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

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

Design for Environmental Health and Safety through GREEN CHEMISTRY

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

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.

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

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

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

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

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

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

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 -

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

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)

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

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

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

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

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

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

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%

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.

Sustainable Product Design

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

Sustainable Health Products and Service Solutions 2050 Questions and Answers