Recycle@SourceTM Solution for reducing

E-Factor in Pharma/API Industry

Nitesh H. MehtaNewreka Green Synth Technologies Pvt. Ltd.Mumbai, Indiawww.newreka.co.in

nitesh.mehta@newreka.co.in

E-Factor for Pharma Industry & its Impact

Pharma Industry – When to start exploring Green Chemistry?

Reality of our processes, plants & effluent streams

Why Recycle?

Pharma Industry – Concerns for recycle?

Concept of Recycle@SourceTM

Case Studies

Conclusions

Flow

E-Factor = Environmental Impact Factor

= kgs waste generated / kg product

Nature of Pharma, Specialty & Fine Chemicals manufacturing:

• Complex molecules & multi-step synthesis

• Chemistry Intensive processes

• Stringent quality & regulatory requirements

• Low process yields (low conversion, low selectivity & low separation efficiency)

The above leads to High E - Factor or Environmental Impact Factor.

Sector E - Factor Product Tonnage

Oil Refining ≤ 0.1 106 - 108

Bulk Chemicals 1 – 5 104 – 106

Fine Chemicals 5 – 50+ 102 – 104

Pharmaceuticals 25 – 100+ 10 - 103

Source: R A Sheldon

E-Factor in Pharma Industry

Stage Average E - Factor

Pre Clinical 185 kg Material Use / kg API

Phase I 123 kg Material Use / kg API

Phase II 117 kg Material Use / kg API

Phase III 96 kg Material Use / kg API

Commercial 45 kg Material Use / kg API

Source Data: ACS GCI Pharmaceutical Roundtable benchmarking exercise 2007

E-Factor in Pharma Industry

Pre Clinical No. of molecules very high

Phase I No. of molecules still high

Volumes involved very low

Phase II Limited No. of molecules

Volumes increased

Phase III No. of molecules further shortlisted

Volumes further increased (kgs to ton)

Commercial DMF Filed

Volumes high (tens of tons)

Phase II & Phase III : Right time to start exploring “Green Chemistry” based

processes.

Will ensure next generation drugs are manufactured through Green Processes.

Pharma Industry – When to start Green Chemistry?

Potential Generics : molecules going off - patent in next 5 years

processes being used are “Synthetic Chemistry” based

same as was filed in DMF during launch (high E – Factor)

volumes expected to increase after patent expiry ( effluents )

price expected to crash after patent expiry (pressure on costing)

Generics : patents already expired

processes being used are “Synthetic Chemistry” based

mostly same as was filed in DMF during launch (high E – Factor)

volumes are high (huge quantities of effluents)

high competition (pressure on costing)

Potential Generics & Generics : ideal cases to start exploring “Green

Chemistry” based processes.

Pharma Industry – Where to start Green Chemistry?

Step 1 Step 2 Step 3 Step 4

Step 1

2 - 3 Raw Materials

Reaction Medium

Extraction Medium

Intermediate/Product

Effluents

Reaction & Extraction

Medium

Intermediate/Product

By-products

Organic Impurities

Inorganic Impurities

Reality of our processes

Reality of our processes

Step 1 Step 2 Step 3 Step 4

4 - 5 different

chemicals

4 - 5 different

chemicals

4 - 5 different

chemicals4 - 5 different

chemicals

No option except

Effluent Treatment Plant or

Incineration

Cocktail of 15 - 25

different chemicals Impossible

to

separate,

recover or

recycle

Manufacturing Site

Reality of our plants

Mfg. Block for

Campaign

Products

Mfg. Block for

Dedicated

Products

Dedicated

Product

Step 1 Step 2 Step 3

Product 1 Product 2 Product 3

Step 1 Step 2 Step 3

Step 1 Step 2 Step 3 Step 4

Step 1 Step 2

Each effluent stream has its own:

• Physical properties

• colour, pH, temperature

• Chemical composition

• organics, inorganics

• Volume

• Characteristics

• COD, BOD, TDS, etc.

• Toxicity & hazard

What we have is:

• multiple effluent streams with widely differing quantities & characteristics

Reality of our effluent streams

Reality of our effluent streams

Effluent stream from

dedicated productsEffluent stream

from product 1

Effluent stream

from product 2

Effluent stream

from product 2

Cocktail of 40 - 50

different chemicals

End-of-the-pipe Treatment

(primary & secondary treatment, triple effect evaporator,

incineration, solid waste disposal sites, land fill, etc.)

Our Environment

Impact on our Health & our Business

Impact: huge threat to water bodies & human health

Quantity : Billions of kgs of liquid effluents from Chemical Industries

include solid & gaseous effluents

include all wastes from all other sectors (mining, steel, power,…..)

Practice : End-of-pipe-treatment (converting one kind of effluent in to other)

Issue : Toxicity not fully known (Ecotoxicity data available for less than

1% of human pharmaceuticals…Ref: journal “Regulatory

Toxicology Pharmacology, April’2004)”

Degradation : very slow, impact unknown after degradation

Impact on Economics

Direct Cost : loss of solvent, raw material & finished product, loss of utilities,

treatment cost, higher overheads, loss of business…

Indirect Cost : unreliable supplies, loss of credibility in market, anxiety, etc.

Just 3% of all water on planet is Fresh Water

Only 1% of all this Fresh Water is ready available for human use

In 20th Century, population tripled. Water consumption up 6 times

1 in 5 people don’t have access to safe drinking water

1 in 3 people lack access to adequate sanitation

As per UN, a child dies of water related disease every 15 seconds

By 2050, another 3 billion people on planet. Water for them?

India: 1 bn people need fresh water daily, limited water resources,

increasing outsourcing business & expanding chemical industry

Impact on our Water Resources

Why Recycle?

Solvents61%

Water31%

Reactants & other

reagents8%

Solvent & Water contribute more than 90% of the Reaction Mass

Most cases, average composition of Effluents will be close to

composition of reaction & extraction medium.

Recycle of reaction & extraction medium can take care of 90% of effluent

problems.

Source Data: ACS GCI Pharmaceutical Roundtable benchmarking exercise 2007

Stringent quality requirements – impurities may build-up due to recycle

Product for direct human consumption – high stakes

Regulatory limitations

Customer approvals

Economics – not pressing (good margins, yield improvement or saving

of treatment costs doesn’t provide enough drive)

Pharma Industry – Concerns around Recycle

Step 1 Step 2 Step 3 Step 4

2 - 3 Raw Materials

Reaction Medium

Extraction Medium

Finished Product

EffluentsStep 1

Reaction & Extraction

Medium

By-products

Organic Impurities

Inorganic Impurities

Recycle@SourceTM

Recycle@SourceTM

: Concept

Case Study: Recycle of sulphuric acid stream

Result/Outcome: 10 Recycles of sulphuric acid stream

Effluent load reduced by 90%

Raw Material saving (only make-up of Sulphuric Acid reqd.

97 - 98% Yield in hand (almost theoretical)

Case Study: Recycle of neutral stream

Feedback from customer: Recycled mother liquor for over 2.5 years.

Over 800 batches (at times on campaign basis)

Just make-up for Water loss (saved over 1mn lit fresh water)

Amine Quality – 99%+ on HPLC, 10% Yield improvement

Patented

Technology

Reduction &

Spent GCat

Filtration

Isolation

Vessel

CENTRIFUGE

WaterDinitroGCatRCat

Mother Liquor

Storage

Vessel

Mother Liquor Recycle (NaCl containing stream)

ProductMore than 10 recycles

E-Factor = 90%

Patented TechnologyYield = 8 - 10%

RCat

Treatment

Recyle CatTM

Filter

Spent

RCat

Representative diagram to explain the concept of Recycle@SourceTM solution as applied

to Dye Intermediate (MPDSA Sodium Salt)

Recycle@SourceTM Solution in MPDSA Sodium Salt

NaCl

Possibility to start exploring Green Chemistry with:-

Molecules with big volumes (impact on environment is high & savings will be high

too) – especially generics & potential generics

Molecules in IInd & IIIrd stage of clinical trials so that the next generation API

manufacturing is “Green”

Products & process steps with “High E – Factor”

Can be done in-house, in collaboration with private companies or academic

institution, outsourcing from other companies specializing in GC.

Conclusions

Pharma Industry – Multiple products, multi-step process & each process

generates a different type of effluent stream

Multiple effluent streams with widely differing quantities & characteristics

Our molecules are complex, very less idea about their environmental consequences

Concern for not Recycling – completely valid

Can explore Recycle@SourceTM in early stage pharma synthesis

Volumes of intermediates (hence effluents) usually high

Usually involves chemistries which inherently create pollution

Non DMF steps

Less Regulatory constraints

Easier to get customer’s approval

Conclusions

Thank you &

Have a Greener 2015 - 16