As bio/pharma companies and their suppliers seek ways to improve their carbon footprint and meet sustainability targets, what have been recent noteworthy advances in green chemistry in small-molecule drug synthesis?

By Patricia Van Arnum, Editorial Director, DCAT, pvanarnum@dcat.org

EPA’s Green Chemistry Challenge Awards
This week (September 26, 2024), the US Environmental Protection Agency (EPA) announced the winners of the 2024 Green Chemistry Challenge Awards, which recognize new and innovative green chemistry technologies, from academia and across all industries, which incorporate the principles of green chemistry into chemical design, manufacture, and use. EPA’s Office of Chemical Safety and Pollution Prevention sponsors the Green Chemistry Challenge Awards in partnership with the American Chemical Society’s Green Chemistry Institute and other members of the chemical community.

As defined by EPA, green chemistry is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances and which achieves certain key goals as outlined below:

• Prevents pollution at the molecular level;
• Is a philosophy that applies to all areas of chemistry, not a single discipline of chemistry;
• Applies innovative scientific solutions to real-world environmental problems;
• Results in source reduction because it prevents the generation of pollution;
• Reduces the negative impacts of chemical products and processes on human health and the environment;
• Lessens and sometimes eliminates hazards from existing products and processes; and
• Designs chemical products and processes to reduce their intrinsic hazards,

EPA’s Green Chemistry Challenge Awards specifically recognizes chemical technologies that incorporate the 12 Principles of Green Chemistry, a well-established set of guidelines that serve as a common and recognized standard in green chemistry (1, 2).

The 12 Principles of Green Chemistry

1. Prevent waste: Design chemical syntheses to prevent waste. Leave no waste to treat or clean up.

2. Maximize atom economy: Design syntheses so that the final product contains the maximum proportion of the starting materials. Waste few or no atoms.

3. Design less hazardous chemical syntheses: Design syntheses to use and generate substances with little or no toxicity to either humans or the environment.

4. Design safer chemicals and products: Design chemical products that are fully effective yet have little or no toxicity.

5. Use safer solvents and reaction conditions: Avoid using solvents, separation agents, or other auxiliary chemicals. If you must use these chemicals, use safer ones.

6. Increase energy efficiency: Run chemical reactions at room temperature and pressure whenever possible.

7. Use renewable feedstocks: Use starting materials (i.e., feedstocks) that are renewable rather than depletable. The source of renewable feedstocks is often agricultural products or the wastes of other processes; depletable feedstocks are often fossil fuels (petroleum, natural gas, or coal) or mining operations.

8. Avoid chemical derivatives: Avoid using blocking or protecting groups or any temporary modifications if possible. Derivatives use additional reagents and generate waste.

9. Use catalysts, not stoichiometric reagents: Minimize waste by using catalytic reactions. Catalysts are effective in small amounts and can carry out a single reaction many times. They are preferable to stoichiometric reagents, which are used in excess and carry out a reaction only once.

10. Design chemicals and products to degrade after use: Design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment.

11. Analyze in real time to prevent pollution: Include in-process, real-time monitoring and control during syntheses to minimize or eliminate the formation of byproducts.

12. Minimize the potential for accidents: Design chemicals and their physical forms (solid, liquid, or gas) to minimize the potential for chemical accidents including explosions, fires, and releases to the environment.

For its 2024 Green Chemistry Challenge, EPA awarded winners in several categories: Academic Category; Small Business Award:  Greener Synthetic Pathways:  Design of Safer and Degradable Chemicals: and Specific Environmental Benefit – Climate Change.

In 2024, Merck & Co., Inc., won the award in the category of  Greener Synthetic Pathways for developing a new continuous manufacturing process for its immuno-oncology drug, Keytruda (pembrolizumab). Typically, these types of proteins are produced in large batches. The company now uses a continuous process to produce pembrolizumab, in which the protein is filtered away from the cells continuously instead of performing a one-time filtration step at the end of a batch. This process can produce more pembrolizumab per reactor volume, which allows for the use of smaller equipment and thus reduces the facility’s physical footprint. The continuous process reduces the energy and water needed as well as using consumables (such as filters) more efficiently. The smaller physical footprint of the facility helps prevent pollution due to a reduction in energy consumption and therefore air emissions. Merck estimates this continuous manufacturing single-use process reduces energy consumption for this process by about 4.5-fold; reduces water use by 4-fold; and reduces raw material usage by about 2-fold, thus reducing energy use and greenhouse gases for the facility, according to information from EPA.

ACS Green Chemistry Institute Pharmaceutical Roundtable
Another important body in the field of green chemistry is the American Chemical Society’s Green Chemistry Institute Pharmaceutical Roundtable, which serves as body to advance the integration of green chemistry and engineering in the pharmaceutical industry. Established in 2005 by the American Chemical Society’s Green Chemistry Institute, the Pharmaceutical Roundtable, which is composed of bio/pharmaceutical companies and CDMOs/CMOs, advances green chemistry and engineering by forming teams to address specific topics of interest to the industry. These areas of interest span a wide scope of fields of study and include the following: artificial intelligence analytical chemistry, biopharmaceuticals, biocatalysis, chemistry in water, continuous flow, green chemistry in active pharmaceutical ingredients, green chemistry and chemical legislation, greener peptides, greener oligos, manufacturing mass intensity, medicinal chemistry, process mass intensity prediction, process mass intensity lifecycle assessment, reagent guides, solvent guides, and supply-chain issues.

Earlier this year (2024), the ACS Green Chemistry Institute Pharmaceutical Roundtable, through its annual awards, awarded GlaxoSmithKline and Boehringer Ingelheim with the 2024 Peter J. Dunn Award for Green Chemistry and Engineering Impact in the Pharmaceutical Industry and PharmaBlock, a Nanjing, China-based CMO, as the winner of its 2024 CMO Excellence in Green Chemistry Award.

The Peter J. Dunn Award for Green Chemistry & Engineering Impact in the Pharmaceutical Industry, established in 2016, recognizes outstanding industrial implementation of novel green chemistry and/or engineering in the pharmaceutical industry that demonstrates compelling environmental, safety, cost, and/or efficiency improvements over current technologies.

GSK was recognized for developing a more sustainable peptide manufacturing route for maleimidocaproyl monomethyl auristatin F (mcMMAF), part of a drug used to treat multiple myeloma. A first-generation route had already been commercialized, but the company developed a second-generation route that reduced solvent consumption by 16,160 kgs for every kilogram, greenhouse gas emissions by 71%, and energy consumption by 76%, according to the American Chemical Society’s Green Chemistry Institute in announcing the awards. Additionally, the route eliminated all single-use silica gel chromatographic separations, achieving an overall 76%  reduction in process mass intensity (3).

Boehringer Ingelheim was recognized for its work developing a short and eco-friendly manufacturing process for spiroketone CD 7659, an intermediate. A new three-step asymmetric synthesis route improved the yield nearly five-fold from 10 to 47%, reduced organic solvent usage by 99%, eliminated use of halogenated solvents, and reduced water usage by 76%. The sustainability achievements were further highlighted by a process mass intensity of 117, a 72% relative process greenness (RPG) score, and an “excellent” innovation Green Aspiration Level (iGAL), placing it in the top 10% of industry processes. (3).

The CMO Excellence in Green Chemistry Award seeks to recognize outstanding efforts by CMOs in pharmaceutical green chemistry in support of pharmaceutical research, development, and manufacturing that demonstrate compelling environmental, safety, and/or efficiency improvements. The award recognizes greener advances in synthetic route development for starting materials, intermediates, or active pharmaceutical ingredients (APIs), including reaction conditions and chemical or manufacturing technologies.

PharmaBlock was recognized for a sustainable manufacturing process for commercial and developmental stage intermediates through two consecutive flow reactions using micro-packed bed technology. The project demonstrated the use of micro-packed bed technology to produce tert-butyl 3-oxoazetidine-1-carboxylate and tert-butyl 3-aminoazetidine-1-carboxylate through oxidation reactions and reductive amination reactions at scale, resulting in improvements to safety, equipment volume efficiency, process mass intensity, greenness, and cost efficiency (3).

References
1.US Environmental Protection Agency, “The Basics of Green Chemistry,” https://www.epa.gov/greenchemistry/basics-green-chemistry

2. P.T. Anastas and J.C. Warner,  Green Chemistry: Theory and Practice. Oxford University Press: New York, 1998.

3. American Chemical Society Green Chemistry Institute (GCI), “The ACS GCI Pharmaceutical Roundtable Announces 2024 Industry Award Winners” March 2024.