Yield Reaction Mass Efficiency (RME)A measure of the chemistry efficiencyNo. of stages and no. of chemistry steps Measure of the route complexityTotal no. of solvents and solvents per stage solvent is the biggest influence on massMass Intensity and Mass Productivity (Efficiency)MI: total mass required to make 1 kg APIMP: total mass to make API ( %)Materials of ConcernEarly identification – materials matterProcess life cycle environmental impact: FLASC and Solvent Score
Lessons learned - the pharma experience
Lessons learned through measuring Green Chemistry performance: The Pharmaceutical ExperienceDavid J. C. Constable, PhDGaithersburg, MD 20878 DESCA - 2012Telephone: 301-926-1402e-mail: David.JC.Constable@gmail.com 5 March 2012
Carbon Efficiency Reaction Mass Efficiency YieldOutline Atom Economy Stoichiometry Mass Efficiency First Challenges of the Pharma Context Batch Chemical OperationsSecond Metrics and Process Ask the right questions Total Water Third Choose the Right Metrics There are a lot of optionsFourth What did we Learn? There is value in analysis Total CO2 Fifth Conclusions Positive change is possible Net Mass Excluding Process Water Energy Solvent Recovery Energy
The Pharmaceutical Industry isChallenged by Complexity O F OH O HO O O O S H HO OH O O O O H NH N O O N O O H OH O H OH O F H N O HO OH H O F HOThey are complex: paclitaxel F fluticasone salmeterol atorvastatin HN • target molecules, reagents and reactants • synthetic routes: 6+ stages • processes and wastes: mixed aqueous and organic Cl streams Cl sertralineNeed for early and rapid definition of the synthetic routeBut there is a high failure rate for target molecules N O N N O N O S N N O F H N O esomeprazole risperidone
The Pharmaceutical IndustryRegulatory Climate is Challenging • Highly regulated by government agencies • process changes • use of recovered/recycled solvent • Route and Process changes post-approval give the appearance of being costly • Regulatory / Legislative restrictions on solvent and materials selection • EU Solvent Directive, REACH, IPPC, ICH etc
Finding the Right Balance can be aChallenge Commercial Focus on Speed to Market Green process Attrition design earlywhen costs are lower
Green Chemistry and Metrics WELCOME TO Pine View, Colorado Established 1872“All he’s done is call it Green” Population 732 The person who sat behind me, GRC Green Elevation 5755 Chemistry Meeting, Oxford, 1999, as related by John Hayler, GSK TOTAL 8359* “If you don’t keep score, you’re only practicing” Jan Leshley, former CEO SB & GSK *Audited by 3iDataCen (Formerly, the Center for irrelevant, immaterial and inconvenient Data)
Key Message Ask the right questions!Avoid “the perfect uselessness ofknowing the answer to the wrongquestion” The Left Hand of Darkness Ursula K. LeGuin 1969
Develop a process that fits in with existing ways of workingHighlight keysustainability issues for Complete at known stagesmaterials and process of development Document PRMR Identify and information communicate opportunitiesVehicle for discussion with chemists, engineers and management
Green Metrics TemplateCompound Number Benchmarking data againstRoute Designation A3 projects in the same phaseCampaign # and Date CDD4Intended Purpose of Campaign Ph II, POC workAmount made 4.8kg Life cycle impact (FLASC) &Date of Assessment and Reference 2-Aug-06 Solvent Acceptability Score YOUR DATA AVERAGE VALUES FOR CS- FTIH PROJECTS • f(mass, number, type ofNumber of Stages 6 solvent)Number of Chemistry Steps 7Number of Stages Outsourced 3Overall Yield % theoretical 37.3%Mass Intensity kg/kg API 207.57 691 Priority materials of concernAqueous Mass Intensity* 86.76 flagged according to the GSKMass Productivity % 0.48% 0.29Reaction Mass Efficiency % 8.57% 5.5 Chemicals Legislation GuideTotal Number of Solvents 10 8.8Number of Solvents per Stage 2.33 2.4 e.g. for Compound XTotal Mass of Solvents / Kg API 195.9 (94% of reaction wt) 591 • Route A – noneCurrent Material Cost / Kg API(from B+) • Route B – DichloromethaneFLASC Score (1-5) 1.9 1.4 • Route C – 1,4-dioxaneSolvent acceptability score (1-5) • Route D – Dichloromethane 1.2 0.5Materials of concern none THF 30.2% Methanol 15.75%Major Contributors to Overall Mass Toluene 12.5%of Materials Ethanol 10.9%Additional Comments
Green Metrics Template Page 2 Mass Productivity benchmarked against current GSK data by phase of development FLASC score for your project measures the environmental impact of materials in a route benchmarked against GSK processes General guidance to help interpret the metrics values and sources of further information
FIND THE RIGHT METRICS • Make objective comparisons • Benchmark progress • Drive change • Demonstrate improvement • Increase transparency
Principles of Green Chemistry andEngineering – Simplified* • Maximize resource efficiency • Eliminate and minimize hazards and pollution • Design systems holistically and using life cycle thinking*See: Green Chemistry and Engineering: A Practical Design Approach.Jimenez-Gonzalez C, Constable DJC. John Wiley and Sons. 2011, p 35- 37.http://www.amazon.com/Green-Chemistry-Engineering-Practical-Approach/dp/0470170875
Key Metrics are Essential Can we change the chemistry?• Yield Telescope, maximise• Reaction Mass Efficiency (RME) convergency, pay• No. of stages and no. of attention to order of side chain coupling chemistry steps• Total no. of solvents and solvents Recycle/reuse 80 – 90 % of the mass! per stage• Mass Intensity and Mass Focus on Productivity (Efficiency) optimising use of a few• Materials of Concern key materials• Process life cycle environmental impact Starting Materials matter!
Reaction Mass Efficiency (RME) RME = efficiency of conversion of reactants into product. It includes: Yield Atom Economy Stoichiometry of the reactants
Reaction Mass Efficiency For a generic reaction: A+B C m.w.of product C RME yield m.w.of A (m.w.of B x molar ratio B/A) or more simply: mass of product C RME X 100 mass of A mass of B
Top 10 Chemistries Used 2004 - 2005 N-acylation 11% N-alkylations 8% others 39% recrystallisation 8% salt formation/salt swap 6% hydrolysis (base) 6% OH activation/functional group change 3% S-alkylation 6% O-alkylation Chlorinations 3% 6% hydrogenation 4%
Solvent Use in Pharma is Significant• In 2008, 10 solvents Water 32% Solvents 56% represented approximately 80% of all solvents used in GSK Other 5%• Solvent use is the largest contributor to: Reactants 7% • Primary manufacturing process mass intensity Composition by mass of types of material used to manufacture an API • Primary manufacturing life American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable Benchmarking 2006 & 2008 cycle environmental impacts (e.g., ~80% mass, ~75% energy)
Process Water 50 38.9 40Average wt% water 32.5 28.6 29.7 30 20 10 0 CS to FTIH FTIH to PoC towards PoC to CP III full Phase III scale Pre-clinical commercialisation Data shows that the amount of process water used in washings and extractions per kg API could be optimised further
used 0 5 10 15 20 25 E th IP No of stages 30 A Solvents y la ce ta M t e et ha IM no S/ l E th a no H l ep t an e TH FD To ic h lo lu e ro ne m et ha A Top 10 Most Frequently Used ne ce tic ac A id ce to ni tri le
mass, % Et hy la 0 2 4 6 8 10 12 14 16 18 ce ta 20 t e IP AD ic h lo TH ro F m et ha ne M et ha no To l l IM uen S/ e Et ha Ac no l Top 10 Solvent Use by Mass et on itr ile H ep ta ne Ac et on e
Solvent Use % Solvent Mass 100 80 mass % 60 2005 40 2006 20 0 CS to FTIH FTIH to PoC PoC to CP III Phase III towards full scale Pre-clinical commercialisation• Solvent mass is ~90 wt% of reaction mass excluding water• Dilution of reactions is consistent across all phases of development• The type of solvent used does change; e.g., the majority of dichloromethane is removed by Proof of Concept
Mass Productivity Headline Data 2.5 < 50 kg per kg API Mass Productivity % 2.0 100 kg per kg 1.5 API 1.0 0.5 0.0 CS to FTIH FTIH to PoC towards full III PoC to CP III Phase scale Pre-clinical commercialisation API = Active Pharmaceutical Ingredient
What does it take to achieve MP > 1?*RME > 25% for MP > 1%RME 15 – 25% yields a 40% probability of MP > 1%Having < 4 stages increases probability for a MP > 1% % probability of MP stages >1% 2 85 3 75 4 50 5 50 >6 15 *Based on about 40 mature R&D processes
Materials of ConcernChemicals for which there is evidence of probable serious effects tohumans or the environment • carcinogens, mutagens or reproductive hazards (CMR’s), • toxic and bioaccumulate or persist in the environment (PBT’s), • very persistent or very bioaccumulative in the environment (vPvB), • ozone depleting chemicals (ODC’s), • endocrine disruptors (ED’s) • those known to cause asthma (asthmagens)Materials of Concern should be identified early todevelop strategies to eliminate or substitute.
Materials of Concern in 2006 Average mass % of materials of concern in processes 25 99.4% solvents 98.7% solvents 20 % by mass 15 100% solvents 10 65% Solvents 5 0 CS to FTIH FTIH to POC POC to PhIII PhIII towards full scale Pre-clinical commercialisation
Materials of Concern 2006 – top 6 90 81% dichloromethane 80 70 Mass % 60 50 40 30 20 10 0 ne e ne P CM F in M M ha xa rid D N D et o Py Di xy 4- ho 1, et m Di 2- 1,Finding alternative solvents to replace dichloromethane remains a key greenchemistry challenge
Are pharmaceutical processesbecoming greener?If solvent mass is ~ 90% of the reaction mass and ~ 75% ofthe life cycle energy and mass, what about the other 10% ofthe reaction mass?Are there correlations with current measures of greenness? Reaction Mass Efficiency vs. GSK FLASC Score vs. Chemical Mass Reaction Mass Efficiency vs. Molecular Weight Added Mass Intensity per Chemistry Transformation 60 RME vs MI per Step CS to FTIH GSK FLASC score vs Chemical Mass FTIH to POC 60 50 5.0 CS to FTIH PoC to PhIII FTIH to POC PhIII 4.5 GSK FLASC Score 50 40 PoC CS to FTIH to FTIH 4.0 PhIII FTIH to POC RME RME % 40 3.530 PoC to FTIH PhIII % 3.030 2.520 20 2.0 10 1.510 1.0 0 0 00 100 50 200 300 100 400 150 500 600 200 700 0 50 100 150 Added200 MW 250 300 350 Chemical Mass kg MI per step kg
Average Non-Solvent Mass 250 200 Non Solvent Mass kg/kg API 150 Cs to FTIH FTIH to POC PoC to PhIII 100 PhIII 50 0 0 2 4 6 8 10 12 No of StagesOptimization of reagent and reactant mass during development willhave the biggest impact for complex syntheses
Assessing over 100 pharmaceuticalprocesses tells us something important • No correlation between non-solvent mass and several different measures of greenness. • Mass based metrics do not appear to account for the complexity of the chemistry. • Mass based metrics do not account for the nature and impact of chemicals. • Is there more we should be doing to influence the selection of reagents to reduce the impact of solvents?
Life Cycle Assessment – The very big picture Raw material and energy consumption R&D:Process Development Resource Raw Material Intermediate Products Final ProductMaterial Selection Extraction ManufactureHazard & Risk assessment Sales and Marketing Ultimate Ecological Fate Store Distribution Final Consumer Use Emissions to air, water and land
Using a Streamlined Life Cycle Tool is KeyFLASCTM - Fast Lifecycle Assessment of Synthetic Chemistry) • Web-based tool and methodology • Simple to use (but not simplistic) • Determines and benchmarks the relative sustainability of chemicals • Based on cradle-to-gate LCA impacts
Life Cycle Impact - FLASC scores 65% of the Life FLASC - all data Cycle impact of the 27% of the Life average GSK 5.0 Cycle impact of the process* average GSK 4.5 process* 4.0 3.9 3.5 3.5 FLASC 3.0 ave 2.8 2.5 37% of the Life Cycle impact of the 2.0 1.9 average GSK 1.5 process* 130% of the LifeCycle impact of the 1.0 average GSK CS to FTIH FTIH to PoC PoC to CP III Phase III full scale towards process* Pre-clinical commercialisation The environmental life cycle impact of all new processes post-PoC is potentially much lower than for current processes in manufacturing * 25 GSK routes developed during 1990 to 2000 were assessed. The average performance was assigned a FLASC rating of 2.3
Life Cycle Impacts can be Decreased FLASC and Solvent Acceptability score Few years ago: histogram Most FLASC and Solvent50% Scores in lower range40% FLASC score (medians 2.4 & 2.2) SAS score30%20%10%0% <2.5 2 - 2.5 2.5 - 3 3 - 3.5 3.5 - 4 >4 FLASC and Solvent Acceptability score histogram 50% FLASC score Now: 40% SAS score Most FLASC and Solvent 30% Scores in middle range (medians 3.0 & 2.7) 20% 10% 0% <2.5 2 - 2.5 2.5 - 3 3 - 3.5 3.5 - 4 >4
Conclusions• Biggest impact from solvents: ~90 wt% of reaction mass• Effect on mass efficiency / intensity from replacing and substituting hazardous with non-hazardous chemicals is unknown• GSK’s life cycle assessment metrics suggest that processes in development are potentially getting greener
Summary• The Strategy is to regularly influence during product development• Green Metrics help Project Teams• Green Metrics should include life cycle assessment• Metrics should be collected for every pilot plant campaign• Metrics alone do not tell the whole story• Assessment of “greenness” is, and should be, a multivariate exercise
Future Challenges• Less toxic alternatives for hazardous solvents and reagents• Integration of chemistry and technology • Application of continuous processing, novel reactors, solvent systems • Bioprocessing • Further development of tools to objectively compare bioprocesses with chemical processes • Greater attention to downstream processing issues • Integration of life cycle considerations• Renewable feedstocks.• New, cleaner, reactions and methodology.
Acknowledgements Concepción (Conchita) Jiménez-González Richard Henderson GSK’s Sustainable Processing Team: • John Hayler • Clare Ruddick • Graham Geen • Jonathan Emeigh • Mario Almi • Tom Roper
ACS Webinar March 8thMeasures of Green Chemistry Performance http://acswebinars.org/constable Any Questions?