1. Cleaner Production Downstream Expectations and Industry Case Studies
Green Chemistry at Bristol-Myers Squibb
WEC Meeting
Hamburg, April 14 – 15, 2005
Presented by: Ludwig Metz, Bristol-Myers Squibb

2. Content of Presentation
BMS Green Chemistry
BMS Taxol Story
Sustainable Product Design

3. Design for Environmental Health and Safety through GREEN CHEMISTRY

4. What does Green Chemistry Mean?
Choosing a non-regulated solvent?
All aqueous processing?
Outsource intermediates or products (N.I.M.B.Y.)?

5. Green Chemistry is reducing or eliminating
The Presidential Green Chemistry Challenge
What is “Green 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.

6. The 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

7. Sustainable Development
Marriage of Green Building Designs with Green Process Designs
Increasing value to shareholders and the community, while reducing the environmental footprint

8. Green Chemistry: Design for EHS Benefits
Safer Chemistry
Employee Exposure Reduction
Reduce use of Target Chemicals
Waste Reduction
Minimize new Regulatory Impact
Support BMS Sustainability Goals 2010
Cost Reduction/Avoidance

9. Green Chemistry A driver for sustainable development POLLUTION
PREVENTION
COMPLIANCE
PRODUCT
LIFE CYCLE
PROCESS
SAFETY
MNGT
GREEN
CHEMISTRY
A driver for sustainable development

10. 2004 Presidential Green Chemistry Challenge Award
Taxol Story
TAXOL GREENNESS PROJECT
2004 Presidential Green Chemistry Challenge Award
From U.S. Environmental Protection Agency

11. Taxol®
Paclitaxel
Approved for treatment of ovarian, breast, non-small cell lung cancer, and AIDS-related Kaposi’s sarcoma in over 50 countries

12. Taxol Early Development
1963 -
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
1971 -
1979 -
1983 -
1991 -

13. Taxol 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

14. European Yew Tree (Taxus baccata)
Semisynthetic 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 Tree (Taxus baccata)

15. Plant Cell Fermentation (PCF) Taxol
Callus derived from needles of the
Chinese yew tree (Taxus chinensis)

16. Plant Cell Fermentation and Extraction Process
Production cell bank
Callus growth on solid agar plate
Seed build-up in liquid culture
Fermentation I: Growth phase
Fermentation II: Production phase
Whole broth extraction
Chromatographic purification
Crystallization

17. Sustainability 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

18. Waste 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

19. Other 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

20. Business Imperative for Sustainability
All factors aligned with Bristol-Myers Squibb’s
Green Chemistry Program
Sustainability 2010 goals
Compliance with all local, state and federal environmental regulations

21. Other Business Factors
Product Quality
PCF conditions are more easily controlled to ensure consistent production of high quality Taxol
Cost of Goods
Process comparison
Natural
Semi-Synthetic
PCF
PCF has potential for further reductions through development of more productive Taxus cell lines
32%
20%

22. Acknowledgements 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.

23. Sustainable Product Design

24. Sustainable Health Products 2050
Requirements of Pharmaceuticals
Costs
Environment
Effect
Intelligence
Production

25. Sustainable Health Products and Service Solutions 2050
Questions and Answers