GreenChemistry_JVNReddy

AUROBINDO PHARMA LIMITED

BULK DRUG MANUFACTURING IN INDIA

TO GO GREEN

Dr. JVN ReddyAssociate Vice President – EHS

12th Nov., 2010


Global Pharmaceutical Industry

Estimated at US $ 808 BillionEstimated at US $ 808 Billion

Registering annual growth of 3.5%

Top 10 Pharmaceutical Companies account for around 42% of

global sales

Focuses on three main areas – therapeutics, diagnostics and vaccines

Therapeutics account for largest share which include:

-- Oncology

-- Central Nervous System

Infectious Diseases-- Infectious Diseases

-- Lifestyle Diseases

-- Cardiovascular

-- Inflammation and immunology


Global Pharmaceutical Industry – Emerging Trends

Pharma sector is characterizedPharma sector is characterized

-- high knowledge

-- capital intensive

-- long cycle time

-- uncertainty of R & D Activities

Undergoing several structural changes

Greater focus on developing countries


Indian Pharmaceutical Industry

Estimated at US $ 21 2 Billion (Accounts for 2 % of global market by value)Estimated at US $ 21.2 Billion (Accounts for 2 % of global market by value)

Fourteenth largest producer of pharma products by value and third by volume

Contributes 10% of global production volume

Among world’s top 5 producers of APIs

Largely self-sufficient, especially in formulations

Relies on US, Germany, UK and France on certain APIs/Intermediates

Therapeutics account for largest share which include:

-- Oncology

Central Nervous System-- Central Nervous System

-- Infectious Diseases

-- Lifestyle Diseases

-- Cardiovascular

-- Inflammation and immunology


Indian Pharmaceutical Industry

Comprises large medium and small units World’s most price competitiveComprises large, medium and small units – World s most price competitive

Andhra Pradesh is one of the major hubs of pharma mfg in India

Large number of US-FDA certified plants (highest outside US)


Green Chemistry

Also called sustainable chemistry

Philosophy of Chemical Research and Engineering

-- that leads to design of products and processes that minimize use of raw materials (input) and generation of hazardous substancessubstances


Green Chemistry

Attempts are being made to quantify ‘greenness’ of chemical processes

Efforts are also made to factor other variables, viz.,

-- Chemical YieldP i f R ti C t-- Price of Reaction Components

-- Safety in Handling Chemicals-- Hardware Demands -- Energy profilegy p-- Ease of Product Work-up and Purification-- Consumption of natural resources and generation of wastes-- Utilization of by products


Green Chemistry

Seen as powerful tool that researchers must use to evaluate environmental impact of nanotechnology


Environmental Chemistry Vs Green Chemistry

Environmental Chemistry

Chemistry of Natural Environment and Pollutant Chemicals in nature their effects-- Chemistry of Natural Environment and Pollutant Chemicals in nature, their effects, etc.

-- Focuses on Chemical Phenomenon in environment; regionally as well as globally

Green Chemistryy

--Seeks to reduce and prevent pollution at its source

-- Applies to all branches of chemistry and engineeringApplies to all branches of chemistry and engineering


Key Developments in Green Chemistry

Use of supercritical carbon dioxide as green solvent

Use of aqueous hydrogen peroxide for clean oxidations

Use of hydrogen in asymmetric synthesis


Other examples:

Super critical water oxidation

-- Supercritical water oxidation or SCWO is a process that occurs in water at temperatures and pressures above a mixture's thermodynamic critical point.

-- Under these conditions water becomes a fluid with uniqueproperties that can be used to advantage in thedestruction of hazardous wastesdestruction of hazardous wastes

Dry media reactions

-- Develop Reactions which proceed in solid state without use of solvents


12 Principles of Green Chemistry developed by Paul Anastas12 Principles of Green Chemistry developed by Paul Anastas, USEPA

1. Prevent Generation of Waste than to treat/clean up of waster after it is formed

2. Synthesis be designed to maximize incorporation of all materials used in process into final product

3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or not toxicity to human health and environmentand environment

4. Chemical products be designed to preserve efficacy of function while reducing toxicityg y


12 Principles of Green Chemistry12 Principles of Green Chemistry ……

5. Use of auxiliary substances (e.g. solvents, separation agents, etc.) should bemade unnecessary wherever possible and innocuous when usedmade unnecessary wherever possible and innocuous when used

6. Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure

7. A raw material or feedstock should be renewable rather than depleting wherever technically and economically practicabletechnically and economically practicable

8. Reduce derivatives—Unnecessary derivatization (blocking group, protection/ deprotecion, temporary modification) should be avoided whenever possible

9. Catalytical reagents (as selective as possible) are superior to stoichiometric reagents


12 Principles of Green Chemistry12 Principles of Green Chemistry ……

10. Chemical Products be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation product –p g pLife Cycle

11. Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of required/hazardousprocess monitoring and control prior to the formation of required/hazardous substances

12. Substances and the form of a substance used in a chemical process should be chosen to minimize potential for chemical accidents, including releases, explosions, and fires.


These 12 basic principles summarize ….

Design of processes to maximize the amount of raw material that ends up in the product

U f f i t b i b t i l diUse of safe, environment-benign substances, including solvents, whenever possible

Design of energy efficient processesDesign of energy efficient processes

Best form of waste disposal; not to create in the first place


USA P id ti l G Ch i t Ch ll A dUSA -- Presidential Green Chemistry Challenge Awards

Recognition of individuals and businesses for innovations in G Ch i tGreen Chemistry

Instituted five awards –

1. Academic

2. Small Business

3. Greener Synthetic Pathways

4. Greener Reaction Conditions

5. Designing Greener Chemicals

Several Other Nations are institutionalizing similar awards Se e a Ot e at o s a e st tut o a g s a a a dsand introducing regulations


Drug Discovery and Development OverviewDrug Discovery and Development -- Overview

Encompasses several stages;

-- Pre-disvoery

-- Discovery

-- Pre-clinical Studies

-- Clinical Trials (Phases I – III)

(Process takes 6-7 years; one of the most costly elements of drug discovery process)y p )

-- FDS Review

-- Manufacturing

Post Approval Research-- Post Approval Research

One FDA-Approved Drug out of 5,000 – 10,000 potential candidate molecules

(NCEs) at Pre-discovery/discovery stage

India significantly lags behind US and Western Europe in terms of R&D

expenditure


Key Gaps in Indian Pharmaceutical R&DKey Gaps in Indian Pharmaceutical R&D

-- Low Investment

-- Limited success in new drug discovery

-- Limited efforts in NDDS

-- Lack of efficient use of available technologies

-- Limited use of bioinformatics

-- Limited focus on drug design

-- Limited accessibility to biological testing facilities

Lack of adequate infrastructure for non human primate testing-- Lack of adequate infrastructure for non-human primate testing


Major constraints faced by Indian IndustryMajor constraints faced by Indian Industry

-- Small size of Indian Companies vs. Global Standards

-- Risk aversion to funding innovation

-- lack of ‘competency-based’ trust amongst cross functional members

-- Limited Collaboration between industry and Universities/CSIR Labs

-- Skill Gapp

-- lack of IPR implementation


T h l T d i I diTechnology Trends in India

API f t d b b t h ( l li d t lAPIs are manufactured by batch processes (glass line and steel

reactors)

Has limited level of automationHas limited level of automation

-- Limited most to automation of temperature control processes

-- Attributed to multi-product facilitiesAttributed to multi product facilities

-- Majority of processes are under continual improvement process

Made significant technology development in process chemistry for

generic products


T h l T d i I diTechnology Trends in IndiaAPIs are manufactured by batch processes (glass line and steel

t )reactors)

Has limited level of automation

-- Limited most to automation of temperature control processes-- Limited most to automation of temperature control processes

-- Attributed to multi-product facilities

-- Majority of processes are under continual improvementMajority of processes are under continual improvement process

Made significant technology development in process chemistry for

generic products

Indian pharmaceutical majors have developed certain processes that are better than their European counterparts


T h l T d i I diTechnology Trends in India

Process improvements undertaken regularly; extent varies drastically

Objectives for process improvement are mainly for one or more of

Shortening of processShortening of processProductivity enhancementCost reductionReduction in impuritiesReduction in waste generationReduction in waste generationEnergy ConservationSHE Compliance

M j it f i t f h i t th thMajority of process improvements focus on process chemistry rather than chemical engineering principle


Certain Process Improvements made by Indian Companies

Company was isolating allCompany was isolating all intermediates

To were lachrymatory and hazardous

Modified process addressed above

Process modification in Lumefantrine

Modified process addressed above issues and led to higher yields

Made process operator friendly and reduced cycle time

Productivity increased from 3.6 MT/month to 14 MT/month



Process modification in Metoprolol /

Modified process controlled impurity formation

Resulted in producing better qualitytartrate/succinate epoxide

Resulted in producing better quality intermediate



Process modification in Metoprolol

Modified process controlled impurity formation

Resulted in elimination of purificationResulted in elimination of purification step

Increased yield and plant productivity



Follow ‘green manufacturing

Large Scale Companies in India

Follow ‘green manufacturing practices’ to a large extentOwing to strict environmental normsOwing to increasing awareness Large Scale Companies in India g gamongst local populationAchieving better environmental complianceReduction cost of waste disposalReduction cost of waste disposal Measures include

‐ optimizing use of solvent ‐ improving solvent profileimproving solvent profile ‐ using alternate raw materials‐ changing processes to reduce waste


Other initiatives include

-- Use of bio-catalysisUse o b o cata ys s

-- METAL-MEDIATED CHEMISTRY

-- Use of Waster as reaction media as far as possible

-- Disposal of organic residues through alternate destruction technologies, viz., cement units where wastes act as co-fuel

-- ‘ZLD’ Technology and Complete Recycle of Wastewater


Certain process improvements include:

Process modification Leading to higher yieldReduction batch cycle timeMaking process operator friendly


Certain recognized Green Chemistry Initiatives

Polystyrene used in packing and foodPolystyrene used in packing and food transportation

Huge manufacturing in US alone

CFC and other ozone depleting

Dow Chemical in 1996

CFC and other ozone depleting substances used in polystyrene mfg.

Alternatives include flammable, explosive and toxic hydrocarbons

100% CO2 blowing agent for Polystyrene Foam Production

Dow Chemical discovered supercritical CO2 works equally as well as blowing agent

CO2 d i i d i hCO2 used in process is reused in other industries

Net CO2 released from process is ‘zero’zero



Lactide enantiomer isolated fromLactide enantiomer isolated from polylactic acid (PLA) used in textiles, apparel, cutlery and food packaging industries

Nature Works in 2002 This improved PLA process doesn’t require use of hazardous organic l t t i l i th PLAGreener Reaction Conditions for

improved polylactic acid polymerization process

solvents typical in other PLA processes

Results in high quality polymer that isResults in high quality polymer that is recyclable and compostable



Developed a clean enzymatic processDeveloped a clean, enzymatic process for inter esterification of oils and fats

Process eliminated trans‐fats to benefit human health

Archer Daniels Midland (ADM) and Novozymes 2005

Reduced use of toxic chemicals and water

Prevented vast amounts of

Greener Synthetic Pathways for enzyme inter esterification process

byproducts

Reduced the amount of fats and oils wasted



Professor Galen J. Suppes, Used Cu‐Cr catalyst improved processProfessor Galen J. Suppes, University of Missouri in

Columbia in 2006

Used Cu‐Cr catalyst improved process conditions

Propylene glycol produced in this way

System of converting waste glycerin from biodiesel production to propylene

glycol

Propylene glycol produced in this way is cheap to replace more toxic ethylene glycol that is primary ingredient in automobile antifreeze

glycol


C l iConclusion:Indian Pharma Industry embracing Green Concepts; in its infant

tstage

Still lacks academic focus on green manufacturing methods

Green Concepts are limited mostly to environmental complianceGreen Concepts are limited mostly to environmental compliance

Some of ‘approaches embraced’ in environmental management

can not be truly termed as ‘green’.can not be truly termed as green .


C l iConclusion:

There have been green chemistry advocates who see it as an

innovative way of thinking

O th th h d th Ch i t h th t GOn the other hand, there are Chemists who argue that Green

Chemistry is no more than a public relations label

A lot of Chemists use the term “Green Chemistry” independentlyA lot of Chemists use the term Green Chemistry independently

from Green Chemistry paradigm as proposed by Anastas and

WarnerWarner

THIS EXPLAINS THE UNCERTAINTY OF THE SCIENTIFIC

STATUS OF GREEN CHEMISTRY

AUROBINDO PHARMA LIMITED, UNIT

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