WEC MeetingHamburg, April 14 – 15, 2005Presented by: Ludwig Metz, Bristol-Myers Squibb

Cleaner ProductionCleaner ProductionDownstream Expectations and Industry Downstream Expectations and Industry

Case StudiesCase Studies

Green Chemistry at Bristol-Myers Squibb Green Chemistry at Bristol-Myers Squibb

Content of PresentationContent of Presentation

• BMS Green Chemistry

• BMS Taxol Story

• Sustainable Product Design

Design for Environmental Health and

Safety through GREEN CHEMISTRY

Green ChemistryGreen Chemistry

What does Green Chemistry Mean?What does Green Chemistry Mean?

• Choosing a non-regulated solvent?

• All aqueous processing?

• Outsource intermediates or products (N.I.M.B.Y.)?

What is “What is “Green ChemistryGreen Chemistry””

Green Chemistry is reducing or eliminating

the use or generation of hazardous substances - including feedstocks, reagents, solvents, products and

byproducts - from a chemical process.

The Presidential Green Chemistry ChallengeThe Presidential Green Chemistry Challenge

The Presidential Green Chemistry ChallengeThe Presidential Green Chemistry Challenge

March 16, 1995: President Clinton announced the Presidential Green Chemistry Challenge

• Part of the reinventing Environmental Regulations Initiative to “promote pollution prevention and industrial ecology …”

• Voluntary partnership with Environmental Protection Agency (EPA), trade associations, scientific organizations, academia and the chemical industry

Sustainable DevelopmentSustainable Development

• Marriage of Green Building Designs with Green Process Designs

• Increasing value to shareholders and the community, while reducing the environmental footprint

• Safer Chemistry • Employee Exposure Reduction• Reduce use of Target Chemicals• Waste Reduction• Minimize new Regulatory Impact• Support BMS Sustainability Goals 2010• Cost Reduction/Avoidance

Green Chemistry:Green Chemistry:Design for EHS BenefitsDesign for EHS Benefits

A driver for sustainable development

GREENCHEMISTRY

PRODUCTLIFE CYCLE

POLLUTION PREVENTION

PROCESSSAFETY MNGT

COMPLIANCE

Green ChemistryGreen Chemistry

2004 Presidential Green 2004 Presidential Green Chemistry Challenge AwardChemistry Challenge Award

TAXOL GREENNESS PROJECT

From U.S. Environmental Protection Agency

Taxol StoryTaxol Story

TaxolTaxol®®

Paclitaxel

Approved for treatment of ovarian, breast, non-small cell lung cancer, and AIDS-related Kaposi’s sarcoma

in over 50 countries

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Taxol Early DevelopmentTaxol Early Development

Extract of the bark of the Pacific yew tree (Taxus brevifolia) shows anti-tumor activity (Wall, Wani)

Paclitaxel isolated and identified (Wall, Wani)

Paclitaxel shown to prevent cell division by promoting disassembly of microtubules (Horowitz)

Phase I clinical trials begin

Bristol-Myers Squibb selected by NCI as commercial partner in developing Taxol

1963 -

1971 -

1979 -

1983 -

1991 -

Taxol Supply IssuesTaxol Supply Issues

• Yew bark contains only ~0.0004% taxol

• Yew trees killed during harvesting

• Pacific yew trees provide the habitat of the endangered spotted owl

Semisynthetic TaxolSemisynthetic Taxol

• Leaves and twigs are a source of 10-deacetylbaccatin III (10-DAB)

• Biomass contains ~0.1% 10-DAB

• Renewable source cultivated throughout Europe

European Yew TreeEuropean Yew Tree((Taxus baccataTaxus baccata))

Plant Cell Fermentation (PCF) Plant Cell Fermentation (PCF) TaxolTaxol

Callus derived from needles of the

Chinese yew tree (Taxus chinensis)

Production cell bank

Seed build-up in liquid culture

Fermentation I: Growth phase

Fermentation II: Production phase

Plant Cell Fermentation and Plant Cell Fermentation and Extraction ProcessExtraction Process

Callus growth on solid agar plate

Whole broth extraction

Chromatographic purification

Crystallization

Sustainability of SupplySustainability of Supply

• PCF is a reliable year-round source of Taxol

• Yield is not susceptible to the influence of weather conditions, pests and diseases

• PCF Taxol production is faster than cultivation of biomass

• PCF Taxol production levels can be matched to commercial demand

Waste ReductionWaste Reduction

PCF Taxol production eliminated:

• ~ 240 MT per annum of biomass waste from 10-DAB production

• ~ 6.4 MT per annum of reagents classified as hazardous materials

• 9 different solvents, greatly simplifying composition of waste streams and improving recycle potential

• ~ 350 kg per annum of solid waste

Other Environmental BenefitsOther Environmental Benefits

Reduced Occupational Exposure

• Eliminated 6 solid-handling steps

• Eliminated handling of 24 reagents classified as hazardous reagents

Reduced Energy Usage

• Eliminated 2 steps that utilize cryogenic temperatures

• Eliminated 6 drying steps

Business Imperative for Business Imperative for SustainabilitySustainability

• Green Chemistry Program

• Sustainability 2010 goals

• Compliance with all local, state and federal environmental regulations

All factors aligned with Bristol-Myers Squibb’s

Other Business FactorsOther Business Factors

Product Quality• PCF conditions are more easily controlled to

ensure consistent production of high quality Taxol

Cost of Goods• Process comparison

• PCF has potential for further reductions through development of more productive Taxus cell lines

Natural Semi-Synthetic

PCF

32%20%

AcknowledgementsAcknowledgements

Technical Operations

- Chemical Development

- Chemical Development Analytical Services

- Manufacturing

Process R&D, Pharmaceutical Research Institute

Environmental Health and Safety

Quality Assurance and Compliance

Business Development

Legal Affairs

Global Regulatory Sciences

Phyton, Inc.

Sustainable Product DesignSustainable Product Design

Costs

Environment

Product

ionIntelligence

Effect

Sustainable Health Products Sustainable Health Products 20502050

Requirements of Pharmaceuticals

Sustainable Health Products and Sustainable Health Products and Service Solutions 2050Service Solutions 2050

Questions and Answers