Pfizer's Green Chemistry Program

[ACSGCI]

20 Years of Scientific Breakthroughs That Both Change Patients’ Lives and Sustain a Healthy Planet

By Juan Colberg, Seda Arat, Maria Gonzalez Esguevillas, Scott France, Kailey Huot, Rajesh Kumar, Daniel Laity, Manjinder Lall, Johnny Lee, Javier Magano, Jared Piper, Paul Richardson, Philipp Roosen, Rebecca Watson.

One definition for Green Chemistry (GC) is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. Pfizer has embraced this concept and applied it across the life cycle of its products, facilitating process design, manufacturing, and utilization. Green chemistry principles provide a unique framework to guide process development, which ultimately leads to an optimal chemical process from both an environmental and economic perspective.

Birth of the Pfizer GC Program

Pfizer’s Green Chemistry initiative began in 2001 as a grassroots effort, then led by Dr. Buzz Cue, Vice-President of Chemical Research and Development, and together with colleagues who looked to reduce the amount of waste associated with chemical operations. Under the Green Chemistry banner and with crucial sponsorship from senior leaders, Pfizer formally established the program a year later. Starting with the Chemical R&D group in Groton, Connecticut, it quickly expanded to include other R&D groups and sites at Pfizer, including the U.K. labs in Sandwich, and the R&D center in La Jolla, California. Elements that differentiated the Pfizer GC program from others included a green chemistry leader position, an active green chemistry team that included members from all small-molecule research sites across the globe, a strong engagement with our manufacturing commercial partners, and commitments across many other parts of the organization.

To achieve this, Pfizer introduced the following objectives:

• Foster a culture of transparent communication amongst colleagues, the pharmaceutical industry, regulatory authorities, academia, and the public
• Educate both current and, importantly, future generations of scientists and engineers about Green Chemistry, to instill a GC work ethic
• Proactively integrate Green Chemistry into research and product development, and retroactively into current Pfizer products where feasible
• Use metrics to benchmark, track, and improve our environmental performance, in real-time

As part of our GC initiatives over the last 20 years, we have continued to promote, both internally and externally, the selection and use of environmentally-preferred chemicals to eliminate waste and conserve energy in our chemical processes.

Educational Programs and Tools

As Pfizer’s portfolio evolves to encompass innovative modalities to treat and manage disease, so does its Green Chemistry program. A pivotal aspect of our program’s success has been the commitment from the organization to provide—and support the creation of—ways to share knowledge, best practices, and techniques across not only Pfizer but also as a means of educating future chemists and engineers within the academic community.

Education is at the core of the Green Chemistry program, with an emphasis both on providing educational materials and organizing seminars for our own workforce or for a new generation of scientists outside of the company. As part of these efforts, we engaged our internal and external communities with a series of educational workshops to promote the application of Green Chemistry Principles and the use of more environmentally sustainable technologies and approaches.

Internally, we hold annual workshops to provide an overview of Pfizer’s GC program to new colleagues and summer interns to proactively cultivate a better understanding of the principles of green chemistry¹, why they are important and what the impact can be in the pharmaceutical industry. Furthermore, to facilitate a seamless transition from early discovery to process chemistry, Pfizer implements GC principles in medicinal chemistry programs to expedite the drug discovery process.

Externally, we have a student workshop that we share with universities and colleges. The events started as workshops hosted in our R&D facilities and were soon expanded to further engage faculty members and universities and to reach students from a broader range of disciplines. In 2007, the Groton Green Chemistry Team conceived the “Workshop on Wheels” (WoW) initiative, which consisted of conducting the workshop at a college or university with a small team of Pfizer colleagues. An important element of WoW was the active engagement of faculty and students in organizing and conducting the workshops. The first WoW was held at the University of Puerto Rico in 2007, followed by many others where Pfizer has partnered with numerous universities to bring WoW to their campuses (for example, UConn, UCSD, UMass, University of Rhode Island, Yale).

Also, as part of the education/improvement initiative, the green chemistry team developed a set of tools to help facilitate the adoption of green chemistry within our organization. These provide our chemists and engineers information to select efficient, green transformations and solvents using criteria that include greenness, utility, physical properties, regulatory concerns (REACH, TSCA), safety/health/environmental (SHE) impact, and scalability². The green chemistry team also introduced LCA/PMI (life cycle analysis/process mass intensity) metrics to help track and measure our scientist’s ability to make greener chemistry decisions in delivering our portfolio to patients.  After the rollout of this tool, we observed a dramatic reduction in the use of undesired solvents in our R&D operations.  This program eventually led to a 60% reduction in methylene chloride, a 90% reduction in n-hexane, and a 98% reduction in chloroform usage. This practice continued throughout the development lifecycle and later translated into our commercial processes as products transitioned from R&D to our commercial groups.

Applications of GC Principles to Commercial Products

One of the early success stories for the company was how GC Principles dramatically improved the manufacturing process for sertraline hydrochloride, the active ingredient of Zoloft used to treat depression, anxiety, and other mood disorders³. Applying the principles of green chemistry, the new process doubled the product yield, reduced raw material use by 60%, and eliminated approximately 1.8 million pounds of hazardous materials. The original process involved the use of titanium tetrachloride which produced great volumes of titanium dioxide (453 tons/year). Consequently, the TiO₂ by-product required a specific hazardous waste disposal procedure. However, with current GC principles in place, every ton of sertraline API produced removes 60,000 gallons of solvent waste compared to the old process. For this achievement, Pfizer was awarded the Green Synthetic Pathways Award of the Presidential Green Chemistry Challenge by the U.S. Environmental Protection Agency in 2002. At peak sales, Pfizer manufactured over 350 tons of sertraline hydrochloride per year.

The work for sertraline hydrochloride represents a highlight for the Pfizer Green Chemistry program and is by no means an isolated example. Shortly after that, the company developed an environmentally friendlier method for manufacturing sildenafil citrate (Viagra) which more than doubled the chemical yield, reduced solvent use by 95 percent, and completely removed noxious reagents tin chloride and hydrogen peroxide from the process⁴.

Another green chemistry milestone for Pfizer was the pioneering utilization of biocatalysis to reduce costs and emissions in the manufacturing of pregabalin (Lyrica)⁵ and atorvastatin (Lipitor). In fact, the merits of the present-day manufacturing process for pregabalin entail energy savings equivalent to reducing three million tons of carbon dioxide emissions, which is equivalent to removing a million small cars from the road for a year.

Other achievements include the 2005 Crystal Faraday Award for Green Technology, the 2006 AstraZeneca award for “Excellence in Green Chemistry and Engineering” for the pregabalin process, and the 2009 BCE Environmental Leadership Award (a long-standing UK environmental award started in 1975) for Innovative Management Systems to promote Green Chemistry.

Pfizer Green Chemistry Program and the Supply Chain

Environmental regulations have increased across the globe, as well as customer demand for greener processes which places pressure on the industry to maintain environmentally sound and responsible practices in our supply chain operations.  In addition, in recent years external stakeholders have demanded companies address the environmental performance of their external supply chain. Organizations such as the U.N. have stated that companies do not “outsource responsibility and insource economic benefits”. To address this, Pfizer realized a need to prospectively collect environmental sustainability performance information from suppliers for products and services provided. A recent publication by members of the IQ Green Chemistry working group and the ACS Green Chemistry Institute Pharmaceutical Roundtable (which Pfizer has played a key role in the leadership of since being one of the three founding companies back in 2005, and now consists of ~ 40 organizations) quantified that about half of the drug manufacturing process waste is generated externally⁶.

Green chemistry metrics have been a way for the pharma sector to track and improve performance in their internal supply chain operations. As such, Pfizer has been working in recent years to balance our environmental, social, and economic objectives first within our key vendors, and asking them to adopt/maintain a sustainability program with meaningful goals for metrics compliance. Pfizer’s successful policing initiative has expanded to include all our vendors.

How to Maintain a Successful Story

As an important industrial sector of the rapidly changing global business community, pharma is adapting to the changing needs of society while continuing to deliver medicines to our patients. With a view toward its business strategy, Pfizer is continuously reviewing and improving efforts to find more sustainable solutions to our operations and reduce the impact on the environment. In recent years, the industry has received greater pressure from non-governmental organizations (NGOs) around the world demanding that we deliver our products in an environmentally responsible way. There has also been more visibility and a greater number of queries from investors for company environmental programs. As customers demand that our operations take greater care of the environment, this, in turn, becomes important for shareholders and investors. In a 2020 ESG report, Pfizer publicly shared the commitment to moving to carbon-neutral operations by 2030, including the manufacturing of our products⁷. With API synthesis contributing the largest amount for the carbon footprint operations, addressing this concern will require attention by Chemical R&D. Drug development and route design will continue to invest in more efficient approaches that not only help to reduce cost and resources but also produce technologies and workflows that help us deliver on our environmental commitments.

Key technology areas for Pfizer include:

1. Identify and implement abundant earth-metals in catalysis where possible. Many chemical industrial processes utilize rare, expensive, and sometimes toxic metals. Pfizer has made considerable progress in replacing these with more readily available non-precious metal catalysis (NPMC) options.
2. Continue the development and application of biocatalysis, which provides a greener option (lower PMI process) during new route design and ultimate commercial processes for drug candidates⁸.  This includes the identification and production of new sources in immobilized biocatalysts and enhanced enzyme modification techniques. Although great advances have been made, more is needed, especially to address a true end-to-end green performance, from raw materials to waste management mitigations. The pharmaceutical industry will need to make progress in these areas to comply with new regulations that limit the amounts of residual metals/contaminants disposed into treatment plants and residual organics (for example from biocatalytic reactions) and to manage our commercial manufacturing plants.
   
3. The implementation of continuous manufacturing/flow chemistry technologies. Continuous chemistry could result in more consistent processes and product quality, which in turn can reduce waste generation, product losses, and operation downtime. A smaller footprint from these technologies could also allow for reduced energy, water, and raw material consumption. At Pfizer, we are looking to apply this manufacturing approach to deliver on green chemistry principles and lower environmental values such as process mass intensity (PMI).  
4. Use of smart metrics. Green metrics provide a framework for actions that can be taken to make chemical synthesis and processes more environmentally efficient. Green chemistry metrics are needed for chemistry and engineering to be applied at different development and commercialization areas of drug development. Many factors characterize different levels of manufacturing complexity for each drug candidate. Smart application of metrics by scientists allows delivery of a better process within the stage of development and the complexity of the target molecule. Pfizer has adopted targets for our development operations and tracks metrics such as PMI and others to allow smart decisions across the drug development timeline.
5. Developing computational and predictive tools that harness artificial intelligence algorithms to perform complex tasks and minimize or augment experimentation. Although these tools have already seen significant application in improving laboratory development as well as in scaling processes, Pfizer is committed to continued acceleration in adoption by improving the user experience, simplifying access, and ensuring reliable data outputs.
6. High throughput techniques to generate high-quality data with less waste. Modern synthetic organic chemistry involves an abundance of challenging chemical transformations, intricate unit operations, and innumerable strategies to generate molecular complexity. Single experiments with a narrow analytical focus are insufficient to develop green drug discovery mechanisms and manufacturing processes. High-throughput experimentation (HTE) is key to seek improved and greener processes by extracting knowledge and understanding from large pools of data, rapidly identifying greener reagents, chemical transformations, and ultimately processes of the future.

What is Next for the GC Program?

Pfizer continues to recognize the business benefits of green chemistry and sustainability initiatives, including cost savings, improved efficiency, reduction of waste, meeting customer demands, improved reputation, ability to attract and retain talent, and reduced risks (both supply chain and regulatory) that in turn also benefit our communities, environment, and the globe. The company had published an annual Corporate Responsibility Report since 2007⁹ and has committed to the U.N. Global Compact Principles. Recognizing the profound societal and public health impacts that may result from environmental factors, Pfizer has adopted corporate commitments and stated a purpose to establish “breakthroughs that change patients’ lives”. This mindset guides our actions to mitigate against factors that impact climate change, manage the use of natural resources, and reduce waste arising from the manufacturing of medicines and vaccines in both our internal and external operations.  As part of this commitment, in March 2020, Pfizer announced the creation of a $1.25 Billion Sustainability Bond for Social and Environmental Impact. Proceeds of these bonds will be used to improve access to essential services, green buildings, and investments intended to further improve the environmental performance of Pfizer facilities—reducing the impact of our operations energy usage, water and waste management, and pollution reduction. With respect to green chemistry, this will include minimizing the environmental impact across the supply chain and life cycle of our products through developing greener processes across our portfolio as defined through analyses of benchmarking metrics.

Final Thoughts

Many studies have shown that climate change disproportionately affects those who suffer from socioeconomic inequalities, including many people of color. Minorities tend to live in places that are highly impacted by climate change events, such as hurricanes, wildfires, and flooding. These individuals are also far more likely to live in areas with heavy pollution due to proximity to chemical/manufacturing plants and hazardous waste facilities. Green chemistry principles and greener manufacturing solutions, in addition to more involvement from the scientific community, including those from the areas suffering the most, will be key to addressing and solving these issues.

According to the 2019 “Women, Minorities and Persons with Disabilities in Science and Engineering” report from NSF’s National Center for Science and Engineering Statistics, although African Americans and Hispanics together make up roughly a quarter of the U.S. population, the presence of these minority groups in STEM fields compared to their white counterparts remains far less¹⁰.

Other studies have shown that students are leaving the chemistry enterprise and other STEM career paths at alarming rates.  The number of women, ethnic, and racial minorities significantly surpass those departing from Caucasian and Asian demographics. This will significantly impact the pharma and chemical industry workforce availability, especially with respect to the roles that could address climate change and pollution.

At Pfizer, we are committed to addressing these issues head-on and to making them one of our highest priorities heading into 2030, as reported in our 2020 ESG commitments.

References:

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3. Taber, G. P.; Pfisterer, D. M.; Colberg, J. C. A New and Simplified Process for Preparing N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine and a Telescoped Process for the Synthesis of (1S-cis)-4-(3,4-Dichlorophenol)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine Mandelate: Key Intermediates in the Synthesis of Sertaline Hydrochloride. Org Process Res Dev. 2004, 8, 385.
4. Dunn, P. J.; Galvin, S.; Hettenbach, K. The Development of an Environmentally Benign Synthesis of Sildenalfil Citrate (Viagra™) and its Assessment by Green Chemistry Metrics. Green Chem. 2004, 6, 43.
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8. a) Duan, S.; Li, B.; Dugger, R. W.; Conway, B.; Kumar, R.; Martinez, C.; Makowski, T.; Pearson, R.; Olivier, M.; Colon-Cruz, R. Developing an Asymmetric Transfer Hydrogenation Process for (S)-5-Fluoro-3-methylisobenzofuran-1(3H)-one, a Key Intermediate for Lorlatinib. Org Process Res Dev. 2017, 21, 1340; b) Korht, J. T.; Dorff, P. H.; Burns, M.; Lee, C.; O’Neil, S. V.; Maguire, R. J.; Kumar, R.; Wagenaar, M.; Price, L.; Lall, M. S. Application of Flow and Biocatalytic Transaminase Technology for the Synthesis of 1-Oxa-8-azaspiro[4.5]decan-3-amine. Org Process Res Dev. 2021. DOI: 10.1021/acs.oprd.1c00075.
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