Post on 06-Apr-2018
Tools and Strategies for Green API
Manufacturing
Dr MG (Deepak) Palekar
Head- Strategy & Technology
deepak.palekar@stepsol.com
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.
Sustainable Development in Pharma
Sustainable Development =
Green Chemistry
+ Process Intensification
+ Water Management
- Global Reporting Initiative (GRI) reports for SD
Process Intensification
Any engineering development that leads to
a substantially smaller, cleaner, safer and
more energy efficient technology.
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
Approach
Reactants/ Raw Materials
A + B + Solvent + Additive C + D +
Solvent
Down-Stream Processing
Filtration/ Solvent extraction/
Crystallization/ Distillation/ Drying
Effluents & Waste (RM, by-
products, solvents, catalyst, water)
Organic chemistry can give conversion
as per stoichiometric principles;
the competitive edge is gained by
mastering down-stream processing!
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.
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)
Tools
• Biocatalysis
• Solvents
• Water
• Cavitation
• Chromatographic Separation
• Reactor Design
Biocatalysis
Advantages:
• 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.
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 Hydrolysis of esters, amides, lactones,
lactams, epoxides, nitriles & reverse
reactions
• Diltiazem intermediate
• Resolution of chiral
chemicals
Lyase Addition of small molecules to double
bonds such as C=C, C=N and C=O
Statin Intermediates
Isomerase Isomerisations such as racemizations,
epimerizations & rearrangement
reactions
HFCS from glucose
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.
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
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.
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
Water: Risk for Business
• - Disruption in production & financial loss
• Increased cost
• Govt./ Regulatory interference on water quantity/ price
• Consents, Permits
•Image on issue of sustainability and equitable usage
• Freshwater shortage
Physical RiskReputational
Risks
Financial Risks
Regulatory Risk
Water availability not under control of corporates
Production delays,Limits on production
Strong community opposition to company activities
Financial loss due to non availability of water
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
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
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
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)
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.
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.
DGC- Bubble Dispersion
DGC Advantages
Lower power consumption
Smaller operating volumes
No foaming
Close 100% Gas utilisation
High gas hold-up: 40-50%
Accurate control of interfacial area
(upto 6000 m2/m3)
No internal moving parts
Tolerance to particulates
Ease of scale-up with no loss of
efficiency
Ease of automation and control
Simple, compact set-up with
flexibility of design
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)
UV Lamp 2.0kw
Flow Rate 10 L/min
Gas Flow Rate (O2 flow rate) 0.05 L/min
Temperature 330C
Pressure 0-8 bar
Operating Mode Batch
Volume Of DGC Reactor 17 Litre
Batch Volume 15 Litre
Residence time in DGC 1.5 min
Contact time O2- 42 sec
UV- 36 sec
CASE STUDY- PHARMACEUTICAL
WASTEWATER TREATMENT
COD reduction in DGC
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
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
“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
Progress Step by Step
towards Sustainable
Development!