Tools and Strategies for Green API Manufacturing. Dr MG (Deepak) Palekar Head- Strategy & Technology

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1 Tools and Strategies for Green API Manufacturing Dr MG (Deepak) Palekar Head- Strategy & Technology

2 Sustainable Development It is the pattern of resource use that aims to meet human needs while preserving the environment so that these needs can be met not only in the present but also for generation to come.

3 Sustainable Development in Pharma Sustainable Development = Green Chemistry + Process Intensification + Water Management - Global Reporting Initiative (GRI) reports for SD

4 Process Intensification Any engineering development that leads to a substantially smaller, cleaner, safer and more energy efficient technology.

5 Advantages of Sustainable Development Lower resource consumption (Carbon/ Water/ Energy Footprint) Higher productivity (equipment & manpower) Lower waste/ effluent generation Risk reduction (legal, regulatory, social) Improved process Process patent Enhanced value proposition, improved image Preferred supplier status (with some customers) Lower cost of production higher profitability

6 Approach Reactants/ Raw Materials A + B + Solvent + Additive C + D + Solvent Down-Stream Processing Filtration/ Solvent extraction/ Crystallization/ Distillation/ Drying Effluents & Waste (RM, byproducts, solvents, catalyst, water)

7 Organic chemistry can give conversion as per stoichiometric principles; the competitive edge is gained by mastering down-stream processing!

8 Strategy - Approach Front End (Maximize Atom Efficiency/ Reduce Waste) - Selectivity/ Yield Improvement, Solvent selection, Heterogeneous/ bio-catalyst, Process intensification & DSP Back End (Reduce Effluents) - Recovery of RM/ By- Product/ Solvents, Waste treatment, Water recycle/ management Need a focus on Sustainable Development/ Green Chemistry through a Champion and/ or a Team, which will define the objectives & monitor the progress.

9 Tools Green Chemistry (Organic Synthesis/ Heterogenous Catalysis/ Biocatalysis/ Solvents/ Water) Process Intensification (Reactor design/ Mixing/ Reaction kinetics/ Heat exchange/ Productivity increase per batch) DownStream Processing/ Technologies (Nanotech, Cavitation, Microwave, Chromatography)

10 Tools Biocatalysis Solvents Water Cavitation Chromatographic Separation Reactor Design

11 Advantages: Biocatalysis Milder reaction conditions (typically up to 60 C and atmospheric pressure) High selectivity (stereo/ region/ chemical) Increased productivity (shorter route of synthesis) Higher purity product (low/ no impurities) Lower cost of downstream processing (simpler purification, lesser impurities, lower solvent usage) Can be immobilized and reused There are around 150 biocatalytic processes currently in commercial use in chemical/ pharma industry. New scientific developments in genomics as well as in protein engineering will facilitate tailoring of enzyme properties to increase that number significantly in future.

12 Biocatalysis- Commercial Enzymes Enzyme Class Reactions Applications Oxidoreductase C=O and C=C reduction Reductive amination of C=O Oxidation of C-H,C=C, C-N and C-O Atorvastatin intermediate Montelukast Transferase Transfer of functional groups such as amino, Acyl, phosphoryl, methyl, glycosyl, nitro & sulphur groups Sitagliptin Cyclodextrin from starch Hydrolase Lyase Hydrolysis of esters, amides, lactones, lactams, epoxides, nitriles & reverse reactions Addition of small molecules to double bonds such as C=C, C=N and C=O Diltiazem intermediate Resolution of chiral chemicals Statin Intermediates Isomerase Isomerisations such as racemizations, epimerizations & rearrangement reactions HFCS from glucose

13 Biocatalysis- Industrial Successes Pregabalin/ Pfizer Low protein loading(0.8%) Higher throughput All reactions conducted in water; significant reduction in solvent E-factor improved from 86 to < 20 Starting material reduction, Mandelic acid usage eliminated Energy usage reduced by > 80% Sitagliptin/ Merck > 10% increase in overall yield. > 50% increase in productivity. ~ 20% reduction in total waste. Elimination of heavy metal use Reduction in total manufacturing cost.

14 Solvent Usage Typically 1 kg of API uses 22 kgs of solvent; can add up to 80-90% of total mass of API material balance 1 kg of solvent 1.5 kg CO2, and 2.25 kgs total air emission Top 10 solvents constitute 90% of waste in pharma industry in USA (methanol, Dichloromethane, Toluene, Acetonitrile, Chloroform, N,N-DMF, N-Methyl-2- Pyrrolidone, MTBE, Cyclohexane, Formic Acid) Solvent implications over life cycle: Purchase cost, energy, waste generated; Cost to use/recycle (energy and associated costs) and Disposal cost and emissions

15 Solvent Selection Recyclability (boiling point, azeotrope formation) Health hazards (exposure limit/ toxicity) Flammability & explosion safety Stability and reactivity (peroxide formation, acidity/ basicity effect) Regulatory Expanding GSK s solvent selection guide embedding sustainability into solvent selection starting at medicinal chemistry Richard K. Henderson et. al. Royal Society Chemistry, 2011.

16 Solvent Reduction Efficient recovery techniques Reduction in process steps (Biocatalysis, in-situ reactions) Novel reaction media (Ionic liquids) Novel approach to downstream processing/ separations (Chromatography, cavitation) Efficient reactor design

17 Water: Risk for Business Freshwater shortage Image on issue of sustainability and equitable usage Production delays, Limits on production Physical Risk Reputational Risks Strong community opposition to company activities Water availability not under control of corporates Regulatory Risk Financial Risks Financial loss due to non availability of water Govt./ Regulatory interference on water quantity/ price Consents, Permits - Disruption in production & financial loss Increased cost

18 Cavitation Ultrasonic Cavitation - Crystallization (Particle Size distribution, crystal form) - Milling (Fines control) - Reaction (Higher reaction rate, improved selectivity/ yield) Hydrodynamic Cavitation - Cooling Water treatment (no chemical usage, microbial growth/ scale formation control, lower corrosion, less water blow-down) - Reaction (waste water treatment, oxidation) Advantages: Continuous process, lower energy consumption, improved productivity Challenges: Process Scale-up

19 Chromatographic Separation Applications: Removal of impurities/ Purification of products (Sp. Chemicals/ Pharma intermediates/ APIs) Recovery of Solvent/ metal from waste Advantages: Cleaner process, improved yield, better quality of product, impurity can be removed selectively minimal use of solvent, Continuous process Challenges: Initial investment can be high

20 Success Story Based on material balance, identified areas of atom efficiency, process improvements & waste reduction Reaction- Improved yield/ solvent usage/ reduced water usage (Front end) Color Removal- Replace activated carbon by synthetic resin (DSP/ Chromatography/ lab scale) Crystallization & Milling- using ultrasound (DSP/ Pilot plant scale) Drying Faster drying process (DSP) Waste- Recovery of By-product & Raw Material by chemical process & metal by chemical process/ Chromatography (Back end) Waste- Recovery of solvent from vent/ handling losses (Back end/ Chromatography) Improved productivity/ quality of product, lower waste/ effluents. * Processes marked in black bold are implemented on commercial scale

21 Reactor Design- Process Intensification Microreactor Mixers (Impinging Jet Mixer, Vortex Mixer, Static Mixer Spinning Disk reactor Rotating Packed bed Multifunctional membranes Microwave irradiation Ultrasound irradiation Cavitation Flow reactor (Bubble column reactor, Downflow Gas Contactor)

22 Reactor Design- Successes Productivity increase by 10 to 25% in pharma intermediates/ specialty chemicals through Process Intensification/ Atom Efficiency (increased batch size, better mixing, lower solvent usage) Batch to continuous process for phosgenation using cascade reactor leading to improved conversion/ yield/ product quality Continuous sulfonation using a plug flow reactor leading to higher conversion & selectivity. Falling film reactor (continuous process) for a condensation reaction, leading to higher conversion/ productivity and lower separation cost. Bubble column reactor for chlorination reaction instead of stirred reactor, leading to higher conversion/ selectivity and lower utility cost.

23 Downflow Gas Contactor DGC is a downflow co-current device consisting of a cylindrical upper section and inverted conical lower section (if required when using pure gases) Specially Designed Inlet (SDI) High velocity liquid input through the entry section generates intense shear and energy; and produces a highly agitated gas-liquid dispersion with increased interfacial area and improved mass transfer. Suitable control system include heating, cooling, dispersion level, pressure, flow rates etc.

24 DGC- Bubble Dispersion

25 DGC Advantages Lower power consumption Smaller operating volumes No internal moving parts Tolerance to particulates No foaming Ease of scale-up with no loss of Close 100% Gas utilisation efficiency High gas hold-up: 40-50% Ease of automation and control Accurate control of interfacial area Simple, compact set-up with (upto 6000 m2/m3) flexibility of design

26 Industrial Applications Gas-Liquid and Liquid-liquid reactions (Hydrogenation, Oxidation, Carbonylation, Ethoxylation, Chlorination, Biodiesel production) Effluent treatment (COD/ BOD reduction, Wet Air Oxidation, Non-biodegradable effluent) Gas Absorption (CO2 capture from Biogas/ Flue gas, Ammonia recovery from waste)

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28 CASE STUDY- PHARMACEUTICAL WASTEWATER TREATMENT UV Lamp Flow Rate Gas Flow Rate (O 2 flow rate) Temperature Pressure Operating Mode Volume Of DGC Reactor Batch Volume Residence time in DGC Contact time 2.0kw 10 L/min 0.05 L/min 33 0 C 0-8 bar Batch 17 Litre 15 Litre 1.5 min O 2-42 sec UV- 36 sec

29 COD reduction in DGC

30 STEP- Services Offered Process Intensification/ Process audits Improvements based on Green Technologies Environmental assessment Water footprint and sustainability studies ETP Audits Effluent treatment plant packages Pre-engineered Effluent treatment plants Environmental management plan Pre-tendering services for ETP/ STP Detailed project reports and Feasibility report Sanitary wastewater treatment & collection system Training

31 STEP- Customers BASF India Cadagua Ferrovial India Ltd. SNF, France Hindustan Unilever Ltd. Hindustan Coca Cola Beverages Ltd. Dr Reddy s Labs Godrej & Boyce Aker Solutions/ Reliance Industries Ltd. Ernest & Young XCC/ World Bank

32 Socialism collapsed because it did not allow the market to tell the economic truth. Capitalism may collapse because it does not allow the market to tell the ecological truth. Oystein Dahle, former VP- Exxon (Norway & North Sea) in Hot, Flat & Crowded - Thomas Friedman

33 Progress Step by Step towards Sustainable Development!