Environmental Decision Making & Metrics Session: Methodologies for Assessment and Sustainability Room Location: South American AB Tuesday, June 24, 2008 Sharon W. Austin, Green Engineering Program, Office of Pollution Prevention and Toxics Hello and glad to be here. CEB provides technical support to many OPPT activities in the areas of chemical engineering, industrial hygiene, occupational exposure and env. releases. We also manage the GE activities.“ In September at the Seize the Moment conference, Dave Constable presented a lot of information on pharma operations and impacts of solvents. This has been incorporated within this presentation and slides were prepared in consultation with David / industry, with blessings.

AGENDA Environmental Footprint and Successes Cumulative Waste Loads Manufacturing Inputs & Outputs (Releases) Post Treatment Inputs (Releases) and Outputs Off Site Incineration Metrics Flow Sheet – Opportunities / Barriers / Metrics GE Stewardship Initiative – 3 R’s: Reduce, Recover, Reuse Mission / Project Goals Manufacturing 3 R’s – Opportunities, Barriers Post Treatment Metrics – Chemicals, Energy & GHG Puerto Rico Pilot / Example AIChE Annual Meeting Topical Conference: Government Programs and Partnership Session

Cumulative Waste Loads for a “Typical” Pharmaceutical For API manufacture: “Typical” manufacturing yield from a single stage ranges between 35 and 95% with an average of 86% A “typical” primary manufacturing process is on the order of 6 stages with an overall yield of 30 - 40% Overall yield does not capture use of reagent, solvent, catalyst. If these are included the average total materials use is 16 kg/kg of stage product (intermediate). Even with a 100% yield at each stage, a 16 kg/kg materials use would result in an overall Mass Productivity of about 1%. NO GE activity can replace reductions made by GC solutions in reducing # of stages 99 kg waste to yield 1 kg API - - and this is at 100% yield at every stage. Paradigm shift to look in other places, and have the ability to make these optimizations. Typical: 86% yield per stage 6 stages Total materials avg 16 kg / kg product (intermediate or API) At 100% yield euqated to 99 kg waste to yield 1 kg api Like . . The SOLVENTS!! (like, it’s the Economy, __) 99 kg of waste to yield 1 kg of API!!! Adapted from / Courtesy of: David J. C. Constable, GlaxoSmithKline

Pharmaceutical Flow Diagram - Manufacturing Focus Opportunities Largest Volume of chemical Variety of Uses Cumulative through various production stages Typical focus has been on feedstocks – optimization of the horizontal (GC solutions at reducing stages have greatest impact in reducing solvents generated) FOCUS on the VERTICAL – SOLVENTS INPUTS and OUTPUTs - -- Specifically on outputs - - those streams (already measured / some TRI reported) of output releases going to post treatment operations Both On and Off site Focus on Solvent & Solvent / Water Inputs and Outputs

Next .... Off Site Incineration Metrics Pharmaceutical Flow Diagram – Post-Treatment Environmental Footprint: Not manufacture, but Post Treatment unit operations / peripheral support systems Chemical / Water destructions BTUs – gas / oil / electricity GHG Incineration: off site – no energy recovery, on site – energy recovery Next .... Off Site Incineration Metrics

2006 TRI & Post-treatment LCI Models – Off-Site Incineration Metrics TRI 2006 – NAICS 25411 and 225412 – pharma sector off site incineration (m) codes Incineration ONLY model run. (no energy recovery included) Of the 122 million lbs chemical – thermally destroyed, no longer available for use – ~50 were water soluble (carried 50% water) making aqueous organic mixture with 25% water content 4 million gallons water incinerated – thermally destroyed, no longer available for use Reguired 90 trillion BTUs to incinerate Generated 140,000 metric tons, GHG primarily CO2 Top Solvents: Methanol (soluble), dichloromethane (insoluble) All primary feedstocks Dow announced 20% price increase 05/29/2008 (Washington Post Express)

Where to Focus? What to Measure? Pharmaceutical Flow Diagram: Decision Making and Metrics Where to Focus? Opportunities: Barriers: Chemical Liability of feedstocks still in solvents RCRA Business Case How / What to measure: Baseline: output streams to post treatment Include chemicals / water (destroyed), energy, GHG in metrics Add to baseline with three R’s - - environmental clarity – top two solvents Where to Focus? What to Measure?

Green Engineering and Sustainability for Pharmaceutical Processes Mission: Reduction, Recovery and Reuse of solvents. Solvents as secondary product, not waste. Project Goals: Remove barriers, perceived or real, on the reduction, recovery and reuse of these solvents and Provide the business case in the reduction, recovery and reuse of these solvents in chemicals, energy, emissions, water and other economic and environmental benefits. Work propelled by activities in Puerto Rico - - elimination of TDS / off site incinerated waste pick up Needed to start recovering STOP FOCUSING SOLELY ON THE CHEMISTRY OF REACTANTS Start with superior replacements – demonstrate comparabilty through MASS (LCA) and ECONOMIC Balance

Green Engineering Pharmaceutical Initiative: Reduce , Reuse, Recover – Decision Making GE Manufacturing Flow Diagram with the three R’s Reduce Activities: Input Streams Process Optimizations, RX concentration, Reuse: In Process: Ideal sets of solvents Out of Process: DOC / NIST /MEP By Product Synergies – Third Party Markets Recovery: New RCRA Law Redefines Solid Waste Minimize releases to post treatment – measure streams Metrics based on not only chemicals, but energy, GHG and water saved

Green Engineering Pharmaceutical Initiative: Reduce , Reuse, Recover - Metrics GE Post treatment diagram – output streams For BASELINE metrics Minimize releases to post treatment – measure streams Metrics based on not only chemicals, but energy, GHG and water saved. Metrics example just for off site incineration Did not, but can, incorporate: Energy Recovery WWT – large electricity Solvent Recovery Add up – based on material flow, Env Clarity database, works in partnership LCA for soluble, insoluble solvents EPA – risk component, property assessment tools (SF), material flow (ChemSTEER)

Incineration Treatment Module: Calculation Sheet Puerto Rico – Energy OFF siote incineartion model run for PR 2006 reported TRI solvents First three columns are constant 4th column: Enter KG amounts Remove row(s), adjust total aqueous equation Run did not include Energy Recovery

Incineration Treatment Module: Calculation Sheet Puerto Rico - Emissions GHG emissions from post treatment off site incineration Energy Recovery not included Does also not include WWTP, though water emissions calculated Does not include landfill, though solid waste emissions calculated '* Based on the models published in: Jimenez-Gonzalez C, Overcash MR and Curzons AD. J. Chem. Technol. Biotechnol. 71:707-716 (2001)

Green Engineering Pharmaceutical Initiative: Reduce , Reuse, Recover – Puerto Rico as Pilot DOC / NIST / MEP Scorecard.org: other uses Third party markets Baseline Metrics: output streatms Add to case study: application of the three Rs

AIChE Annual Meeting - November, 2008 Pharmaceutical Topical Conference Government programs and partnership sessions: Reduce: sessions one and two Reuse: sessions one, three and four Recover: session 5 – new RCRA law FDA – Green Product quality

So with that and in closing . . . THANK YOU!  & ???Questions??? Sharon Austin Austin.Sharon@EPA.gov (202)564-8523 If the FDA could come in and say: If you make these kind of process changes that are not going to effect product quality, we would not get ‘aggitated’, file 483, etc would significantly shift how pharma operates and open door(s) to several opportunities. Many out in the audience, especially industry, are probably thinking: “All of this is good, but we do not necessarily have the flexibility to just make these changes - - especially if they impact, even positively, on our purity profiles” New, collaborative term we are introducing: evolved while preparing sessions Chris will let you know more - -- but I got his specific approval / agreement on this slide before including in this presentation - - - which he was happy to do.