Green Chemistry & Engineering for Pharmacuetical Industry Impact of Process Research / Route Scouting towards the Environment during API Life Cycle Dhileep Krishnamurthy, Ph.D.
Outline Introduction Green Chemistry by Design (GCbD), Process Research, and Innovation API Life Cycle A Green Chemistry Prospective Alignment and Relationships between Process Research, GC Principles and Cost Savings Current Challenges at Innovator/Generic Industries in Designing the Greener Synthetic Route (GCbD) Strategies to Achieve GCbD through Effective Process Research Future Challenges and Opportunities 2
A $100 billion Business Opportunity by the Year 2020 for Practicing the Green Chemistry The worldwide chemical industry is valued at around $4 trillion Small improvement in the efficiency using Green Chemistry will have huge impact in savings Small improvement in the efficiency using Green Chmpact in savings Green Chemistry represents a market opportunity that will grow from $2.8 billion in 2011 to $98.5 billion by 2020 Three major segments for Green Chemistry Market 1. Waste minimization in conventional synthetic chemical processes 2. Green replacement for conventional chemical products 3. Use of renewable feedstock to produce chemicals and materials with smaller environment foot print Source: Pike Research Report on 1 st November 2011 from www.marketwatch.com 3
Definitions Process Research Investigative activities that a business chooses to conduct with the intention of making a discovery that can either lead to the development of new products (new synthetic route) or procedures or improvement of existing product (synthetic route) or procedures 4
Contribution of Synthetic Chemistry in Pharmaceutical Research and Development Discovery Process R&D Production Discovery Synthesis New Route (Cost, EI, Speed) Final Process Medicinal Chemistry Process Research/ Route Scouting Process Development and Pilot Plant Production Process Research: Design a scalable, atom-efficient, cost-effective, technically robust, and environmentally considerate route for API GCbD 5
Process Research/Process Chemistry Vs Green Chemistry Process Research in Chemical Industries can also be defined as Innovation in Process Chemistry Innovation = Invention + Impact (time, economics, and Environment) Therefore, in order to innovate Process Research must use Green Chemistry A personification of innovation as represented by a statue in The American Adventure in the World Showcase pavilion of Epcot center 6
API Life Cycle A Chemistry Prospective 10-15 Years Innovator >20 Years Generic
API Life Cycle A Volume Prospective Medicinal Chemistry Early Pre-Clinical and Clinical Studies Late Clinical Studies (after Phase IIb) NDA and Launch Second Generation Process Generics mg to g 1 Kg to 100 Kg Up to 1MT >1-10 MT >10 MT >10 MT 8
Alignment of API Economics with Greener Route (GCbD) Characteristics of Cost Effective Route Goes hand in hand with GCbD 1. Over all yield, Convergence and number of Steps 2. Chemo, Regio and Stereo Selective routes 3. Throughput (function of plant related operation and process constraints) Process Constraints: a. Chemical Yield b. Cycle time c. Number of Chemical Steps and Convergence d. Use of higher molecular weight protecting group and reagents e. Number of energy consuming operations Indirect Cost: Cost related to overcoming poor Quality, Safety and removal or recycling costs for waste
Process Research versus Green Chemistry Parameters Use a minimal number of synthetic steps Easy isolation, no SiO2 Avoid cryogenic conditions high selectivity (chemo, stereo and regio) Avoid hazardous reagents and reactions Inexpensive, available raw materials minimize oxidation state adjustments minimize the use of protecting groups Process chemistry consideration Efficiency (most important) Scalability, throughput Scalability, robust, lower cost Efficiency/easy purification Safety, scalability Cost, lead time Efficiency Efficiency, atom economy Environmental consideration Less energy and wastes Less waste (solvents) Less energy Less waste Safety, less pollution Know-how for waste management Less waste, potential pollution (metals) Less waste
Green Chemistry and Cost Savings S. No. GCP GE API Cost Factors 1 Prevention Better than clean up Cost to design (R&D) saves clean up cost 2 AE To avoid side products Reduced waste saves clean up cost 3 Less hazardous synthesis Non-toxic SMs Less Safety Issues 4 Design safer chemicals Efficacious products Less Safety Issues and higher quality 5 Safer solvents and auxiliaries Volume productivity Higher throughput 6 Design of energy efficiency 7 Use of renewable feedstock Reactions at STP Avoid use of depleting RM Savings in the energy consumption Expensive feedstock (need more R & D) 8 Reduce derivatization Avoid protection and de-protection High throughput, reduced cycle time 9 Catalysis Waste minimization Savings in the cost of stoichiometric quantity of reagents 10 Design for degradation Benign disposal Cost of environmental health 11 Real time analysis Pollution prevention Higher Quality, Reduced genotoxic impurity, 12 Safer chemistry To prevent accidents Cost to safe practices and long cycle time
Why Process Research is Important? Effective Process Research helps to reduce Cost, increase Quality, increase Safety and Environmental Impact and helps to achieve GCbD, which builds the foundation for API Process Development coupled with engineering excellence further improves the API Cost, Quality, Safety and Environmental Impact In general, it is not a good practice to develop a non-green route (the route not designed by Process Research) to production because the organization has to spend enormous amount resources to deal with the cost, Quality, safety and environmental issues
Process Research, Green Chemistry and API Cost Almost all of the Green Chemistry principles can be implemented at the process research Stage of development of an API or related molecules Therefore, Green Chemistry by Design (GCbD) is very critical for a selected synthetic route Process Research/Route scouting stage contributes maximum to cost, quality and EI for the API In order to design the greener route, Process research at the pharmaceutical industries need to be scientifically driven with the intend of commercialization Ideally, during process research stage process research chemists should think like academic scientists and should completely understand the environmental and scale up issues and therefore they can maximize their ability to design Greener synthetic routes Process Research scientists also need to ensure all the basic raw materials are obtained from renewable feed stock and not from petroleum based products (this will be a challenge due to cost effective technologies are not completely in place)
Current Challenges in API Route Selection Process (both at Innovator and Generic) timely demonstration of PoC of a selected route route must be cost effective to meet the organizational budget requirements (during development stage) and to meet market needs (during commercialization) route should minimize environmental impact route should be amenable scale to production level as needed route and intermediates must possess freedom to operation (free of any IP issues) processes must have a good control for GTI and other impurities need to operate utilizing minimum resources right-first-time approach for route selection
Current Challenges in API Route Selection Process (GCbD) (both at Innovator and Generic) Innovator Generic Short time line (no option) Resource Challenge (Seldom Outsourced due to IP issues and availability competency) Short time line (can start early) Resource Challenge (this area is currently evolving and may adopt innovator model) Changes in the route is acceptable up to certain extent Securing IP position is easy Limited extent of prior art is available More complex and is based on various factors Securing IP position is Challenging due to competition Large amount of prior art is available from innovator and academic publications and patents
Publication trend data in Organic Synthesis for 10 years 4000000 3500000 3000000 2500000 2000000 1500000 1000000 500000 0 01 02 03 04 05 06 07 08 09 10 11 12
Route Scouting/Process Research Work Flow
Functional Excellence in GCbD in the Process R & D Instrument New R&D Practices Academic Collaboration GCbD Human Capital (Internal or External) Human Capital Technology (Internal or External)
Present and Future R & D Directions toward the Greener Route Selection Route selection process can began early enough to achieve higher level of GCbD (need to be applied case by case to mitigate potential business risk) Flexible capability building with both in house team and with partners Potential Partners can be either CROs are productive academic institutions (for accessing special human capitol and certain high throughput instruments for screening studies) Take advantage of vast scientific literature data which was not available to innovators
Chemocatalysis i. Organometallics ii. Organocatalysis Biocatalysis i. Recombinant enzyme based Synthetic Biology Discovering new greener alternatives to non-green transformations Molecular Modeling Reaction Kinetics Technology
High throughput Screening and Automation Screen, and identify novel reactions for practical synthetic routes Develop catalysts libraries to screen a wide range of catalytic reactions and secure IP position DOE Reaction Analysis Data Mining Research and identify new automation equipment expertise / tools to promote efficiency 21 18.02.2013
High throughput Screening and Automation Conducting 100s of reactions in parallel for a given transformation (feasibility stage) Automation of weighing, quenching and analysis Advantages: In a short period of time (1 week) identification of economical, IP free and green reagent is possible for a given transformation Human error can be eliminated and additional analysis time can be reduced with automation.
External Partnership in Process Research & Development Process Research (GCbD) Involves academic mind set with a focus on IP, safety, economy, environment, quality and delivery (Emerging) Process Development Involves execution via optimization of disclosed procedure focused on manufacturing and delivery (Matured)
Some Examples of GCbD Wilstӓtter Lewis Acid Keck, G. E., Krishnamurthy, D. Org. Synth, 1997, 75, 12.
Some Examples of GCbD Krishnamurthy, D. et al. WO 2004052310 A2 20040624
Key Skill Sets for Route Scouting Scientists Highly Innovative Drive to gain a detailed scientific understanding of chemistry Ambition to discover and develop the shortest and most efficient synthesis Pay attention to detail during experimentation and good experimentation skills Highly motivated towards interacting with collaborators, reading day to day literature and discussions with colleagues and piers
12 principles of GCbD for selecting the route for any synthetic molecule Design Stage 1. Reduce the number of chemical transformation, think outside box during retro synthetic analysis 2. Ensure the starting material is obtainable from renewable feed stock 3. Opt for selective organic reactions (enantio, regio, chemo and stereo selective) 4. Use catalysis for each and every reaction 5. Avoid toxic, unstable and hazardous intermediates 6. Minimize the number of oxidation and reduction reactions
12 principles of GCbD for selecting the route for any synthetic molecule Execution Stage 1. Use all the available technologies and tools as much as possible 2. Use the best synthetic organic laboratory practices during execution (be persistent, meticulous and pay attention to details during experimentation) 3. Evaluate the possibility for flow reaction whenever possible 4. Evaluate in parallel all the proposed routes to obtain quick PoC 5. Conduct multiple experiments in parallel to obtain the quick results (automation, catalysis screening) 6. Minimize the solvent usage and use renewable green solvents
Impact Reduction in delivery time line Lead Indicator First time right (minimize CIP) Quality (minimize OOS) Safety (minimize no. of process related incidents) Dissemination of Knowledge Quality publications (Internal and External) patents and presentations
Way Forward Ideation & Learning Ideation, Learning & Application Ideation, Learning, Application & Institutionalization Involvement of scientists Knowledge sharing Learning Publication Conferences Collaborations Increased Sustainability
Opportunities Potential tapping of piece of $100 billion Green Chemistry market by the year 2020 by Entrepreneurs Increased Industrial Academic Collaborations with respect to Green Chemistry Establishment of more number of institutes all over the world for teaching and Research like John Warner s Institute of Green Chemistry More number of Ph.D will be awarded in more specific areas of Green Chemistry such as, Green Reagent Design, Green Reaction Design, Green Route Design etc.
For Further Reading 1. Sheldon, R. A. Chem. Soc. Rev. 2011, ASAP. 2. Butters, M. et al. Chem. Rev. 2006, 106, 3002-3027. 3. Song, J, Frutos, R, Tampone, T, Krishnamurthy, D, Senanayake, C. H. Comprehensive Chirality, 2012.