buy-in from R&D/Manufacturing

Lack of mid-level management…

Top 3

Lack of top management…

20 18 16 14 12 10 8 6 4 2 0

What are the main barriers you see within your company to apply green chemistry (re)design in your manufacturing processes (please select Top 1, Top 2 and Top 3) (33 companies)

Regulatory risk (e.g., FDA, EMEA,…

Cost savings and environmental regulations are reported as the two most significant drivers for GC adoption by the industry (see Fig. 7). For large R&D pharma the top three drivers are: cost savings (50%), regulation (43%) and reputation (36%). Not surprisingly, for other pharma regulation is the most significant driver reported by 50% of participants as Top 1 and by 20% as Top 3, followed by customer demand (35%) as Top 2. This confirms previous studies outlining the importance of regulatory mandates for generic drug companies and API manufacturers which are almost entirely compliance driven and experience few pressures from investors and NGOs5,60,65. The study further confirms the importance of cost savings for all pharma segments and the significance of reputation as a driver for GC investments by large R&D companies6-7. Figure 7. Main drivers for adopting GC by pharmaceutical companies In your view, what are/would be the main drivers for your company to adopt GC? (please select the top 3) (34 companies) 35 30 25 20 15 10 5 0

Top 1 Top 2


Ability to attract and retain talent

Investor pressures

Reputation

Customer demand

Regulation (e.g., mandates for water quality; green…

Top 3

Cost Savings

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These GC drivers align with the most significant outcomes of GC programs reported by participating companies (see Fig. 8). Cost savings are reported as the most significant measure of success by all “big pharma” (93%) and 85% of other pharma. Two other important measures of success include capacity savings (57% and 54% for “big pharma” and others, respectively) and awards/external recognition (50% and 46%, respectively), confirming previous research7. Figure 8. Most significant outcomes of GC program What are some significant outcome/measures of success from your green chemistry program (34 companies) 82%

44%

41%

15%


Capacity savings

Awards/external recognition

12% Cost savings

90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

NA (we do not use green chemistry)

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Conclusion and recommendations The main contribution of this paper is that it provides the first benchmarking study of GC adoption by the entire pharmaceutical supply chain based on information from industry representatives leading such efforts in the U.S., Europe, China, and India. The findings confirm previous research that “big pharma” has established effective green chemistry programs well integrated with the business strategy, with clear goals, metrics of success, external collaborations and internal support. The study found that 77% of “big” pharma have publicly stated commitment to GC, 85% report having cross-functional team or a GC leader to advance such efforts, all of them use GC tools and metrics, invest in GC technology and are involved in external collaborations. While generic drug companies, small R&D pharma and API manufacturers have not embraced GC to such an extent and have not publicly disclosed much information, the study demonstrates that they are showing significant interest and some advances in this area. The research found that 19% of these companies have publicly stated commitment to GC, 35% use cross-functional team to lead GC efforts, 57% report using some GC metrics with the top three including PMI, E-factor and number of steps, 76% report some level of investment in green technology, and 32% have some external collaborations (typically including partnerships with universities). Many of these


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companies report utilizing publicly available GC tools such as Solvent Selection Guide (57%), Reagent Guide (38%) and PMI tool (38%). The study found that time pressures to deliver new drugs and regulatory risk are the top two barriers to greater adoption of GC by the pharmaceutical supply chain. Thirty percent of “other” pharma report regulatory risk as their main barrier, which confirms previous research regarding the potential risk (real or perceived) from re-filing for regulatory approval of a previously approved drug. In addition, 29% percent of “big pharma” and 15% of “other” pharma report the lack of mandates and pressures for green chemistry adoption as a major barrier. Cost savings and environmental regulations were cited as the top two drivers for adopting GC by the study participants. While there are no mandates for green chemistry adoption by the sector (for example California Green Chemistry Initiative currently excludes drugs from its list of consumer products), many current environmental regulations indirectly promote the adoption of such practices (e.g., REACH, TSCA, NEPA, the Swedish incentive scheme). The study demonstrates that despite the lack of global GC regulation, the practice has become increasingly important not just for “big pharma” but also for small R&D pharma, generic drug manufacturers and API manufacturers, as a way to reduce costs and environmental risks, improve reputation and market positioning. For instance, 93% of “big pharma” and 85% of “other” pharma report cost savings as their most important measure of success; followed by capacity savings (57% and 54%, respectively) and awards and external recognition (50% and 46%, respectively). Future opportunities to expand GC adoption by the entire supply chain include greater adoption of tools and metrics, government mandates for greening drug manufacturing and increasing customer demand for “green” drugs. In addition, adoption of standardized GC requirements for suppliers by the entire sector and public disclosure of suppliers’ performance, is critically important. The research has several limitations. First, due to the limited resources the study involved 34 companies; future research should aim to include a larger number of companies in order to allow for additional analysis and comparisons. Second, due to the lower response rate by generic drug manufacturers and small R&D pharma it was not possible to do separate analysis for these segments. Third, the study did not include any survey questions to examine the important issue of pharmaceuticals in the environment (PIE). Finally, using a survey for data collection presents some inherent limitations such as data reliability and validity, potential bias of respondents who choose to participate in the survey, or incorrect answers due to limited knowledge on particular issue. While the research team carefully selected the participants and designed the questions to be specific and non-subjective, it is recommended that future research includes additional data collection methods such as interviews and publicly available data. Based on the literature review and study results the authors see the need for the following actions to advance GC adoption by the entire supply chain: • Harmonize global environmental regulations similar to the quality regulations between FDA/EU and Japanese agencies in the 1990s; for instance initiate an ICH-like approach to common global environmental guidelines for benign manufacture with globally agreed upon critical environmental parameters (CEPs) as proposed by previous studies.6, 32, 80



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•

•

•

•

•

•

Implement a “fast track” or other more streamlined approval for drugs with GC to eliminate the regulatory risk (perceived or real) as proposed previously 5, 52, 65. Such a strategy could help address one of the top barriers reported by the study participants – regulatory risk (e.g., FDA, EMEA, DMF) (see Figure 6). A “fast track” approval is also consistent with the triple bottom line approach of minimizing environmental impacts, while promoting social benefits (access to life-saving medicines) and economic success (reducing the costs and risks for companies designing drugs with green chemistry). The generic drug user fee amendment (GDUFA) has established goals for accelerating approval of generic drug ANDA amendments.81 Perhaps expanding these goals to include prior approval supplements (PAS) for green chemistry API process improvements represents such an opportunity. Incorporate environmental considerations into GMP guidelines as proposed by the Swedish Medical Products Agency to drive changes along the entire supply chain.36, 37,45 Based on the study findings the authors propose promoting a wider use of LCA by the entire supply chain by incorporating LCA training in organic chemistry education and providing free tools for chemists and engineers. We are aware that a user-friendly LCA tool is being developed by the ACS GCI Pharmaceutical Roundtable and we encourage them to share it broadly within the synthetic chemistry community as they have done with other tools in the past. Introduce new incentive schemes similar to the Swedish initiative, to educate large customers such as hospital associations and government purchasing entities, on the environmental and health benefits of “greener” drugs and thus increase customer demand.45 Based on the study findings, the authors propose to establish clear and publicly stated criteria for supplier environmental performance, conduct assessments and audits, and promote greater transparency by reporting the site of origin of APIs and suppliers’ environmental performance. There is a need to provide suppliers with training and tools to advance GC practices as they often have limited expertise and resources. Finally, the authors see the need to conduct additional research specifically focused on generic drug companies and API manufacturers in China and India to better understand their current practices, barriers and emerging opportunities for wider adoption of GC practices.

This study demonstrates that 25 years after the emergence of green chemistry and 12 years after the creation of the ACS GCIPR, a small fraction of the companies in the global pharmaceutical supply chain have adopted GC in a strategic way. While “big pharma” to a large extent has implemented GC as part of their business strategy this is not always the case for smaller R&D companies, generics and API manufacturers which have made some advances but report much lower level of investment in GC metrics, tools, and education. With the increasing outsourcing to low cost countries like China and India and the shift to generic drugs, the real impact of green chemistry on the environment will come from applying such practices along the entire supply chain. Acknowledgments The authors would like to thank Steven Meszaros and Anabel Buchan Sitrangulo with the Pharmaceutical Industry Supply Chain Initiative (PSCI), and Nitesh Mehta and Krishna Padia 20 ACS Paragon Plus Environment

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with Newreka and Green ChemsTree Foundation, India, for their support promoting the survey among member companies. References 1. U.S. EPA, 2015, “Green Chemistry”, available at: http://www2.epa.gov/green-chemistry accessed June 21, 2017. 2. Anastas, P. and J. Warner, 1998, “Green Chemistry: Theory and Practice”, Oxford University Press: New York, 1998. 3. U.S. EPA, 2017, “Presidential Green Chemistry Challenge Winners”, available at: https://www.epa.gov/greenchemistry/presidential-green-chemistry-challenge-winners, 2017. 4. Watson, W., 2012, “How Do the Fine Chemical, Pharmaceutical, and Related Industries Approach Green Chemistry and Sustainability?” Green Chemistry (14): 251-259, DOI 10.1039/C1GC15904F. 5. Veleva, V. and B. Cue Jr., 2017, "Benchmarking green chemistry adoption by “big pharma” and generics manufacturers", Benchmarking: An International Journal, 24 (5):14141436, https://doi.org/10.1108/BIJ-01-2016-0003. 6. Cue, B., J. Berridge and J. Manley, 2009, “PAT and green chemistry: The intersection of Benign by Design and Quality by Design”, Pharmaceutical Engineering, March/April, 29 (2): 8-18, http://honors490-2014penner.wikispaces.umb.edu/file/view/PAT_final_print_ISPE_March_April_2009.pdf, accessed on Nov. 6, 2017. 7. Veleva V. and M. Sarkar, 2015, “Pfizer: Environmental and Business Benefits of Green Chemistry”, Case # 9B15M043, Richard Ivey School of Business, The University of Western Ontario, Canada, http://www.iesep.com/en/pfizer-environmental-and-business-benefits-ofgreen-chemistry-117504, accessed on Nov. 6, 2017. 8. DeVito, S., C. Keenan, and D. Lazarus, 2015, “Can pollutant release and transfer registers (PRTRs) be used to assess implementation and effectiveness of green chemistry practices? A case study involving the Toxics Release Inventory (TRI) and pharmaceutical manufacturers”, Green Chemistry, 5:2679-2692, DOI 10.1039/C5GC00056D. 9. Deloitte, 2016, “2017 Global life sciences outlook”, https://www2.deloitte.com/global/en/pages/life-sciences-and-healthcare/articles/global-lifesciences-sector-outlook.html, accessed on 11/5/2017. 10. KPMG, 2011, “China’s pharmaceutical industry - Poised for the giant leap”, http://www.elsiproject.eu/fileadmin/user_upload/elsi/brosch%C3%BCren/DD/Chinas_Pharma_Industry__KPMG_2011__REPORT_.pdf , accessed on 11/6/2017. 11. Pharmaceutical Supply Chain Initiative (PSCI), 2017, “About Us: Helping Suppliers Meet Industry Expectations”, https://pscinitiative.org/home, accessed on 11/6/2017. 12. Dunn, P., 2012, “The importance of green chemistry in process research and development”, Chemical Society Review, 41:1452-1461, DOI 10.1039/C1CS15041C. 13. Sheldon R., 2007, “The E-factor: fifteen years on”, Green Chemistry, 9:1273-1283, DOI 10.1039/B713736M.. 14. Cannon, A., Pont J. and J. Warner, (2012), “Green chemistry and the pharmaceutical industry”, Chapter 2 In: Green techniques for organic synthesis and medicinal chemistry, First Edition. Edited by Wei Zhang and B. Cue Jr. John Wiley & Sons, Ltd.



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15. IMS, 2016, “IMS Health Study: U.S. Drug Spending Growth Reaches 8.5 Percent in 2015”, April 14, https://www.imshealth.com/en/about-us/news/ims-health-study-us-drug-spendinggrowth-reaches-8.5-percent-in-2015, accessed on 11/5/2017. 16. SelectUSA, 2015, “The Pharmaceutical and Biotech Industries in the U.S.”, available at: http://selectusa.github.io/mobile/industry-snapshots/pharmaceutical-and-biotech-industriesunited-states.html, accessed on 11/6/2017. 17. DrugStoreNews, 2016, “Generic Industry Report 2016”, http://www.drugstorenews.com/sites/drugstorenews.com/files/GenericReport_2016.pdf, accessed on 11/6/2017. 18. Sheldon, R. A. 1994, "Green Chemistry performance metrics: E-factor." Chem Tech 24: 3847. 19. Jimenez-Gonzalez, C., Curzons A., Constable D. and V. Cunningham, 2004, “Cradle-to-Gate life cycle inventory and assessment of pharmaceutical compound”, International Journal of Life Cycle Assessment, 9 (2): 114-121, https://doi.org/10.1007/BF02978570. 20. Henderson, R., Kindervater, J. and J. Manley, 2007, “Lessons learned through measuring green chemistry performance – the pharmaceutical experience”, presented at the 11th Annual Green Chemistry and Engineering Conference, Washington DC, June 2007. 21. Daughton, C., 2016, “Pharmaceuticals and the Environment (PiE): Evolution and impact of the published literature revealed by bibliometric analysis”, Science of the Total Environment, Vol. 562, 15 August, pp. 391-426, https://doi.org/10.1016/j.scitotenv.2016.03.109. 22. Khetan, S. and T. Collins, 2007, “Human pharmaceuticals in the aquatic environment: A challenge to green chemistry”, Chem. Rev. 107: 2319-2364, DOI: 10.1021/cr020441w. 23. Benotti, M., R. Trenholm, B. Vanderford, J. Holady, B. Stanford and S. Snyder, 2009, “Pharmaceuticals and endocrine disrupting compounds in the U.S. drinking water”, Environmental Science & Technology, 43 (3): 597-603, DOI: 10.1021/es801845a. 24. Caliman, F. and M. Gavrilescu, 2009, “Pharmaceuticals, personal care products and endocrine disrupting agents in the environment – A review”, Clean, 37 (4-5): 277-303, DOI: 10.1002/clen.200900038. 25. Kolpin, D.W., Furlong, E.T., Meyer, M.T., Thurman, E.M., Zaugg, S.D., Barber, L.B., and Buxton, H.T., 2002, “Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000--A national reconnaissance,” Environmental Science and Technology, 36 (6): 1202-1211, DOI http://dx.doi.org/10.1021/es011055j. 26. Natural Resource Defense Council (NRDC), 2010, “Dosed Without Prescription”, January, available at: https://www.nrdc.org/health/files/dosed4pgr.pdf, accessed on 10/2/2017. 27. U.S. Food and Drug Administration (FDA), 2016, “Environmental impact considerations”, https://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/EnvironmentalAssess ments/, accessed on 11/6/2017. 28. Europa, 2001, “DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use”, http://ec.europa.eu/health//sites/health/files/files/eudralex/vol1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf, accessed on 11/6/2017. 29. U.S. EPA, 2016, “Laws & Regulations: Summary of the Toxics Substances Control Act”, https://www.epa.gov/laws-regulations/summary-toxic-substances-control-act, accessed on 11/6/2017. 30. European Commission (EC), 2016, “Environment: REACH”, http://ec.europa.eu/environment/chemicals/reach/reach_en.htm, accessed on 11/6/2017. 22 ACS Paragon Plus Environment

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31. DeVito, S., 2016, “On the design of safer chemicals: a path forward”, Green Chemistry, 18, 4332-4347, DOI: 10.1039/C6GC00526H. 32. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), 2016, “ICH Impurities: Guideline for residual solvents Q3C(R6)”, http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html, accessed on 11/6/2017. 33. Larsson D., C. de Pedro, and N. Paxeus, 2007, “Effluent from drug manufactures contain extremely high levels of pharmaceuticals”, Journal of Hazardous Materials 148: 751-755, DOI:10.3390/w5031346. 34. Pruden, A., Larsson, J., Amezquita A., Collignon P., Brandt, K., Graham D., Lazorchak, J., Suzuki S., Silley P., Snape J., Topp, E., Zhang T., and Y. Zhu, 2013, “Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment”, Environmental Health Perspectives, 121 (8):878-885, http://dx.doi.org/10.1289/ehp.1206446. 35. Barry, F., 2014, “Embarrassment” holding back green manufacturing, says Sweden”, InPharmaTechnologist.com, Dec. 22, http://www.in-pharmatechnologist.com/RegulatorySafety/Embarrassment-holding-back-green-manufacturing-says-Sweden, accessed on 11/4/2017. 36. MacDonald, G., 2015, “GMP assessments should consider environmental impact say campaigners”, In-Pharmatechnologist.com, July 6, http://www.inpharmatechnologist.com/Ingredients/GMP-assessments-should-consider-environmentalimpact-say-campaigners, accessed on 11/4/2017. 37. Unger, C., 2012, “Sustainable development is gaining ground both in the EU and globally”, Ch. 1 in: Pharmaceuticals in a Healthy Environment, MistraPharma Research, 2008-2011, Editors: Ingvar Brandt, Magnus Breitholtz, Jes la Cour Jansen, Karin Liljelund, Joakim Larsson, Christina Rudén and Mats Tysklind, Stockholm, Sweden. 38. Tucker, J., 2006, “Green chemistry, a pharmaceutical perspective”, Organic Process Research & Development, 10 (2): 315-319, DOI: 10.1021/op050227k. 39. Tucker, J. and M. Faul, 2016, “Drug companies must adopt green chemistry”, Nature, Vol. 534, pp. 27-29, doi:10.1038/534027a. 40. Sharma, V., 2015, “Applicability of green chemistry in pharmaceutical processes”, Pharma Bio World, March, pp. 34-36, http://www.piramal.com/pharmasolutions/wpcontent/uploads/Applicability-of-Green-Chemistry-in-Pharmaceutical-Processes.pdf, accessed on 11/6/2017. 41. Pinto R., and S. Silvestre, 2014, “Pharmaceutical green chemistry: Is just green chemistry or is something else more?” Journal of Chemical Engineering and Chemistry Research, 1 (5): 290-301, http://www.ethanpublishing.com/uploadfile/2014/1202/20141202102937656.pdf. 42. ACS CGI Pharmaceutical Roundtable, Membership, 2017, available at: http://www.acs.org/content/acs/en/greenchemistry/industry-business/pharmaceutical.html 43. Leahy, D., Tucker J., Mergelsberg I., Dunn P., Kopach M., and V. Purohit, 2013, “Seven important elements for an effective green chemistry program: An IQ consortium perspective”, Organic Process Research & Development, 17, 1099-1109, DOI: 10.1021/op400192h. 44. Innovative Medicine Initiative (IMI), 2017, “CHEM 21: Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries,” http://www.imi.europa.eu/projectsresults/project-factsheets/chem21, accessed on 11/6/2017. 23 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

45. Government Offices of Sweden (GOS), 2015, “The National Pharmaceutical Strategy 20162018”, https://lakemedelsverket.se/upload/omlakemedelsverket/NLS/The%20National%20Pharmaceutical%20Strategy%202016-2018.pdf, accessed on 11/7/2017. 46. U.S. SIF, 2016, “2016 Trends Report Highlights”, http://www.ussif.org/files/Trends/US%20SIF%202016%20Trends%20Overview.pdf, accessed on 11/7/2017. 47. Practice Greenhealth, 2017, “About”, available at: https://practicegreenhealth.org/about, accessed on 11/6/2017. 48. Healthier Hospitals Initiative, 2017, “HHI Challenges”, http://www.healthierhospitals.org/hhi-challenges, accessed on 11/7/2017. 49. Reputation Institute, 2016, “Pharmaceutical industry reputation in recovery as Global Pharma Reptrack® finds public perceptions improving,” https://www.reputationinstitute.com/CMSPages/GetAzureFile.aspx?path=~\media\media\me dia\press-release-for-2016-pharmareptrak_final_052516.pdf&hash=2dc09d5d2f11f53cc1da33218e407ef49acc5024a5ed72028e bb4cf36157e9d0, accessed on 11/6/2017. 50. APCO Worldwide, 2014, “Return on Reputation Indicator: State of the Asia-Pacific Pharmaceutical Industry 2013”, http://www.apcoworldwide.com/docs/default-source/defaultdocument-library/ROR/ror-apac-overview.pdf?sfvrsn=0, accessed on 11/7/2017. 51. Constable, D., A. Curzons, and V. Cunningham, 2002, “Metrics to “green” chemistry – which are the best? Green Chemistry, 4: 521-527, DOI: 10.1039/B206169B. 52. Cue B., 2011, “How is Pharma Gauging its Greenness?” Pharmaceutical Manufacturing, April 19, http://www.pharmamanufacturing.com/articles/2011/059/, accessed on 11/7/2017. 53. Dunn, P., 2013, “Pharmaceutical Green Chemistry Process Changes — How Long Does It Take To Obtain Regulatory Approval?” Green Chemistry, 15: 3099-3104, DOI: 10.1039/C3GC41376D. 54. Assaf, G., G. Checksfield, D. Critcher, P. Dunn, S. Field, L. Harris, R. Howard, G. Scotney, A. Scott, S. Mathew, G. Walker and A. Wilder, 2012, “The Use of Environmental Metrics To Evaluate Green Chemistry Improvements to the Synthesis of (S,S)-reboxetine Succinate,” Green Chemistry, 14: 123-129, DOI: 10.1039/C1GC15921F. 55. Roschangar, F., R. Sheldon and C. Senanayake, 2015, “Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration LevelTM concept, Green Chem. 17: 752-768, DOI: 10.1039/C4GC01563K. 56. Jimenez-Gonzalez, C., C. Ponder, Q. Broxterman, and J. Manley, 2011, “Using the right green yardstick: Why process mass intensity is used in the pharmaceutical industry to drive more sustainable processes”, Org. Process Res. Dev., 15: 912-917, DOI: 10.1021/op200097d 57. Trost, B., 1991, “The atom economy – a search for synthetic efficiency”, Science: Washington 254.5037 (Dec 6, 1991): 1471, DOI: 10.1126/science.1962206. 58. Jimenez- Gonzalez, C., Ponder, C. Hannah R. and J. Hagan, 2012, “Green engineering in the pharmaceutical industry”, Chapter 27 In: Green Techniques for Organic Synthesis and Medicinal Chemistry, by Wei Zhang and Berkeley W. Cue, Eds., John Wiley & Sons, United Kingdom. 59. Manley, J., P. Anastas, and B. Cue Jr., 2008, “Frontiers in green chemistry: meeting the grand challenges for sustainability in R&D and manufacturing”, Journal of Cleaner Production, 16: 743-750, https://doi.org/10.1016/j.jclepro.2007.02.025. 24 ACS Paragon Plus Environment

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60. Matus, K., X. Xiao, and J. Zimmerman, 2012, “Green chemistry and green engineering in China: drivers, policies and barriers to innovation”, Journal of Cleaner Production, 32: 193203, https://doi.org/10.1016/j.jclepro.2012.03.033. 61. Mehta, N., 2014, “Six barriers to implementation of green chemistry in India”, Business Standard, January 6, http://www.business-standard.com/content/b2b-chemicals/six-barriersto-implementation-of-green-chemistry-in-india-114010600785_1.html, accessed on 11/7/2017. 62. Cui, Z., E. Beach, and P. Anastas, 2011, “Green chemistry in China”, Pure Appl. Chem., 83 (7): 1379-1390, doi:10.1351/PAC-CON-10-12-02. 63. PharmaTech, 2011, “Tracking pharmaceutical and API growth in China”, http://www.pharmtech.com/tracking-pharmaceutical-and-api-growth-china, accessed on 11/7/2017. 64. Mathew, G. and M. Unnikrishnan, 2012, “The emerging environmental burden from pharmaceuticals”, Economic & Political Weekly, Vol. XLVII, No.18, May 5th, http://www.indiaenvironmentportal.org.in/files/file/Burden%20from%20Pharmaceuticals.pdf , accessed on 11/7/2017. 65. Kidwai, M., 2001, “Green chemistry in India”, Pure Appl. Chem., 73 (8): 1261-1263, http://dx.doi.org/10.1351/pac200173081261. 66. Matus, K., W. Clark, P. Anastas and J. Zimmerman, 2012, “Barriers to implementation of green chemistry in the United States”, Environmental Science & Engineering, 46 (20): 10892–10899, DOI: 10.1021/es3021777. 67.International Consortium for Innovation and Quality in Pharmaceutical Development (I Q) Green Chemistry Working Group Report, 2012, https://iqconsortium.org/initiatives/working-groups/green-chemistry/, accessed on 11/7/2017. 68. Tucker, J., 2010, “Green chemistry: Cresting a summit toward sustainability”, Organic Process Research & Development, 14 (2): 328-331, DOI: 10.1021/op9000548. 69. Bryan, M., Dillon B., Hamann L., Hughes G, Kopach M., Peterson E., Pourashraf, M. Raheem I., Richardson P., Richter D., and H. Sneddon, 2013, “Sustainable practices in medicinal chemistry: Current state and future directions”, Journal of Medicinal Chemistry 56: 6007-6021, DOI: 10.1021/jm400250p. 70. Sheldon, R., 2017, “The E factor 25 years on: the rise of green chemistry and sustainability”, Green Chemistry, 19: 18-43, DOI: 10.1039/C6GC02157C. 71. Anastas. P., and D. Allen, 2016, “Twenty-five years of green chemistry and green engineering: The end of the beginning”, ACS Sustainable Chemistry and Engineering, 4 (11): 5820-5821, DOI: 10.1021/acssuschemeng.6b02484. 72. Horvath, .I, 2008, “Solvents from nature”, Green Chem., 10: 1024-1028, DOI: 10.1039/B812804A. 73. Prat, D., A. Wells, J. Hayler, H. Sneddon, R. McElroy, S. Abou-Shehada and P. Dunn, 2016, “CHEM21 selection guide of classical and less classical solvents”, Green Chem., 18: 288296, DOI: 10.1039/C5GC01008J. 74. Alder, C., J. Hayler, R. Henderson, A. Redman, L. Shukla, L. Shuster and H. Sneddon, 2016, “Updating and further expanding GSK’s solvent sustainability guide”, Green Chem., 18: 3879-3890, DOI: 10.1039/C6GC00611F. 75. Adams, J., C. Alder, I Andrews, A. Bullion, M. Campbell-Crawford, M. Darcy, J. Hayler, R. Henderson, C. Oare, I. Pendrak, A. Redman, L. Shuster, H. Sneddon and M. Walker, 2013,



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“Development of GSK’s reagent guides – embedding sustainability into reagent selection”, Green Chem., 15: 1542-1549, DOI: 10.1039/C3GC40225H. 76. Prat D., O. Pardigon, H. Flemming, S. Letestu, V. Ducandas, P. Isnard, E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani and P. Hosek, 2013, “Sanofi’s solvent selection guide: A step toward more sustainable processes”, Org.Process Res. Dev, 17: 1517-1525, DOI: 10.1021/op4002565. 77. Diorazio L., D. Hose and N. Adlington, 2016, “Toward a more holistic framework for solvent selection”, Org. Process Res. Dev., 20: 760-773, DOI: 10.1021/acs.oprd.6b00015. 78. Jones, N, 2013, “A scarcity of rare metals is hindering green technologies,” Yale Environment 360, November 18, http://e360.yale.edu/features/a_scarcity_of_rare_metals_is_hindering_green_technologies, accessed on 11/7/2017. 79. Alonso, E., Sherman, A.M., Wallington, T.J., Everson, M.P., Field, F.R., Roth, R., and Kirchain, R.E., “Evaluating rare earth element availability: a case with revolutionary demand from clean technologies,” Environ. Sci. Technol. 2012 (46): 3406−3414, DOI: 10.1021/es203518d. 80. International Council for Harmonization of Technical Requirements (ICH), 2017, “Process of Harmonization”, http://www.ich.org/products/process-of-harmonisation.html, accessed on 10/31/2017. 81. U.S. FDA, 2017, “Generic Drug User Fee Amendments,” https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm, accessed on 10/31/2017. 82. Kuehn, B. M. 2008, “Traces of Drugs Found in Drinking Water: Health Effects Unknown, Safer Disposal Urged”, J. Am. Med. Assoc. 299 (17): 2011–2013, DOI: 10.1001/jama.299.17.2011. 83. Schulman, L. J.; Sargent, E. V.; Naumann, B. D.; Faria, E. C.; Dolan, D. G.; Wargo, J. P. 2002, “A human health risk assessment of pharmaceuticals in the aquatic environment”, Hum. Ecol. Risk Assess, 8 (4): 657–680, http://c.ymcdn.com/sites/www.productstewardship.us/resource/resmgr/imported/HumanHealt hRiskAssessofPharmsinAquaticEnv.pdf, accessed on 11/7/2017. 84. Snyder, S. A.; Westerhoff, P.; Yoon, Y.; Sedlak, D. L., 2003, “Pharmaceuticals, personal care products, and endocrine disruptors in water: Implications for the water industry”, Environm. Eng. Sci., 20 (5): 449–469, https://doi.org/10.1089/109287503768335931.


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For Table of Contents Use Only

To what extent do you use Green Chemistry (GC) principles in your company? 74% 56%

15%

24%

We use GC in analytical/quali…

12%

We use GC in API plus…

We use GC in synthetic API…

We use GC in manufacturing

We use GC in chemical…

15%

We use GC in biological API…

35%

27%

We use GC in drug discovery

80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0%

We do NOT use GC at all

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Twenty-five years after the advent of green chemistry only a small number of pharmaceutical companies have adopted it in a strategic way despite the growing interest in this area by the entire industry. Green chemistry contributes to sustainability by significantly reducing the amount of waste co-produced, lowering companies’ carbon footprint and manufacturing costs which improves profitability and efficiency necessary for reducing costs and improving access to medicines.



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Vesela R. Veleva, ScD Dr. Veleva is a faculty member in the Department of Management and the Center for Sustainable Enterprise and Regional Competitiveness (SERC) at the University of Massachusetts Boston. Presently she also serves as Interim Director of the Healthcare Management Program at the College of Management, UMass Boston. Her research focuses on the circular economy, green chemistry, industrial ecology, environmental health and corporate social responsibility. She has published in peer reviewed journals including the Journal of Cleaner Production, Greener Management International, Corporate Environmental Strategy, and Benchmarking: An International Journal. She has published several teaching cases and a book - “Business, Environment and Society: Themes and Cases” (Baywood Publishing Co., 2014). Dr. Veleva has presented at numerous conferences including the Global Cleaner Production and Sustainable Consumption Conference, and the National Council for Science and Environment Annual Conference. Dr. Veleva has a doctorate in Cleaner Production and Pollution Prevention from the University of Massachusetts Lowell, an M.S. in Pollution & Environmental Control from the University of Manchester UK, and a BS in Electrical Engineering from the Technical University of Varna, Bulgaria.


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Berkeley W. Cue, Jr., Ph.D. Dr. Cue consults for pharmaceutical and technology companies through BWC Pharma Consulting, LLC. While he was at Pfizer (1975-2004) he was responsible for Pharmaceutical Sciences at the Groton, Connecticut R&D center. He was a member of the site leadership team and the Global Pharmaceutical Sciences Executive Team. He created and led Pfizer's worldwide green chemistry efforts until he retired, after almost 29 years. From 2004, he was first a governing board member then the chair of the governing board of the ACS Green Chemistry Institute, where he helped found and led their Pharmaceutical Roundtable. He also was an advisor and founding member of the Green Chemistry and Commerce Council (GC3). He has given over 150 presentations on green chemistry and sustainability, published nearly two dozen peer reviewed articles and holds almost twenty patents. With Professor We Zhang at UMass-Boston he edited two green chemistry texts, “Green Techniques for Organic Synthesis and Medicinal Chemistry,” published by Wiley in June 2012, and the second edition in 2017. At UMass Boston he is an adjunct professor in the chemistry department, a member of advisory boards for their College of Science and Mathematics and the College of Management’s Center for Sustainable Enterprise and Regional Competiveness (SERC). In 2011 he was appointed a Fellow of the American Chemical Society and received a Green Chemistry Champions Award from the GC3. In 2013 he received EPA Region 1’s Lifetime Environmental Merit Award. In 2016 he received the UMass Boston Award for Distinguished Leadership and Community Service. He is a member of the ACS, and New England Association of Chemistry Teachers (NEACT). Dr. Cue graduated with a BA in Chemistry from UMass Boston in 1969. He earned his PhD from the University of Alabama (1969-1973) and was a National Cancer Institute Postdoctoral Fellow (1973-1975).



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Svetlana Todorova, PhD Dr. Svetlana Todorova is a visiting lecturer in Business Statistics at the D’Amore-McKim School of Business, Northeastern University, Boston, Massachusetts. Before joining Northeastern University she was a chief assistant professor in Statistics at Varna University of Economics, Bulgaria. Dr. Todorova’s research interests are highly interdisciplinary. Her research focuses on the applications of statistics in the fields of business, economics, education, and most recently sustainability, “zero waste”, and green chemistry. She is an author and co-author of over 30 publications, including monographs, book chapters, peer reviewed journal articles, and papers, presented at various international conferences. She holds a B.S. in Socio-Economic Information and a M.S. and PhD in Statistics, all from Varnа University of Economics, Bulgaria.


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Benchmarking Green Chemistry Adoption by the Global

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