1. Michael Raymond Panel: C. Stewart Slater, Ph.D. Mariano Savelski, Ph.D. Gregory Hounsell Department of Chemical Engineering Rowan University

2. Introduction Methods Current Situation LCA of Pharmaceutical TRI Waste Study of an “Average” Pharmaceutical Facility LCA of Common Pharmaceutical Solvents Solvent Recovery / Reduction Case Studies Case Study on Solvent Recovery Flexibility Conclusions Future Work and Recommendations

3. Through the use of TRI data and LCA, the full environmental impact of solvent recovery and/or reduction may be realized. This may then be used to more effectively design systems geared at reducing solvent use and emissions. 80 to 90% of the mass that goes into producing an Active Pharmaceutical Ingredient (API) → solvents Small volumes mean solvent waste is most often incinerated either on-site or off-site Often only “in process” emissions are considered and emissions from manufacture and incineration are overlooked C.S. Slater, and M.J. Savelski, (2009). Innov. Pharma. Tech., 29, 78-83. C.S. Slater, et. al, (2010). in Green Chemistry in the Pharmaceutical Industry, ch. 3, 49-82.

4. Emergency Planning and Community Right to Know Act – 1986 – States must create local emergency units that must develop plans to respond to chemical release emergencies – The EPA must compile an inventory of toxic chemical releases from manufacturing facilities – this database is known as the Toxic Release Inventory (TRI) TRI – Publicly available database – Updated annually – Useful tool in determining trends in the control, use, and release of toxic chemicals

5. TRI classifies waste by categories based on waste allocation Advantages Powerful tool to identify environmental opportunities Highlights most harmful waste sources Aids in determining industry wide areas for improvement Disadvantages Does not signify toxicity All chemicals listed are toxic, but degree of toxicity may vary greatly Does not display the harm of individual chemical releases USEPA. United States of America. 2008 Toxics Release Inventory (TRI) National Analysis., 2009.

6. Small volume batches are common - Waste recovery not considered feasible 80-90% of the mass that goes into making an API is attributed to solvents – small scale solvent recovery system can achieve 90% emission reduction The TRI can be used to focus efforts and improve feasibility of implementing recovery system – May target the most common pharmaceutical solvents – May target the most harmful solvents to the environment and community

7. Limitations on what defines a company that must report – 1988 – TRI reporting begins – 1998 – many industry sectors added, most significant to Pharmaceutical industry Solvent Recovery Facilities Facilities handling PBT (Persistent, Bioaccumulative, and Toxic) chemicals Any facility which uses over 10,000 pounds of a TRI chemical over a calendar year Which chemicals are defined as “toxic” by the EPA – Criteria Air Pollutants (CAPs) – six categories defined by the EPA Clean Air Act – Two Examples HAP - air pollutant that has an adverse human health effect, such as cancer Particulates – Many HAPs and CAPs are included in the TRI – Particulates are not

8. Excludes data prior to 1991 as reporting to TRI was voluntary Three distinct segments – 1991 to 1993: expanding U.S. pharmaceutical industry and government programs for reducing toxic releases – 1994 to 2000: expanding U.S. pharmaceutical industry and additions to TRI reporting – 2001 to 2008: TRI reporting regulations mostly complete Total Waste Managed by the Pharmaceutical Sector

9. Linear Decrease - 235 MM kg of waste to 87.8 MM kg of waste Signifies increase on focus in two areas – Waste and emissions reductions – reducing the amount of toxic chemicals used Total Waste Managed by the Pharmaceutical Sector: 2001 to 2008

10. Life Cycle Assessment (LCA) - systematic method for analyzing the environmental impact of a product, process, or service through a cradle-to-grave approach ISO-14040 to ISO-14047: methodology for LCA development and interpretation Software Packages – SimaPro 7.1® (PRé Consultants, Amersfoort, Netherlands) – EcoSolvent ® (Safety and Environmental Group, Zurich, Switzerland) (SimaPro 7.1 ®) (EcoSolvent ®)

11. Four Steps to Developing an LCA: Goal Definition and Scoping – Define the products or processes – Define the boundaries Inventory Analysis – Indentify energy and materials used – Identify environmental emissions Impact Assessment – Assess any potential human effects – Assess any potential ecological effects Interpretation – Evaluating the Inventory Analysis and Impact Assessment results – Make an informed decision on which process or product is environmentally superior

12. “The importance of solvents and solvent use in the manufacture of complex drug products often comes as a surprise to analysts” -GlaxoSmithKline Role of solvents in the production of an Active Pharmaceutical Ingredient (API): Do not enter into reaction chemistry – Serve as medium for reactions – Used in purification and washing steps Constitute 80 – 90% of reaction mass Contribute 60% of energy demand End of Life Cycle = Incineration LCA provides two environmental incentives: Reduce virgin solvent required Reduce amount of solvent waste C. Jiménez-González, et. al, Int. J. LCA, 2004, 9, 114-121. C.S. Slater, and M.J. Savelski, (2009). Innov. Pharma. Tech., 29, 78-83.

13. Top 10 TRI Solvents in the Pharmaceutical Industry Production of 1 kg of API = 25 – 100 kg of solvent waste Top 10 TRI solvents constitute 72% of pharmaceutical TRI waste Top 4 TRI solvents constitute 64% of pharmaceutical TRI waste Note: Acetone does not appear as it is not labeled a TRI chemical.

14. Amount of Waste Attributed to Each of the Top 4 TRI Chemicals Reported by the Pharmaceutical Sector Consistently top 4 TRI waste contributors Waste from methanol alone reduced 76% TRI makes problem areas easier to notice and target

15. Life Cycle Inventory (LCI) created manufacture, use, and incineration of each of the top 10 TRI pharmaceutical solvents – Record of the emissions attributed to a product through raw material acquisition, manufacture, use, and final disposal – Crucial to the development of an LCA LCI created for remaining chemicals modeled as a “generic solvent” Example LCI for Manufacture of 1 kg of the Top 10 Pharmaceutical Solvents and a “Generic Solvent”

16. LCI for Manufacture of 1 kg of the Top 10 Pharmaceutical Solvents and a “Generic Solvent” Chlorobenzene displays largest mass of emissions per kg of solvent manufactured

17. LCI for Incineration of 1 kg of the Top 10 Pharmaceutical Solvents and a “Generic Solvent” Neither N-Methyl-2-Pyrrolidone (NMP) nor ammonia exist in the Ecosolvent database. NMP modeled as N,N-Dimethylformamide (DMF) – same class of dipolar aprotic solvents Ammonia excluded from analysis

18. Cradle-to-Grave LCI of 1 kg of the Top 10 Pharmaceutical Solvents and a “Generic Solvent” Chlorobenzene displays the largest mass of cradle-to-grave life cycle emissions NMP incineration is modeled as DMF incineration Ammonia incineration is excluded

19. Cradle-to-Grave Emissions Chlorobenzene – 4% of TRI waste – 13% of TRI life cycle emissions Half of the total life cycle emissions are attributed to 3 solvents – Methanol – 17% – Dichloromethane – 20% – Chlorobenzene - 13% LCA makes the effect of TRI chemicals more apparent.

20. Cradle-to-Grave Emissions Divided total life cycle emissions by 152 – the number of pharmaceutical facilities reporting to the TRI in 2008 Total Mass of Waste – 0.58 MM kg Solvent Life Cycle Emissions – 2.55 MM kg – Solvent Manufacture – 1.21 MM kg – Solvent Incineration – 1.34 MM kg

21. Emissions from solvent manufacture and incineration correlates to 75% of total emissions – remainder is from in-process use Total Life Cycle Emissions for the Production of an API – 3.4 MM kg

22. Solvent Recovery Scenario – 80% of solvent waste is recovered and recycled back into the process “Greener” Solvent Scenario – Solvents that release fewer emissions during manufacture and incineration are employed in the process, replacing the original solvents Telescoping Scenario – A process employing multiple steps is reduced to a process employing 2/3 the number of steps Solvent Recovery Scenario“Greener” Solvent Scenario Telescoping Scenario

23. Total Life Cycle Emissions: 78% reduction – Base Case Scenario: 3.4 MM kg – Best Scenario: 0.76 MM kg – Total Reduction: 2.65 MM kg Best Scenario Manufacture Emissions: 96% reduction Incineration Emissions: 90% reduction In Process Use Emissions: 34% reduction Best Scenario: Implementation of all three green scenarios.

24. Life Cycle Emissions Profile for the Production of 1 kg of Solvent to Air, Water, and Soil* *In each case, emissions to soil are negligible. Emissions to air make up majority Only IPA has a large percentage of emissions to water – Commercial production of IPA requires large amounts of reaction water Comparatively large amount of emissions from THF production due to a proportionately larger energy demand U.S. Pat., 5,081,321, 1992.

25. Life Cycle Emissions Profile for the Production of 1 kg of Solvent to Air 96 – 99% of emissions to air are CO 2 – Majority of CO 2 emissions in manufacturing sector from refining, petrochemical, and chemical plants – 97% of air emissions from transportation attributed to CO 2 By reducing amount of fresh solvent required, the emissions from manufacturing and transportation are significantly reduced

26. Oncology Drug – Bristol Myers Squibb – Pilot scale production of drug in clinical trials – Azeotropic mixture of THF and water from dehydration of pharmaceutical intermediate – Currently use CVD (Constant Volume Distillation) – requires large amount of THF entrainer – Solution – Add pervaporation unit Celecoxib – Pfizer – Commercial scale production of the API in the arthritis drug Celebrex® – Mixture of IPA, water, and impurities from final crystallization/production step – Stream has high TDS (total disolved solids) and various azeotropes – Currently incinerate waste off-site – Solution – Add distillation-pervaporation-distillation unit J.C.M. Farla, et al., Energy Convers. Manage., 1995, 36, 827-830. G.D. Searle, LLC, Highlights of prescribing information: Celebrex, 2009. M.J. Savelski, et al., presented in part at The 8th International Conference on EcoBalance, Paper 02-02, 2008. C.S. Slater, et al., Proceedings of the 2008 Meeting of the American Institute of Chemical Engineers, 2008. M.J. Savelski, et al., presented in part at the 12th Annual ACS Green Chemistry & Engineering Conference, Paper 133, 2008.

27. Synthetic Intermediate - Novartis – Commercial production of a synthetic pharmaceutical intermediate – Batch adsorption with activated carbon used to reduce concentration of Pd in crude reaction mixture, then wash vessel with large amount of solvents – Currently incinerate solvent waste – MeOH, solid waste, and activated carbon – Solution – Switch to fixed bed adsorber (FBA) with synthetic resin Selamectin – Pfizer – Small scale production of the API in the veterinary pharmaceutical Revolution® – Mixture of acetonitrile and acetone – Currently incinerate waste – Solution – Add distillation column C.S. Slater, et al., presented in part at the American Institute of Chemical Engineers Annual Meeting, Paper 223f, 2007.

28. 94% reduction in overall emissions 64.3 kg of emissions avoided per kg of API produced

29. 91% reduction in overall emissions 64.1 kg of emissions avoided per kg of API produced

30. 91% reduction in overall emissions 10.3 kg of emissions avoided per kg of intermediate produced

31. 76% reduction in overall emissions 73.1 kg of emissions avoided per kg of API produced

32. Expanding use of a recovery system to other processes can greatly increase the environmental implications Especially effective for facilities operating different production campaigns throughout the year Investigated alternate uses for the Pfizer selamectin recovery system Two feasible opportunities – Recovery of IPA from an IPA/toluene waste stream From the production of Nelfinavir, the API in Pfizer's drug Viracept ®, used in the treatment of HIV – Recovery of toluene from a waste stream of toluene, acetone, branched octane, and trace cyanide From the production of hydrocortisone acetate, an API in TriOptic S ®, a treatment for bacterial infections in the eyelid and conjunctiva in dogs and cats

33. 75% reduction in CO 2 emissions (264,000 kg/yr) 76% reduction in overall emissions (282,000 kg/yr)

34. 65% reduction in CO 2 emissions (212,000 kg/yr) 67% reduction in overall emissions (255,000 kg/yr)

35. 50% reduction in CO 2 emissions (660,000 kg/yr) 52% reduction in overall emissions (732,000 kg/yr)

36. Solvent recovery / reduction systems can be designed to target the most common and/or environmentally unfriendly solvents Solvent manufacture and incineration play a significant role in the life cycle emissions of an API These emissions can be reduced by implementing a solvent recovery / reduction system The environmental potential of implementing the solvent recovery system is significantly increased by examining all possible applications By looking at the entire life cycle these emission reductions become apparent

37. Continue to observe and analyze TRI data Software development – Modular software to be implemented in industry Combine design software (ASPEN®) and LCA software (Simapro®) User friendly interface (Excel®) – Aid in design of solvent recovery systems – Predict resulting emissions reductions – Predict economic benefits

38. Professor C. Stewart Slater, Ph.D. Professor Mariano Savelski, Ph.D. Partial support for this has been provided by a grant from the US Environmental Protection Agency, NP 97257006-0. Nora Lopez of EPA Region 2 The following companies and personnel: – Bristol-Myers Squibb – San Kiang, Thomas LaPorte, Stephen Taylor, Lori Spangler – Novartis – Thomas Blacklock, Michael Girgis – Pfizer – Greg Hounsell, Daniel Pilipauskas, and Frank Urbanski Timothy Moroz and Maria Nydia Ruiz-Felix for their prior efforts Anthony Tomaino, Joseph Hankins, Christopher Mazurek, and James Peterson for their efforts in undergraduate research The Royal Society of Chemistry and personnel – Sarah Ruthven and Gill Cockhead

41. Emissions from ManufactureEmissions from Incineration Cradle-to-Grave Emissions LCA makes the effect of TRI chemicals more apparent Chlorobenzene – 4% of the mass of TRI waste – 13% of TRI life cycle emissions Half of the total life cycle emissions are attributed to 3 solvents – Methanol – 17% – Dichloromethane – 20% – Chlorobenzene - 13%

42. Base Case – TRI.Net Displays 152 pharmaceutical plants in the U.S. – Manufacturing and Incineration values are the result of dividing the LCA Manufacturing and Incineration totals by 152 – In Process Use is from a ratio found by historic data at GSK of process emissions to manufacturing emissions Solvent Recovery – Assumes 80% of the solvent is recovered – Reduces emissions from manufacturing and incinerating solvents by 80% – In process emissions remain approximately the same Green Solvent –A ratio of manufacturing emissions of the five greenest solvents and the five least green solvents from the top 10 solvents was found –Used to estimate decrease in manufacturing emissions – A ratio of incineration emissions of the five greenest solvents and the five least green solvents from the top 10 solvents was found –Used to estimate decrease in incineration emissions Telescoping –Assumes 1/3 of the unit processes are removed from the overall production process –All emissions are reduced by 33%