Green Chemistry Initiatives : ACS GCI Pharmaceutical ...

1 American Chemical Society ACS Green Chemistry Institute . Green Chemistry Initiatives : ACS GCI Pharmaceutical roundtable Juan Colberg Pfizer's Green Chemistry Program Leader Sr. Director of Technology & Innovation Pfizer and Green Chemistry It is integral to the way we do business and delivers sustainable, long-term profitability through safer more efficient processes; increased product yield that are compatible with protecting the environment; and the health and safety of our colleagues, customers, and the communities where we live and work . Pfizer's Green Journey American Chemical Society ACS Green Chemistry Institute . Presentation Outline Why Green Chemistry in the Pharma Industry Why American Chemical Society Green Chemistry Institute Pharmaceutical roundtable as a Partner Green Chemistry in Action: Green Technology American Chemical Society ACS Green Chemistry Institute.

2 Pfizer's Green Chemistry Pfizer Green Chemistry Program Pfizer Green Chemistry Mission A Global GC Program Leader To introduce, educate and promote GC Policy and Steering Committee- application of Green Chemistry across Pfizer. GC teams at all Chemistry Research Key Philosophy: Voluntary restraint Sites is better than enforced constraint. Green Chemistry includes protection Integrated GC into all development of the environment and worker safety. activities Informing and influencing the Green Chemistry research agenda. Practical Green Chemistry tools Awards American Chemical Society ACS Green Chemistry Institute . How to Build a Green Chemistry Culture 7 Important Elements of a Green Chemistry program Empowered Green Chemistry teams with management support Metrics and targets Resources and tools Education Investment in Green technology Awareness and recognition External collaboration D.

3 K. Leahy, J. L. Tucker, I. Mergelsberg, P. J. Dunn, M. E. Kopach and V. C. Purohit Org. Proc. Res. Dev., 2013, 17 (9), pp 1099 1109. American Chemical Society ACS Green Chemistry Institute . Pfizer's Green Journey American Chemical Society ACS Green Chemistry Institute . In 2005 the ACS GCI Pharmaceutical roundtable came together to catalyze innovative approaches to improving process efficiency and product quality through Green Chemistry and engineering. By working together, the roundtable provides leadership and influence throughout the industry and supply chain. Strategic Priorities American Chemical Society ACS Green Chemistry Institute . Inform and Influence the Research Agenda Influencing technical agenda's of funding agencies by defining needs and advocating investment in specific areas of Green Chemistry and engineering innovation.

4 Identifying and tracking emerging Green technologies with potential Pharmaceutical applications. Communicating/educating Green Chemistry and engineering technology developments within academia, member companies and other groups. American Chemical Society ACS Green Chemistry Institute . ACS GCI Pharmaceutical roundtable Key Green Chemistry Research Areas Current Reactions Amide Formation Key Ideas outside the reaction theme OH Activation Solvent-less Reactor Cleaning Amide Reduction Greener alternatives to polar Greener Mitsunobu Reactions aprotic solvents Oxidation/Epoxidations More Aspirational Reactions C-H Activation or Aromatics Key Green Chemistry research areas . Chiral Amine Synthesis a perspective from Pharmaceutical manufacturers, Green Chemistry , 9 (5), Asymmetric Hydrogenation 411-420, 2007. Greener Fluorination Methods N-Centered Chemistry American Chemical Society ACS Green Chemistry Institute.

5 Funding Research Grants Greener biologics Grignard in greener purification methods solvents Continuous Flow C-H activation Iron Catalysis Oxidation/Epoxidations Amide Reduction Amide Hydrogenation Non-precious metal Amide Formation catalysis Chiral Amine Synthesis Cross-coupling in Green solvents American Chemical Society ACS Green Chemistry Institute . Funding Research Grants $ million leveraged $ million from federal funding awarded to agencies academic researchers American Chemical Society ACS Green Chemistry Institute . Funding Research Grants $ million leveraged $ million awarded from federal funding to academic agencies researchers American Chemical Society ACS Green Chemistry Institute . Green Chemistry Program: Analytical tools Green Innovation Collaboration Data Management Created for the development of manufacturing sustainable pharmaceuticals Green and sustainable RAPID - Rapid Advancement in Process Pharmaceutical Intensification Deployment manufacturing via Achieving a Transformative Modular biocatalysis Manufacturing Future API and/or DP development and Sustainable Separation manufacturing Center for test- Processes bed/prototyping for Advanced Manufacturing Chemical concepts Computational Tools Innovations that can dramatically Control Systems reduce energy expenses in advanced manufacturing, ACS Green Chemistry Institute.

6 Define and Deliver Tools for Innovation Solvent Selection Guide Reagent Guide Process Mass Intensity American Chemical Society ACS Green Chemistry Institute . Contribute to High-Value Tools Interactive Reagent Guides Solvent Selection Guide 10 guides & counting >130 reagents American Chemical Society ACS Green Chemistry Institute . Impact of solvents in the Process Greenness within the Pharmaceutical Industry Solvent and water contribute >80% to the process mass intensity PMI. PMI = 100. 1 kg of API needs 100 kg of materials Solvents and water represent > 80% of these Emphasizes need for research to reduce the use and hazard of the solvent C. Jimenez-Gonzalez et al, OPRD, 2011, 15, 912. Source: 2008 ACS Green Chemistry Institute Pharmaceutical roundtable benchmarking exercise of 10 member companies 50. American Chemical Society ACS Green Chemistry Institute.

7 Solvents VOCs (Volatile Organic Compounds). Active Pharmaceutical Ingredient Manufacture Waste stream: 60-70% consist of solvents Energy usage: ~75% attributed to solvent Photochemical ozone creation potential: 70% attributed to solvents Greenhouse gases: 50% attributed to solvents Cost: 10-40% is attributed to solvents Cleaning 30-40% total VOC solvent use in Pharmaceutical plant is used in cleaning! A 4,000L reactor uses how much solvent in a traditional cleaning process? Clean Tech. Environ. Policy 2005, 7, 41. ~5,000L Constable, Solvent Considerations in Green Chemistry . 52. EPSCR START 2005 ACS GCI IGCW-180o seminar, Green Chem. 2002, 4,521 December 2013. American Chemical Society ACS Green Chemistry Institute . Metrics Metrics Tools- Process Mass Intensity Why Metrics? You can't manage what you don't measure.

8 We measure what we care about we care about what we measure Standardize measurement of chemical process greenness when possible Proper choice of metrics is critical for behavior of system'. Green metrics correlate to process economics 77. American Chemical Society ACS Green Chemistry Institute . Metrics Common Green Chemistry Common Unit of Consideration for Optimum Value Inventor Common Process Metrics Process Metrics Abbreviation Measure Waste? Yield? Stoichiometry? Solvents? Water? Chemical Yield CY % 100%. Atom Economy AE % 100% Trost (1991). Environmental Impact Factor E-Factor 0 Sheldon (1992). Mass Intensity MI 1 Constable, Curzons (2001). Process Mass Intensity PMI 1 ACS GCI. Pharmaceutical roundtable (2007). Process Mass Efficiency PME % 100% EPA & Hanson (2006). Mass Productivity MP % 100% Constable, Curzons (2001).

9 Reaction Mass Efficiency RME % 100% Constable, Curzons (2001). Effective Mass Yield EMY % 100% Hudlicky (1999). Reaction Mass Intensity RMI 1 Senanayake (2012). Carbon Efficiency CE % 100% Constable, Curzons (2001). Solvent Intensity SI 0 Constable, Curzons (2001). Wastewater Intensity WWI 0 Constable, Curzons (2001) 80. Roschangar, F.; Sheldon, ; Senanayake, "Overcoming barriers to Green Chemistry in the Pharmaceutical industry the Green Aspiration Level . American Chemical concept", Green Chem. 2015, 17, 752 768. Note: input materials = all used materials Society except ACS Green . Chemistry Green Chemistry Metrics Chemistry Process Yield E-Factor Selectivity PMI. Atom Economy Life cycle Reaction Mass Efficiency American Chemical Society ACS Green Chemistry Institute . PMI Calculator Tool Step Name/Number 1. Embedded calculations Value Units Physical Batch Size Assay Purity Only need to fill in amounts Assay Batch Size Yield Assay Kg product Product Purity Raw Materials Physical Charge of reagents, solvents, and Substrates (kg).

10 Water Spreadsheet calculates step Reagents Solvents and overall PMI for linear Aqueous sequences Calculates separate PMI for PROCESS STEP METRICS. Mass Substrate (kg) 0. solvents, water, and Mass Reagents (kg) 0. Mass Solvents (kg). Mass Aqueous (kg). 0 reagents Step PMI. Step PMI Excluding H2O. #DIV/0! #DIV/0! Publicly available spreadsheet Cumulative PMI #DIV/0! Cumulative PMI Excluding H2O #DIV/0! American Chemical Society ACS Green Chemistry Institute . Green Aspiration Level (GAL). F. Roschangar, J. Colberg, P. J. Dunn, F. Gallou, J. D. Hayler, S. G. Koenig, M. E. Kopach , I. Mergelsberg, J. L. Tucker, R. A. Sheldon and C. H. Senanayake, Green Chem., 2017, 19, 281. American Chemical Society ACS Green Chemistry Institute . Quantifying Impact Cost of Goods and E-Factor 120 250 E-Factor and Cost 100 Data can drive efficient drug 200 development 80 Data serves to assess efforts 150 among peers 60.