AUROBINDO PHARMA LIMITED

BULK DRUG MANUFACTURING IN INDIA TO GO GREEN

Dr. JVN Reddy

Associate Vice President EHS

12th Nov., 2010

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Global Pharmaceutical Industry

Estimated 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 -- Lifestyle Diseases -- Cardiovascular -- Inflammation and immunology

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Global Pharmaceutical Industry Emerging Trends

Pharma sector is characterized -- high knowledge -- capital intensive -- long cycle time -- uncertainty of R & D Activities Undergoing several structural changes Greater focus on developing countries

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Indian Pharmaceutical Industry

Estimated at US $ 21 2 Billion (Accounts for 2 % of global market by value) 21.2 Fourteenth largest producer of pharma products by value and third by volume Contributes 10% of global production volume Among worlds 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 -- Infectious Diseases -- Lifestyle Diseases -- Cardiovascular -- Inflammation and immunology

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Indian Pharmaceutical Industry

Comprises large medium and small units Worlds most price competitive large, World s Andhra Pradesh is one of the major hubs of pharma mfg in India Large number of US-FDA certified plants (highest outside US)

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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 substances

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Green Chemistry
Attempts are being made to quantify greenness of chemical processes Efforts are also made to factor other variables, viz.,
-- Chemical Yield -- P i of Reaction C Price f R ti Components t -- Safety in Handling Chemicals -- Hardware Demands -- Energy p gy profile -- Ease of Product Work-up and Purification -- Consumption of natural resources and generation of wastes -- Utilization of by products

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

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Environmental Chemistry Vs Green Chemistry Environmental Chemistry

-- Chemistry of Natural Environment and Pollutant Chemicals in nature, their effects nature effects, etc. -- Focuses on Chemical Phenomenon in environment; regionally as well as globally

Green Chemistry y
--Seeks to reduce and prevent pollution at its source -- Applies to all branches of chemistry and engineering

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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

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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 unique properties that can be used to advantage in the destruction of hazardous wastes

Dry media reactions

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

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

1.

Prevent Generation of Waste than to treat/clean up of waster after it is formed Synthesis be designed to maximize incorporation of all materials used in process into final product Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or not toxicity to human health and environment Chemical products be designed to preserve efficacy of function while g y reducing toxicity

2.

3.

4.

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12 Principles of Green Chemistry

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

6.

7. A raw material or feedstock should be renewable rather than depleting wherever technically and economically practicable 8. Reduce derivativesUnnecessary derivatization (blocking group, protection/ deprotecion, temporary modification) should be avoided whenever possible

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

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12 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 p p g product Life Cycle Analytical methodologies need to be further developed to allow for real-time, inprocess monitoring and control prior to the formation of required/hazardous substances 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.

11.

12.

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These 12 basic principles summarize .

Design of processes to maximize the amount of raw material that ends up in the product Use f f U of safe, environment-benign substances, i l di i tb i b t including solvents, whenever possible Design of energy efficient processes Best form of waste disposal; not to create in the first place

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

Recognition of individuals and businesses for innovations in Green Chemistry G Ch i t Instituted five awards
1. 2. 3. 4. 5. Academic Small Business Greener Synthetic Pathways Greener Reaction Conditions Designing Greener Chemicals

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

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Drug 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 y process) ) discovery p -- FDS Review -- Manufacturing -- 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

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Key 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 non human

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Major 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 p -- Skill Gap -- lack of IPR implementation

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Technology Trends in India T h l T d i I di

APIs API are manufactured by batch processes (glass line and steel f t db b t h ( l li d t l reactors) Has limited level of automation -- Limited most to automation of temperature control processes -- Attributed to multi product facilities multi-product -- Majority of processes are under continual improvement process Made significant technology development in process chemistry for generic products

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Technology Trends in India T h l T d i I di

APIs are manufactured by batch processes (glass line and steel reactors) t ) Has limited level of automation -- Limited most to automation of temperature control processes -- Attributed to multi-product facilities -- Majority 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

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Technology Trends in India T h l T d i I di

Process improvements undertaken regularly; extent varies drastically Objectives for process improvement are mainly for one or more of
Shortening of process Productivity enhancement Cost reduction Reduction in impurities Reduction in waste generation Energy Conservation SHE Compliance

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

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CertainProcessImprovementsmadebyIndianCompanies
Companywasisolatingall Company was isolating all intermediates Towerelachrymatoryandhazardous Modifiedprocessaddressedabove Modified process addressed above issuesandledtohigheryields Madeprocessoperatorfriendlyand reducedcycletime Productivityincreasedfrom3.6 MT/monthto14MT/month

Processmodificationin Lumefantrine

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CertainProcessImprovementsmadebyIndianCompanies

Processmodificationin Metoprolol tartrate/succinateepoxide /

Modifiedprocesscontrolledimpurity formation Resultedinproducingbetterquality Resulted in producing better quality intermediate

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CertainProcessImprovementsmadebyIndianCompanies

Processmodificationin Metoprolol

Modifiedprocesscontrolledimpurity formation Resultedineliminationofpurification Resulted in elimination of purification step Increasedyieldandplantproductivity

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CertainProcessImprovementsmadebyIndianCompanies
Followgreenmanufacturing Follow green manufacturing practicestoalargeextent Owingtostrictenvironmentalnorms Owingtoincreasingawareness g g amongstlocalpopulation Achievingbetterenvironmental compliance Reductioncostofwastedisposal Reduction cost of waste disposal Measuresinclude optimizinguseofsolvent improving solvent profile improvingsolventprofile usingalternaterawmaterials changingprocessestoreduce waste

LargeScaleCompaniesinIndia Large Scale Companies in India

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Other initiatives include

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

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Certain process improvements include:

Process modification Leading to higher yield Reduction batch cycle time Making process operator friendly

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CertainrecognizedGreenChemistryInitiatives
Polystyreneusedinpackingandfood Polystyrene used in packing and food transportation HugemanufacturinginUSalone CFCandotherozonedepleting CFC and other ozone depleting substancesusedinpolystyrenemfg. Alternativesincludeflammable, explosiveandtoxichydrocarbons DowChemicaldiscovered supercriticalCO2worksequallyas wellasblowingagent CO2usedinprocessisreusedinother CO2 di i di h industries NetCO2releasedfromprocessis zero zero

DowChemicalin1996
100%CO2blowingagentfor PolystyreneFoamProduction

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CertainrecognizedGreenChemistryInitiatives
Lactideenantiomerisolatedfrom Lactide enantiomer isolated from polylacticacid(PLA)usedintextiles, apparel,cutleryandfoodpackaging industries

NatureWorksin2002
GreenerReactionConditionsfor improvedpolylacticacid polymerizationprocess

ThisimprovedPLAprocessdoesnt requireuseofhazardousorganic solventstypicalinotherPLA l t t i l i th PLA processes Resultsinhighqualitypolymerthatis Results in high quality polymer that is recyclableandcompostable

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CertainrecognizedGreenChemistryInitiatives
Developedaclean,enzymaticprocess Developed a clean enzymatic process forinteresterificationofoilsandfats Processeliminatedtransfatsto benefithumanhealth Reduceduseoftoxicchemicalsand water Preventedvastamountsof byproducts Reducedtheamountoffatsandoils wasted

ArcherDanielsMidland(ADM) andNovozymes2005
GreenerSyntheticPathwaysfor enzymeinteresterificationprocess

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CertainrecognizedGreenChemistryInitiatives

ProfessorGalenJ.Suppes, Professor Galen J. Suppes, UniversityofMissouriin Columbiain2006

Systemofconvertingwasteglycerinfrom biodieselproductiontopropylene glycol

UsedCuCrcatalystimprovedprocess Used CuCr catalyst improved process conditions Propyleneglycolproducedinthisway Propylene glycol produced in this way ischeaptoreplacemoretoxic ethyleneglycolthatisprimary ingredientinautomobileantifreeze

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Conclusion: C l i
Indian Pharma Industry embracing Green Concepts; in its infant stage t Still lacks academic focus on green manufacturing methods Green Concepts are limited mostly to environmental compliance Some of approaches embraced in environmental management can not be truly termed as green. green .

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Conclusion: C l i

There have been green chemistry advocates who see it as an innovative way of thinking On th th h d there are Ch i t who argue th t G O the other hand, th Chemists h that Green Chemistry is no more than a public relations label A lot of Chemists use the term Green Chemistry independently Green Chemistry from Green Chemistry paradigm as proposed by Anastas and Warner THIS EXPLAINS THE UNCERTAINTY OF THE SCIENTIFIC STATUS OF GREEN CHEMISTRY

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