Green Chemistry & Engineering for

Pharmacuetical Industry

Impact of Process Research / Route Scouting towards the Environment during

API Life Cycle

Dhileep Krishnamurthy, Ph.D.

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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

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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 1st November 2011 from www.marketwatch.com

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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

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Contribution of Synthetic Chemistry in Pharmaceutical Research and Development

Discovery

Synthesis

Process

Research/

Route Scouting

New

Route (Cost, EI, Speed)

Final Process

Production

Process

Development

and Pilot

Plant

Medicinal

Chemistry

Discovery Production

Process Research: Design a scalable, atom-efficient, cost-effective,

technically robust, and environmentally considerate route for API GCbD

Process R&D

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Process Research/Process Chemistry Vs Green Chemistry

A personification of innovation as represented by a statue in The American Adventure in the World Showcase pavilion of Epcot center

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

Innovator

Generic

10-15 Years

>20 Years

API Life Cycle – A Chemistry Prospective

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API – Life Cycle – A Volume Prospective Medicinal Chemistry mg to g

Early Pre-Clinical and Clinical Studies 1 Kg to 100 Kg

Late Clinical Studies (after Phase IIb) Up to 1MT

NDA and Launch >1-10 MT

Second Generation Process >10 MT Generics >10 MT

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

Characteristics of Cost Effective Route Goes hand in hand with GCbD

Alignment of API Economics with Greener Route (GCbD)

Parameters Process chemistry consideration

Environmental consideration

Use a minimal number of synthetic steps

Efficiency (most important) Less energy and wastes

Easy isolation, no SiO2

Scalability, throughput Less waste (solvents)

Avoid cryogenic conditions

Scalability, robust, lower cost

Less energy

high selectivity (chemo, stereo and

regio)

Efficiency/easy purification Less waste

Avoid hazardous reagents and

reactions

Safety, scalability Safety, less pollution

Inexpensive, available raw materials

Cost, lead time Know-how for waste management

minimize oxidation state adjustments

Efficiency Less waste, potential pollution (metals)

minimize the use of protecting groups

Efficiency, atom economy Less waste

Process Research versus Green Chemistry

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

Reactions at STP Savings in the energy consumption

7 Use of renewable feedstock

Avoid use of depleting RM

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

Green Chemistry and Cost Savings

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

Why Process Research is Important?

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)

Process Research, Green Chemistry and API Cost

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 (both at Innovator and Generic)

Innovator Generic

Short time line (no option) Short time line (can start early)

Resource Challenge (Seldom Outsourced due to IP issues and availability competency)

Resource Challenge (this area is currently evolving and may adopt innovator model)

Changes in the route is acceptable up to certain extent

More complex and is based on various factors

Securing IP position is easy Securing IP position is Challenging due to competition

Limited extent of prior art is available

Large amount of prior art is available from innovator and academic publications and patents

Current Challenges in API Route Selection Process (GCbD) (both at Innovator and Generic)

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

01 02 03 04 05 06 07 08 09 10 11 12

Publication trend data in Organic Synthesis for 10 years

Route Scouting/Process Research Work Flow

New R&D Practices Academic Collaboration

Human Capital (Internal or External)

Technology (Internal or External)

GCbD

Instrument

Human Capital

Functional Excellence in GCbD in the Process R & D

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

Present and Future R & D Directions toward the Greener Route Selection

• 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

21 18.02.2013

Develop catalysts libraries to screen a wide range of catalytic reactions and secure IP position

Screen, and identify novel reactions for practical synthetic routes

Research and identify new automation equipment expertise / tools to promote efficiency

DOE Reaction

Analysis Data Mining

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.

High throughput Screening and Automation

Process Research (GCbD)

Process Development

Involves academic mind set with a focus on IP, safety, economy, environment,

quality and delivery

(Emerging)

Involves execution via optimization of disclosed

procedure focused on manufacturing and delivery

(Matured)

External Partnership in Process “Research” & “Development”

Keck, G. E., Krishnamurthy, D. Org. Synth, 1997, 75, 12.

Wilstӓtter

Lewis Acid

Some Examples of GCbD

Krishnamurthy, D. et al. WO 2004052310 A2 20040624

Some Examples of GCbD

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

Key Skill Sets for Route Scouting Scientists

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

12 principles of GCbD for selecting the route for any synthetic molecule

Impact

•Reduction in delivery time line

•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

Lead Indicator

Involvement of scientists Knowledge sharing

Learning Publication Conferences Collaborations

Ideation &

Learning

Ideation, Learning & Application

Ideation, Learning, Application & Institutionalization

Increased Sustainability

Way Forward

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.

Opportunities

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.

For Further Reading