Download - GreenChemistry_JVNReddy
AUROBINDO PHARMA LIMITED
BULK DRUG MANUFACTURING IN INDIA
TO GO GREEN
Dr. JVN ReddyAssociate Vice President – EHS
12th Nov., 2010
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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
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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
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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
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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)
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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 substancessubstances
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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 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
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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-- 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
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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 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
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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
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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
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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.
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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
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
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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
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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
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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
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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
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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
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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
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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
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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
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Certain Process Improvements made by Indian Companies
Process modification in Metoprolol /
Modified process controlled impurity formation
Resulted in producing better qualitytartrate/succinate epoxide
Resulted in producing better quality intermediate
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Certain Process Improvements made by Indian Companies
Process modification in Metoprolol
Modified process controlled impurity formation
Resulted in elimination of purificationResulted in elimination of purification step
Increased yield and plant productivity
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Certain Process Improvements made by Indian Companies
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
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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
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Certain process improvements include:
Process modification Leading to higher yieldReduction batch cycle timeMaking process operator friendly
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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
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Certain recognized Green Chemistry Initiatives
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
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Certain recognized Green Chemistry Initiatives
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
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Certain recognized Green Chemistry Initiatives
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
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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 .
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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
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