University Engineering Clinics to Advance Green Engineering in Pharmaceutical Production

1. University Engineering Clinics to Advance Green Engineering in Pharmaceutical Production Mariano J. Savelski and C. Stewart Slater Rowan University, Department of Chemical Engineering, Glassboro, NJ Unleashing Green Chemistry and Engineering in Service of a Sustainable Future U. S. Environmental Protection Agency New York, NY September 23, 2011

2. Introduction • Projects supported by U.S. Environmental Protection Agency – Region 2 • Pollution prevention • Green chemistry • Green engineering/green manufacturing • Sustainable engineering • Design for the environment • Industry-University partnerships • Pharmaceutical sector • Green engineering outcomes • P2 reductions • Training EPA Region 2Serving New Jersey, New York, Puerto Rico, US Virgin Islands and 7 Tribal Nations

3. Comprehensive State University 10,000 FTE Formerly Glassboro State College (est. 1923) “Cold war summit” (1967) Rowan $100 Mil gift (1992) College of Engineering (1996) Consistently top-ranked by U.S. News (2000-2011) Medical School (2012) Rowan University

4. Academic-Industrial Interaction • Process case studies with a green chemistry and engineering component • Three pharmaceutical company partners • Bristol-Myers Squibb • Novartis • Pfizer • Project outcomes show P2 impact • Waste reduced • Energy saved • Carbon footprint reduced • Cost saved • “Paper-projects” / design-based, experimentally-based or combination thereof N P B R Slater and Savelski, World Transactions on Engineering and Technology Education, 9, 6-11, 2011

5. Rowan Engineering Clinics • Modeled after medical schools • Student-faculty problem solving teams • Applied research, development, design • Partnership: Industry, Federal/State Agency, Foundation • Multidisciplinary (Engineering, Sciences, …) • Year or multi-year projects • Junior & Seniors and Graduate students

6. Rowan’s Project Based Curriculum

7. Clinic Timeline • Preliminary contact • Confidential disclosure / IP agreement • Initial meetings: Rowan faculty/students with Process R&D scientists/engineers • Clinic partnership agreements • Set and review project goals/objectives • Review of process documentation • Site visit (plant / R&D) • Weekly project meetings with student team • Students interact as needed with industry partner • End of semester presentation to industry partner

8. Industry Contributions • Interaction with student team • Process background and relevant information • Connections to corporate constituencies, e.g., R&D, manufacturing, EHS • Pharmaceutical company “culture” • How industry prioritizes alternative strategies • Where is the best place to improve a process • Business sense – what will management need to see to make decisions

9. Student’s Needs • What actually goes on in a plant? • What are the drivers that affect the evolution of a process? • What is important and why? • What are cGMPs and the FDA all about? • How do we effectively work as a team? • How do we interact with R&D, engineering, manufacturing, etc?

10. University’s Needs • “Champion” for green engineering and partnering from industry • Project matched to faculty and student expertise • Sufficient resources allocated (time and $) • Realistic timelines and expectations • Reasonable confidentiality agreements – presentations/papers • Projects that ‘map’ to programmatic goals/objectives, ABET criteria

11. Typical Project Outcomes • Literature/vendor review • Engineering analysis of • Discovery/Lab scale process • Intermediate/Pilot process • Production/Manufacturing process • Investigate equipment / process operations • Investigate process design and optimization • Case study • Apply metrics to quantify improvements • Recovery / Production • Waste reduced • Energy saved • Cost saved • Recommend process improvements

12. Bristol-Myers Squibb Project • Partnership with BMS – Process R&D (New Brunswick, NJ) • Integration of pervaporation membrane technology for THF solvent recovery in a synthesis step of a new oncology drug • Clinic team must make a case based Green Engineering principles and meeting pharmaceutical industry needs • API currently in pilot scale production for clinical trials Slater, Savelski, Moroz, Raymond, Green Chemistry Letters and Reviews, 4, 2011,

13. Raw Materials THF 4.01 kg 5.65 kg 1.00 kg Emissions Energy 128 MJ Bristol-Myers Squibb Project • Life cycle analysis points of emissions • Majority of life cycle emissions reduced by recovering/reusing solvent - avoiding solvent manufacture (94% emissions reduction) Slater, Savelski, Moroz, Raymond, Green Chemistry Letters and Reviews, 4, 2011,

14. Novartis Project • Development of greener adsorption process for pharmaceutical synthesis at East Hanover, NJ R&D facility • Heck coupling reaction used to produce pharmaceutical intermediate for multiple drug syntheses • Batch adsorption technique is currently used to remove palladium (Pd) catalyst from a reactor producing drug intermediate • Requires solvent and detergent rinses Raymond, Slater, Savelski, J. Green Chemistry, 12, 1826-1834, 2010,

15. Novartis Project • Proposed greener fixed bed adsorption design • Reduces • MeOH solvent rinses • Adsorbent • Water • Waste • Lab scale process at R&D facility scaled-up via simulation and environmental footprint analyzed • Life cycle emissions reduced 94% (94% CO2) from base case Raymond, Slater, Savelski, J. Green Chemistry, 12, 1826-1834, 2010,

16. Pfizer Project • Investigation of solvent recovery alternatives to reduce solvent waste in celecoxib process – Barceloneta, PR • IPA solvent recovery from final purification steps • Integration of pervaporation with distillation using existing equipment inventory Recovery IPA / Water Washes 50% IPA 50% Water IPA / Water Washes 49.2% IPA 49.6% H2O 0.71% MeOH and EtOH 0.5% TDS Centrifuge Solvents Water API Other Mother Liquor 34.5% IPA 45.2% H2O 8.45% MeOH 2.71% EtOH 9.10% TDS Conc. & Sell ML Wet Product Solids Dryer Celecoxib Dryer Distillates 50.7% IPA 48.8% H2O 0.47% MeOH and EtOH 0% TDS Savelski, Slater, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Conf, Washington, DC, 2008,

17. Pfizer Project • Purification for only part of waste stream • Centrifuge wash and Dyer distillates for recovery • Mother liquor for (sale) use as generic solvent • Overall 57% IPA recovered @ 99.1 wt% for reuse in process • Life cycle emissions reduced by 92% (95% decreases in CO2) over base case Savelski, Slater, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Conf, Washington, DC, 2008,

18. Future Plans • New EPA Region 2 Project • Modeling and simulation of environmental footprint of green solvents and recovery systems for pharmaceutical industry • New partnership with Pennakem LLC • Evaluate life cycle inventory for MeTHF and other green solvents • Modeling and simulation of process applications

19. Benefits of Partnership • Exchange of new engineering ideas • Dissemination and outreach • Presentations at conferences • Workshops for industry, academia, gov’t • Newspapers, web postings • Journal publications / books • Industry gains experience, implements new approaches to engineering • University develops expertise to advance state-of-the-art • New engineers graduate with knowledge of a specific commercial sector

20. Acknowledgements Bristol-Myers Squibb San Kiang, Thomas LaPorte, Stephen Taylor, Lori Spangler Pfizer Jorge Belgodere, Peter Dunn, Greg Hounsell, Daniel Pilipauskas, Frank Urbanski Novartis Thomas Blacklock, Michael Girgis Rowan University Students Scott Barnes, William Carole, Daniel Duffield, Anthony Furiato, Kyle Lynch, Colleen McGinness, Timothy Moroz, Michael Raymond, Nydia Ruiz, David Walsh U.S. EPA Region 2 Grants NP97257006-0 & NP97212311-0