Abstract Process Economics Program Report 241 BIOCATALYSIS (May 2002)

Transcription

1 Abstract Process Economics Program Report 241 BIOCATALYSIS (May 2002) Biocatalysis is a term used to describe the catalytic activity of biological systems, which includes living whole cells, parts of cells and enzymes. Humans have harnessed the capabilities of biocatalysts for centuries to generate useful products. The ability of biocatalysts to selectively produce useful products under relatively mild conditions compared to its chemical catalyst counterpart make biocatalysts an interesting and powerful addition to a process synthesis "tool-box". Recent advances in technology have markedly increased the ability of industry to discover new biocatalysts and optimize their performance. These advances are coming at a time when both the chemical and pharmaceutical industries are facing increasing pressure to produce more effective products and to make them more efficiently. This report discusses the advances in technology for the improvement of biocatalyst performance and the resulting intellectual property being generated. The process economics are analyzed for two processes for the manufacture of the L-amino acid, L-aspartic acid by biocatalysis. Both the existing and new processes are analyzed. In the new process the coupling of two biocatalysts allows for the elimination of a chemical catalyst, and reconfiguration of the process. This process reconfiguration results in the virtual elimination of a by-product produced in the existing process. This report will be of interest to the chemical and pharmaceutical industries currently using or planning the incorporation of biocatalysts into their process portfolio. PEP 00 RGB

2 CONTENTS 1 INTRODUTION SUMMARY INTRODUCTION Rational Design/Computational Methods Directed Molecular Evolution (DME) DNA Shuffling Library Screening/Selection Extremophiles Intellectual Property Process Examples Process Description Conventional Process Process Description CAPITAL COSTS PRODUCTION COSTS Outsourcing Biocatalyst Manufacture Summary HISTORYICAL PERSPECTIVES/BACKGROUND INTRODUCTION WHAT ARE BIOCATALYSTS How Are They Used ADVANTAGES OF BIOCATALYSTS Aspartame Production HOW DO THEY WORK Types of Reactions Need for Cofactors Use in Non-Aqueous Systems iii

3 CONTENTS (Continued) THE FUTURE INDUSTRY STATUS INDUSTRIAL ENZYME MARKET-OVERVIEW INDUSTRIAL ENZYME MARKET-MAJOR PLAYERS INDUSTRIAL ENZYMES MARKET TRENDS New Markets for Biocatalysis PRODUCTS OF BIOCATALYSIS-OVERVIEW PRODUCTS OF BIOCATALYSIS-MAJOR PLAYERS BIOCATALYSIS PRODUCT TRENDS Pharmaceutical Industry Biocatalysts in Chemical Industry FUTURE TRENDS IN BIOCATALYSIS Increased Availability of Biocatalysts Combined Chemocatalysis and Biocatalysis FUTURE FEEDSTOCKS SUMMARY ROEL OF NEW TECHNOLOGIES WHY DO WE NEED NEW TECHNOLOGIES KEY TECHNOLOGIES Advances in Rational Design and Computational Methods DIRECTED MOLECULAR EVOLUTION Mutation Generation DNA SHUFFLING Library Screening/Selection EXTREMOPHILES iv

4 CONTENTS (Continued) COMBINED METHODS COMMERCIAL SUCCESSES INTELLECTUAL PROPERTY ISSUES INTRODUCTION TRENDS Patents for "Tools" Focus on DME Patents DME Patent Disputes Other "Tool" Patents of Interest SELECTED COMPANY PATENTS IN TOOLS Applied Molecular Evolution Diversa Genencor International Maxygen Novozymes (Novo Nordisk) PATENTS FOR ORGANISMS AND ENZYMES Patent Requirements for Depositing Cited Organisms Patent Disputes PATENTS FOR PROCESSES Pharmaceutical Manufacturing Amino Acids by Fermentation Monomers by Fermentation Antibiotics Fuel Desulfurization SUMMARY L-ASPARTIC ACID PRODUCTION USING DUAL-BIOCATALYSTS v

5 CONTENTS (Continued) INTRODUCTION TECHNOLOGY OVERVIEW Chemistry Maleic Anhydride Hydrolysis Fumaric Acid Production Fumaric Acid Production by Biocatalysis L-aspartic Acid Production L-aspartic Acid Recovery Conventional Recovery Process Recycle of the MAM Biotransformation of MAM PROCESS DESCRIPTION Overview Biocatalyst Preparation Formulation of Growth Media Fermentor Sterilization Fermentor Inoculation and Culture Growth Biomass Recovery and Immobilization SYNTHESIS PROCESS STARTUP STEADY STATE Bioconversion PROCESS DISCUSSION Biocatalyst Selection Reactor Design ASPARTIC ACID RECOVERY ph Control vi

6 CONTENTS (Continued) Purge Stream Requirements Excess Water Removal Waste Streams Materials of Construction CAPITAL COSTS Production Costs Outsourcing Biocatalyst Manufacture Summary L-ASPARTIC ACID CONVENTIONAL PROCESS INTRODUCTION TECHNOLOGY OVERVIEW Chemistry Fumaric Acid Production Bioconversion of Fumarate L-Aspartic Acid Recovery PROCESS DESCRIPTION Overview Biocatalyst Preparation Fermentor Preparation Fermentor Inoculation and Biomass Growth Biomass Recovery SECTION 200-SYNTHESIS Fumaric Acid Production Fumaric Acid Neutralization DAF Bioconversion Recovery L-Aspartic Acid AMMONIUM SULFATE RECOVERY vii

7 CONTENTS (Continued) Overview Ammonium Sulfate Recovery PROCESS DISCUSSION Fumaric Acid Production Biocatalyst Selection Reactor Design L-Aspartic Acid Recovery ph Control Purge Stream Concentration WASTE STREAMS CAPITAL COSTS Production Costs Outsourcing Biocatalyst Summary APPENDIX A: PATENT SUMMARY TABLES... A-1 APPENDIX B: DESIGN AND COST BASES... B-1 APPENDIX C: CITED REFERENCES... C-1 APPENDIX D: PATENT REFERENCES BY COMPANY... D-1 APPENDIX E: PROCESS FLOW DIAGRAM... E-1 viii

8 ILLUSTRATIONS 2.1 Conventional L-Aspartic Acid Process L-Aspartic Acid by Dual Biocatalysts DNA and Protein Structure Aerobic Bioreactor High Fructose Corn Syrup Aspartame Molecule Aspartame Production by Enzymatic Coupling Catalytic Energy Diagram Mechanism of Enzyme Activity Cofactor Regeneration Structure of Nictotinamide Adenine Dinucleotide Cofactor Recycling in the Production of L-Tert-Leucine Industrial Enzyme Market by Application Global Market Shares In Industrial Enzymes Rational Design of Enzymes Random Mutagenesis DNA Shuffling Technique Tiered Screening Creating Extremozyme Factories Alpha-Beta Scaffold Dual Biocatalyst L-Aspartic Acid Process... E Amino Acid Configuration Amino Acid Solubility Versus ph Block Flow Conventional L-Aspartic Acid Production Block Flow of L-Aspartic Acid Production by Maleic Acid as the Acidulant Mitsubishi Chemical L-Aspartic Acid Process by Dual Biocatalysts Conventional L-Aspartic Acid Process... E-9 ix

9 ILLUSTRATIONS (Concluded) 8.2 Amino Acid Structure Amino Acid Solubility vs ph Conventional L-Aspartic Acid Process x

10 TABLES 2.1 Capital Costs for 30 Million lb/yr L-Aspartic Acid Facility L-Aspartic Acid Production Costs Aspartic Acid Capital Costs L-Aspartic Acid Production Costs Enzymes Used in the Chemical and Pharmaceutical Industries Causes of Lower Enzymatic Activity in Organic Solvents and Remedies Recent Industrial Enzyme Collaborations and Acquisitions Products of Biocatalysis Biocatalysts Improved by Random Mutagenesis Directed Molecular Evolution Extremophiles Thermostable Enzymes from Pyrococcus Furiosus and Thermtoga SP Patents by Region and Category (Percentage) Patents by Region and Category (Percentage) Selected Tool Patents Owned or Licensed to Applied Molecular Evolution Selected Tool Patents Owned or Licensed by Diversa Selected Tool Patents Owned or Licensed by Genencor International Selected Tool Patents Owned or Licensed by Maxygen Selected Tool Patents Owned or Licensed by Novozymes (Novo Nordisk) Selected Patents Owned by or Licensed to Ajinomoto Selected Patents Owned by or Licensed to DuPont for 1,3 Propanediol Production Selected Patents Owned by or Licensed to DSM Fermentor Media Composition L-Aspartic Acid Production Design Bases and Assumptions L-Aspartic Acid Production Stream Flows L-Aspartic Acid Using Dual Biocatalysts Major Equipment xi

11 TABLES (Concluded) 7.5 L-Aspartic Acid Using Dual Biocatalysts Utilities Summary L-Aspartic Acid Using Dual Biocatalysts Total Capital Investment L-Aspartic Acid Using Dual Biocatalysts Capital Investment by Section L-Aspartic Acid Using Dual Biocatalysts Production Costs L-Aspartic Acid Using Dual Biocatalysts Direct Costs by Section, $ thousands/yr L-Aspartic Acid Using Outsourced Dual Biocatalysts Production Costs Fermentor Media Composition L-Aspartic Acid Production Design Bases and Assumptions L-Aspartic Acid Production Stream Flows L-Aspartic Acid Waste Summary L-Aspartic Acid Conventional Process with Sulfate Recovery Major Equipment L-Aspartic Acid Conventional Process with Sulfate Recovery Utilities Summary L-Aspartic Acid Conventional Process with Sulfate Recovery Total Capital Investment L-Aspartic Acid Conventional Process with Sulfate Recovery Capital Investment by Section L-Aspartic Acid Conventional Process with Sulfate Recovery Production Costs L-Aspartic Acid Conventional Process with Sulfate Recovery Direct Costs by Section, $ thousands/yr L-Aspartic Acid Conventional Process Outsourced Biocatalyst with Sulfate Recovery Production Costs xii