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Green Chemistry Strategies for Drug Discovery
By Emily A. Peterson, Julie B. Manley The Royal Society of Chemistry
Copyright © 2015 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-961-0
CHAPTER 1
Introduction: The Five Ws of Pharmaceutical Green Chemistry
JULIE B. MANLEY
Guiding Green LLC, 457 E. Mier Road, Sanford, MI 48657, USA Email: juliemanley@GuidingGreen.com
1.1 Introduction
Louis Pasteur said, "Chance favors the prepared mind." This chapter is designed to prepare the reader with the foundation upon which to build green chemistry into the business of drug discovery. Understanding green chemistry and its importance is a starting point, and being able to communicate it to the target audience is a necessity. By reviewing pharmaceutical green chemistry in the context of the essential journalism questions nicknamed the Five Ws (What? Why? Who? Where? When?), this chapter will provide an intentionally succinct perspective to act as the infrastructure for the invaluable chapters to follow. The Five Ws will prepare the reader to integrate green chemistry into drug discovery, and make successful integration more seamless and effective.
1.2 What is Green Chemistry?
First and foremost, green chemistry is chemistry, the scientific discipline of arranging molecules to create new materials and products; yet its focus is on the intentional integration of source and hazard reduction into the design of matter. By focusing on the design of materials at the molecular level, innovations are more efficient, cost-effective, safer, and environmentally preferable. Historically, environmental benefits were a side effect of optimizing efficiency and minimizing cost. Green chemistry turns that notion on its head and says that by intentionally designing a more sustainable process, the business needs will be met and even exceeded.
Green chemistry is commonly defined as the design of chemical processes and products to minimize the use and/or generation of hazardous materials. It is further clarified by a set of principles intended to provide a cohesive framework for the design of chemicals with reduced intrinsic hazard. The 12 principles begin with the recognition that it is more efficient to prevent waste from being generated in the first place than to treat it later (Principle 1). It is also more cost-effective to do so; the materials being purchased would be consumed rather than incurring a second cost on the same material for disposal. The principles address all aspects of the chemical lifecycle from the selection of safer materials (Principle 5 and Principle 12), renewably sourced where feasible (Principle 7), and their efficient use in the process (Principle 2). In the design of the chemistry, the principles emphasize the use of less hazardous chemical syntheses (Principle 3), reducing the need for derivatives (Principle 8), using catalysis where possible (Principle 9), incorporating real-time process monitoring (Principle 11), and minimizing energy use by considering ambient conditions when feasible (Principle 6). The principles also address end user considerations including designing the product to be effective while minimizing toxicity (Principle 4). Finally, in consideration of the end of the product life, the principles address the need to design for safe degradation in the environment (Principle 10). While some of these principles may not seem relevant to the drug discovery setting, decisions made in discovery can ultimately have a significant impact on the marketed product. The following chapters are intended to provide the reader with a more thorough understanding of their practical implementation in drug discovery.
For the current purposes, it is important to recognize the implicit challenge with implementing the 12 Principles in their entirety in any one process, and to appreciate this challenge not as a hindrance, but as an opportunity to continue to innovate. Even technologies recognized with the US Presidential Green Chemistry Challenge Award rarely, if ever, meet all 12 principles at any one time. Similarly, a process recognized as an effective implementation of green chemistry could also be further improved as evidenced by Merck's sitagliptin, the active ingredient in Januviat, being recognized in both 2006 and 2010 (with Codexis) with the Presidential Green Chemistry Challenge Award. The principles are a framework upon which to design, and to make informed decisions when a trade of between principles is inevitably needed.
One could argue that green chemistry is less a scientific field than it is specification for performance characteristics. Green chemistry describes how to incorporate design for the environment into current scientific methods. In 2005, metathesis was recognized with the Nobel Prize in Chemistry as a "great step forward for green chemistry". The technology received the highest honor globally in chemistry, not an environmental award, not a green chemistry award. Green chemistry is about doing chemistry more efficiently, safer, and more cost-effectively than it is now. Medicinal chemists, process chemists, analytical chemists, biochemists, and so on are not green chemists; they are scientists in their respective disciplines doing green chemistry. Job descriptions are not written to hire a green chemist per se; they seek qualified candidates able to perform the essential job functions. Arguably, knowledge of green chemistry, in addition to the targeted education and experience, assures the person is capable of utilizing his or her expertise to design and synthesize medicines efficiently, while minimizing cost and environmental impact, thereby meeting the short- and long-term goals of the company. Green chemistry is not a scientific field unto itself; it is the intentional integration of source and hazard reduction into chemistry. Paul Anastas, one of the fathers of green chemistry, has himself even been quoted, "I always say that we will know when green chemistry was successful when the term green chemistry goes away because that is simply the way that we always do chemistry."
1.3 Why Should the Pharmaceutical Industry Incorporate Green Chemistry?
Sustainability, defined as meeting the needs of today without compromising the ability of future generations to meet their needs, was once a more commonly used vocabulary word for long-term financial stability than environmental stewardship. For the past 30 years, stability is not a term many would use to describe the pharmaceutical industry. Mergers and acquisitions have reduced what was once 110 companies to about 30 companies today, and that number is continually changing even as this book is being published. Figure 1.1 illustrates the history of AstraZeneca and Pfizer as examples to demonstrate the effect of mergers and acquisitions. At the time of writing, these two companies were engaged in communications for a possible merger.
R&D spending has been on the rise with approximately $51.1 billion spent in 2013, as compared to half that amount in 2000, and $1.2B in 1980, yet only two of ten marketed drugs return revenues that match or exceed the R&D costs. Restructuring has become the norm to manage these challenges. Whether it is outsourcing R&D or production, or spinning of companies like the Abbott surprising spin off of the R&D segment resulting in the creation of AbbVie, companies are downsizing and decreasing R&D spending throughout the industry. Lilly projected R&D spending to decrease 15–20% and Merck reduced headcount by 20% in 2013–2014 and minimized risk by acquiring experimental drugs.
Companies need to do more with less, and green chemistry provides more for less. It is well established that the pharmaceutical industry generates a substantial amount of waste per kilogram of active pharmaceutical ingredient produced. Estimates indicate an average of over 100 kg material is used per kg product produced (and even in the thousands for pre-clinical processes). With green chemistry, this has been shown to decrease to ~20 kg and even as low as single digits for some commercial processes. By utilizing the 12 principles, materials are used more efficiently, generating less waste and fewer hazards, lowering the standard cost for an active pharmaceutical ingredient. The use of green chemistry principles in drug discovery results in a faster production cycle time, which creates a competitive advantage.
Chemistry and innovation are the core of the pharmaceutical business. Bringing these together to discover and develop safe and effective medicines to help improve lives of patients is the objective. Achieving this goal cost-effectively with minimal environmental impact is the requirement. Green chemistry is the mechanism to meet these needs; it is an innovative, non-regulatory, economically driven approach toward sustainability:
"The core of what we do here is to define transformative medicine that will help the patient. The goal is doing chemistry that gives equal or better results and in a way that benefits the environment."
– Bruce Roth, Vice President, Drug Discovery, Genentech
By viewing the entire life cycle of material and energy processes as an opportunity for design innovation, green chemistry enables the design of drug candidates to not just minimize unintended consequences, but more importantly to empower sustainability. Efficient and selective utilization of resources during the discovery, development, and manufacture of medicines enables the opportunity to meet the needs of today without limiting future generations to achieve theirs.
Chapter 13 will provide a more detailed analysis on the business case for green chemistry in drug discovery, highlighting the advantages for corporate profitability.
1.4 Who is Doing Green Chemistry?
In the early 2000s, green chemistry was talked about in the pharmaceutical industry, and some companies had demonstrated successes but many companies were struggling to understand how to incorporate it into the business. Under the leadership of Dr Paul Anastas, then Director of the American Chemical Society's Green Chemistry Institute®, and Dr Buzz Cue, retired Vice President of Pharmaceutical Sciences at Pfizer, the ACS GCI Pharmaceutical Roundtable was launched as a non-competitive partnership between the Institute and the pharmaceutical industry to catalyze the integration of green chemistry and engineering in the industry. It started with just three companies, Lilly, Merck, and Pfizer, in 2005; other companies were interested but not yet able to justify participation within their organization. Nine years later in 2014, the Roundtable has 16 member companies, namely, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Codexis, Cubist Pharmaceuticals, DSM Pharmaceutical Products, Dr Reddy's, GlaxoSmithKline, Johnson & Johnson, Lilly, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, and Sanofi, and their respective subsidiaries including but not limited to Genentech, and MedImmune. The Roundtable is certainly not the only organization facilitating green chemistry, nor is it intended to imply that all pharmaceutical companies implementing green chemistry are part of the Roundtable. However, the membership of the Roundtable paints a picture that is representative of a majority of the global pharmaceutical industry having at least a basic level of commitment and participation in green chemistry.
Joining an organization may demonstrate commitment but it does not always correlate to active engagement. However, in the Roundtable, companies are not just listening; they are doing. Companies actively participate in benchmarking exercises, research collaborations, tool development, publications, and, more importantly, take the outcomes from the efforts and integrate them into their respective organizations as appropriate. Process mass intensity (PMI), a metric defined by the Roundtable to address the amount of material used in a process per kilogram of active pharmaceutical ingredient (API), is now used broadly throughout the industry. AstraZeneca sets PMI targets for their active pharmaceutical ingredients by the time of commercial launch, and has reported as much as a 90% PMI reduction during the development phase. Lilly similarly implements a methodology to judge suitability for commercialization and encourages the reduction of hazardous material usage, increasing material efficiency, and evaluating chemistry and chemical alternatives. A Lilly Environmental Development Review in 2013 identified a solvent reuse opportunity that was worth up to $5 million annually in recovered solvent and would decrease greenhouse gas emissions by more than 83%.
Recognizing the amount of outsourcing employed in the industry, the Roundtable companies are collectively considering how to engage the supply chain. It would be impossible to meet their mission of catalyzing green chemistry in the global pharmaceutical industry if they only considered what went on within their own walls. In fact, several years after the Roundtable launched, the membership scope was expanded to include contract manufacturers and research organizations as well as generic manufacturers. Many of the tools developed by the Roundtable, including the solvent selection guide and PMI calculator, are available publicly and some companies provide them directly to their suppliers. What if, in the future, greenness of a supplier is incorporated into the preferred supplier profile? Understanding that green chemistry provides an economic incentive along with the environmental and safety benefits makes this a reasonable consideration. A supplier using green chemistry should be producing the desired product more efficiently, with lower costs, and reduced environmental and safety footprint. With that perspective, it really becomes a question of when green chemistry is incorporated into the supplier profile, not if.
Going deeper into the supply chain, chemical manufacturers are also involved in green chemistry implementation in the pharmaceutical industry. As an example, the Grignard reaction is commonly used to forge carbon–carbon bonds, although the reaction has serious safety and environmental concerns. Recent efforts initiated by the pharmaceutical industry evaluated the reagents in less hazardous solvents. Sigma-Aldrich, among others, subsequently applied the learnings and listened to market drivers by providing Grignard reagents in greener solvents such as 2-methyltetrahy-drofuran (2-MeTHF).
The study evaluating the aforementioned reagents was conducted as a collaboration between the Roundtable and Professor Wei Zhang from the University of Massachusetts Boston. Academicians have a critical role in the ability for industry to implement green chemistry. With academia addressing basic research on reactions, materials, and conditions with industrial relevance, industry can utilize the findings to introduce more sustainable alternatives with lower risk. Collaboration between industry and academia provides proof of concept that helps the company implement the technology with a higher level of confidence. Similarly, by incorporating green chemistry into the curriculum and academic research environment, students learn the principles of green chemistry and become the informed job applicant mentioned previously.
In short, to answer the question of who is doing green chemistry, a broad spectrum of the global pharmaceutical industry including the supply chain is incorporating green chemistry into their business, not just because it is the "right" thing to do, but because it is also right for business.
1.5 Where is Green Chemistry Being Applied?
Consistent with the earlier message that green chemistry is more similar to performance criteria than a field unto itself, green chemistry can be implemented in any segment of the pharmaceutical industry. Historically efforts have focused on the small molecule pharmaceutical development, recognizing the large amount of material, predominantly solvent, used to manufacture one kilogram of API. As biologics have become more prevalent, studies have shown that large molecules are not as consistent with the 12 principles as had once been assumed. Although utilizing less solvent, the significant water usage, related energy requirements, and use of disposables leave a lot of room for improvement. These challenges are being addressed as a subgroup within the ACS GCI Pharmaceutical Roundtable dedicated to the needs of green chemistry in the biopharma business. Similarly, Bristol-Myers Squibb's transformation into a next-generation biopharma leader commits to a strong alignment with green and sustainable business practices. A later chapter will address the opportunities for green chemistry in biopharma more directly.
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Excerpted from Green Chemistry Strategies for Drug Discovery by Emily A. Peterson, Julie B. Manley. Copyright © 2015 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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