Downstream Processing in Biopharmaceuticals

Transcription

1 Downstream Processing in Biopharmaceuticals Adoption of Disposable Technology at Improved Economies of Scale to Optimize Production Efficiency and Cost-effectiveness

2 GBI Research Report Guidance GBI Research Report Guidance The report provides an analysis of the various manufacturing techniques, emerging technologies, and key stakeholders in the biopharmaceutical industry. It also explains the role of downstream processing along with the different challenges and unmet needs identified in the biopharmaceutical industry. The report provides information on reagent market and reagent suppliers of downstream processing. The report starts with an executive summary highlighting the key points of the biopharmaceutical Contract Manufacturing Organization (CMO) market, the downstream processing market, and the reagent market. Chapter three briefly describes biopharmaceuticals, their manufacturing, downstream processing, and upstream processing. Chapter four focuses on the role of downstream processing in the biopharmaceutical industry, and analyzes and compares the various manufacturing processes, and gives the key stakeholders in the manufacturing sector. It also provides information on the reagents used, reagent suppliers, equipment suppliers, and reagent market. Chapter five covers the global CMO market, CMO market for biopharmaceuticals, and the CMO market for downstream processing. Chapter six focuses on the challenges and unmet needs in the market, and covers all the major issues related to downstream processing and their desired stage in the future. Chapter seven focuses on emerging technologies and covers all major technological developments in downstream processing, especially focusing on single-use technologies. Chapter eight focuses on industry analysis, and covers key drivers and restraints, the impact of environmental factors, and the market dynamics of the downstream process. Chapter nine covers all the key players in the downstream equipment market, reagent market, and CMO industry across the globe. Page 2

3 Downstream Processing in Biopharmaceuticals: - Executive Summary Cost savings present an excellent opportunity for Western pharmaceutical manufacturers to outsource to Asian CMOs Downstream Processing in Biopharmaceuticals - Executive Summary Global Contract Manufacturing Organizations Market is Set to Grow Steadily due to the Increased Outsourcing of Pharmaceutical Production for Western Pharmaceutical Manufacturers to Asian Countries Initially, the concept of providing total biopharmaceutical solutions was present only within the US and certain European countries. Over the past couple of years, countries such as India, Korea and China have started adopting the same business model. Due to vast differences in production and labor costs, manufacturers are shifting their focus to Asian Contract Manufacturing Organizations (CMOs). The overall cost of drug manufacturing in India is up to XX% cheaper than in Western countries. Cost savings at this scale present an excellent opportunity for Western pharmaceutical manufacturers to outsource to Asian CMOs. Apart from this, CMOs are also applying a strategy of integration. Over the past couple of years, CMOs have been integrating their service portfolios to offer complete solutions to pharmaceutical manufacturers. Through these kinds of relationships, both the CMOs and the pharmaceutical manufacturers can pursue large-scale business opportunities using each other s facilities. GBI Research suggests that the global CMO market is set to grow steadily due to the increased outsourcing of pharmaceutical production for Western pharmaceutical manufacturers to Asian countries. The global CMO market was valued at $XX billion in This market grew at around XX% over 2008, when the market was approximately $XX billion. The major factor driving this market is the increase in the sourcing of biopharmaceutical and generic manufacturing. The market revenues are forecast to reach an approximate value of $XX billion by 2018, growing at a CAGR of XX% from Downstream Processing, Global, Contract Manufacturing Organizations, Biopharmaceutical Market, Revenue ($bn), CAGR ( ) : XX% Revenue ($bn) CAGR ( ) : XX% Source: GBI Research Page 3

4 Table of Contents 1 Table of Contents 1 Table of Contents List of Tables List of Figures Downstream Processing in Biopharmaceuticals - Introduction Downstream Processing in Biopharmaceuticals - Market Overview Overview of Biopharmaceuticals Cytokines Enzymes Hormones Clotting Factors Vaccines Monoclonal Antibodies Cell Therapies Antisense Drugs Peptide Therapeutics Overview of Downstream Processing in Biopharmaceuticals A Typical Downstream Processing Operation Major Check Points during Downstream Processing Downstream Processing in Biopharmaceuticals - Role of Downstream Processing in the Biopharmaceutical Industry Major Reagents, Reagent Suppliers and Reagents Market related to Downstream Process Major Reagents Reagent Suppliers Reagent Market Major Equipment Suppliers Downstream Processing in Biopharmaceuticals - Downstream Processing Market for CMOs Global CMO Market Overview CMO Biopharmaceuticals Market Characterization CMO Market Size for Downstream Processing Downstream Processing in Biopharmaceuticals - Challenges and Unmet Needs in Downstream Bioprocess Challenges Chromatographic Capture Reducing the Purification Steps Titer Increment/Capacity Bottleneck Virus Clearances Scaling Up Unmet Needs Unmet Medical Needs Realistic Achievement of Economies of Scale Technological Development of Disposables at Large Scale Reagent Costs and their Effectiveness Downstream Processing in Biopharmaceuticals - Emerging Technologies and their Implications Single Use Technology/Disposable Technology Advantages Disadvantages Multi-column Chromatography Advantages Disadvantages Tangential Flow Filtration...33 Page 5

5 Table of Contents Advantages Disadvantages Downstream Processing in Biopharmaceuticals - Industry Analysis Key Drivers and Restraints Key Drivers of Downstream Processing Market Key Restraints of Downstream Processing Market Porter s Five Forces Model for Industry Analysis Major Events and their Impact Analysis Downstream Processing in Biopharmaceuticals - Competitive Landscape Market Dynamics of Downstream Processing and Impact Market Structure Key Equipment Players Pall Corporation Millipore Sartorius Stedim Biotech S.A Key Reagent Players Life Technologies Sigma Aldrich Key CMO Players Lonza Boehringer Ingelheim Diosynth Biotechnology Downstream Processing in Biopharmaceuticals - Appendix Market Definitions Abbreviations Bibliography Research Methodology Coverage Secondary Research Primary Research Expert Panel Validation Contact Us Disclaimer...59 Page 6

6 Table of Contents 1.1 List of Tables Table 1: Downstream Processing, Global, Cost Breakups of Upstream and Downstream Processing, Table 2: Downstream Processing, Global, Reagent Suppliers, Table 3: Downstream Processing, Global, Total Reagent Market for Downstream Processing, Revenue ($m), Table 4: Downstream Processing, Global, Total Reagent Market for Downstream Processing, Revenue Forecast ($m), Table 5: Downstream Processing, Global, Equipment Suppliers, Table 6: Downstream Processing, Global, CMO Biopharmaceutical Market, Revenue ($bn), Table 7: Downstream Processing, Global, CMO Biopharmaceutical Market, Revenue Forecast ($bn), Table 8: Downstream Processing, Global, Downstream Processing Market for CMOs, Revenue ($bn), Table 9: Downstream Processing, Global, Downstream Processing Market for CMOs, Revenue ($bn), Table 10: Downstream Processing, Key Equipment Players, Pall Corporation, Major M&A Deals, Table 11: Downstream Processing, Key Equipment Players, EMD Millipore, Major M&A Deals, Table 12: Downstream Processing, Key Equipment Players, Sartorius Stedim Biotech S.A, Major M&A Deals, Table 13: Downstream Processing, Key Reagent Players, Life Technologies, Major M&A Deals, Table 14: Downstream Processing, Key Reagent Players, Sigma-Aldrich, Major M&A Deals, Table 15: Downstream Processing, Key CMO Players, Lonza, Major M&A Deals, Table 16: Downstream Processing, Key CMO Players, Boehringer Ingelhiem, Major M&A Deals, Table 17: Downstream Processing, Key CMO Players, Diosynth Biotechnology, Major M&A Deals, Page 7

7 Table of Contents 1.2 List of Figures Figure 1: Downstream Processing, Global, Biopharmaceutical Types, Figure 2: Downstream Processing, Global, Overview of General Drug Development Process, Figure 3: Downstream Processing, Global, Process Steps, Figure 4: Downstream Processing, Global, Changing Distribution of Cost along with Yield Increment, Figure 5: Downstream Processing, Global, Yield Percentage vs Number of Purification Steps, Figure 6: Downstream Processing, Global, Cost Breakups of Upstream and Downstream Processing, Figure 7: Downstream Processing, Global, Total Reagent Market for Downstream Processing, Revenue ($m), Figure 8: Downstream Processing, Global, CMO Biopharmaceutical Market, Revenue ($bn), Figure 9: Downstream Processing, Global, Downstream Processing Market for CMOs, Revenue ($bn), Figure 10: Downstream Processing, Global, Challenges, Figure 11: Downstream Processing, Global, Emerging Technologies and their Likely Adaptation, Figure 12: Downstream Processing, Global, Industry Analysis, Key Drivers and Restraints, Figure 13: Downstream Processing, Global, Industry Analysis, Porter s Five Forces Model, Figure 14: Downstream Processing, Global, Industry Analysis, Major Market Events and their Impact, Figure 15: Downstream Processing, Global, Industry Analysis, Market Dynamics, Figure 16: Downstream Processing, Key Equipment Players, Business Overview, Pall Corporation, Figure 17: Downstream Processing, Key Equipment Players, Business Overview, EMD Millipore, Figure 18: Downstream Processing, Key Equipment Players, Business Overview, Sartorius Stedim Biotech S.A, Figure 19: Downstream Processing, Key Reagent Players, Business Overview, Life Technologies, Figure 20: Downstream Processing, Key Reagent Players, Business Overview, Sigma-Aldrich, Figure 21: Downstream Processing, Key CMO Players, Business Overview, Lonza, Figure 22: Downstream Processing, Key CMO Players, Business Overview, Boehringer Ingelheim, Figure 23: Downstream Processing, Key CMO Players, Business Overview, Diosynth Biotechnology, Page 8

8 Downstream Processing in Biopharmaceuticals - Introduction 2 Downstream Processing in Biopharmaceuticals - Introduction Downstream processing applies to the process of recovery and purification of biosynthetic products, recycling the components and treating product waste after biological fermentation. There are various stages of downstream processing, such as the removal of insolubles; isolation, purification, and polishing of the product. Downstream processing has a major role in biopharmaceutical manufacturing industry. It accounts for more than XX% of the total manufacturing cost. However, the cost of production may vary as per the titer yield (protein production level). Page 9

9 Downstream Processing in Biopharmaceuticals - Role of Processing in the Biopharmaceutical Industry Downstream 4 Downstream Processing in Biopharmaceuticals - Role of Downstream Processing in the Biopharmaceutical Industry Downstream processing plays a major role in overall drug production, accounting for XX% of the total manufacturing cost. Though the cost may vary according to the titer yield, developers are concerned with devising ways to cut down their increasing costs. Increasing the protein production level, commonly known as titer, is the prime focus in downstream processing and can be achieved in a cell-culture bioreactor. The increasing titers in cell culture have recently changed the focus of process development efforts toward improving the economics of product recovery and purification processes. Figure 4: Downstream Processing, Global, Changing Distribution of Cost along with Yield Increment, g/liter Titer yeild in g/liter 1g/liter 3g/liter Upstream cost percentage Downstream cost percentage Source: GBI Research; Vermasvuori, 2009 g/liter: grams per liter According to research conducted by Sommerfeld and Strube (2005), if titer yield is increased from XXg/XX (gram per liter) to XXg/XX, drastic changes can be observed in the cost ratio of upstream and downstream processing. With the development of new technologies, the overall cost remains low, but downstream processing costs are still much higher than upstream costs. Additionally, if the increase in annual output is accompanied by titer increases, then the changes in the cost ratio of upstream and downstream processing are likely to become even more prominent. On a small scale, fixed costs tend to dominate and any changes in raw materials will have a minimal impact. However, as the scale increases, the role of raw materials becomes more critical. It is therefore important to look at the distribution of the costs. Page 15

10 Downstream Processing in Biopharmaceuticals - Role of Processing in the Biopharmaceutical Industry Downstream The figure and table below give the cost breakups of upstream and downstream processing: Figure 6: Downstream Processing, Global, Cost Breakups of Upstream and Downstream Processing, 2011 Downstream costs have increased substantially due to high costs for labor and materials for production Cost in $ Upstream costs have not increased much due to almost unaffected labor costs Upstream processing for 100 mg Upstream processing for 3,000 mg Downstream Processing for 100 mg Downstream Processing for 3,000 mg Source: GBI Research; Suzanne, 2009 Materials Equipments Labor Table 1: Materials Equipment Labor Downstream Processing, Global, Cost Breakups of Upstream and Downstream Processing, 2011 Upstream Processing for 100mg Upstream Processing for 3,000mg Downstream Processing for 100mg Downstream Processing for 3,000mg Source: GBI Research; Suzanne, 2009l It shows that the cost of downstream processing has increased substantially due to high labor costs and the material cost of purification. However, a slight change in labor cost does not affect the upstream production cost (Suzanne, 2009) Page 17

11 Downstream Processing in Biopharmaceuticals Appendix 10 Downstream Processing in Biopharmaceuticals - Appendix 10.1 Market Definitions Biologics: Products derived from living sources, such as humans, animals, bacteria, and viruses such as vaccines, immune globulin, and anti-toxins. Downstream Bioprocess: When the cell mass from the upstream processing segment are processed to meet purity and quality requirements, this process is referred to as downstream processing. Transgene: When a foreign gene and control sequence is introduced in a genetic structure in order to make some modification, it is called a transgene. Capacity Bottleneck: A bottleneck is a phenomenon where the performance or capacity of an entire system is limited by a single or limited number of components or resources Abbreviations AEX: ATPS: BPVs: CAGR: CFF: CHO: CIP: CMOs: CS: DNA: DSP: EBA: FT: GS: HCP: HIC: MBS: MCC: MF: mrna: PEG: PES: RNA: SEC: SEZ: SIAL: SIP: SMB: Anion Exchange Chromatography Aqueous Two Phase Systems Bioprocess Vessels Compound Annual Growth Rate Cross Flow Filtration Chinese Hamster Ovary Cleaning-In-Place Contract Manufacturing Organizations Cell Systems Deoxyribonucleic Acid Downstream Processing Expanded-Bed Adsorption Flow Through Genetic Systems Host Cell Proteins Hydrophobic Interaction Chromatography Molecular Biology Systems Multi-Column Chromatography Microfiltration Messenger Ribonucleic Acid Polyethylene Glycol Polyethersulfone Ribonucleic Acid US Securities and Exchanges Commission Special Economic Zone Sigma-Aldrich Corporation Steam-In-Place Simulated Moving Bed Chromatography Page 56

12 Downstream Processing in Biopharmaceuticals Appendix TFF: UF: UF/DF: WFI: Tangential Flow Filtration Ultrafiltration Ultrafiltration/diafiltration Water for Injection 10.3 Bibliography Bengio S and Sievers D (2012). Chromatographic Purification in Downstream Processing. BioProcess International. Boehringer Ingelheim GmbH (2011). Annual Report. Available from: Carta G and Jungbauer A (2010). Protein Chromatography: Process Development and Scale-Up. Diosynth Biotechnology (2011). Annual Report. Available from: Dutta R (2008). Fundamentals of Biochemical Engineering. Available from: EMD Millipore (2011). Annual Report. Available from: 12_87112.pdf?Version= [Accessed May, 2012]. Life Technologies Corporation (2011). Annual Report. Available from: Lonza Group Ltd. (2011). Annual Report. Available from: E_final.ashx [Accessed May, 2012]. Marc B, et al. (2009). Single-Use, Continuous-Countercurrent, Multicolumn Chromatography. BioProcess International. Markus L, et al. (2011). Disposable Downstream Processing for Clinical Manufacturing. BioProcess International. Available from: Processing-for-Clinical-Manufacturing [Accessed February, 2012]. Millipore Technical Publications (2012). Increasing Purity on ProSep-vA Affinity Chromatography Media using an Intermediate Wash Step. Available from: [Accessed 8 February, 2012] Pall Corporation (2011). Annual Report. Available from: [Accessed 17 May, 2012]. Pall Corporation (2012). Tangential Flow Filtration Introduction. Available from: [Accessed February, 2012]. Russell J (2012). Reducing Uncertainty Surrounding Biosimilar Production. Genetic Engineering and Biotechnology News. Available from: [Accessed May, 2012] Sartorius Stedim Biotech S.A. (2011). Annual Report. Available from: us_stedim_biotech.pdf Science Daily (2012). Biopharmaceutical. Available from: [Accessed 20 February, 2012] Page 57

13 Downstream Processing in Biopharmaceuticals Appendix Sigma-Aldrich Corporation (2011). Annual Report. Available from: Sommerfeld and Strube (2005). Challenges in biotechnology production generic processes and process optimization for monoclonal antibodies. Available from: Suzanne S (2009). Economic Drivers and Trade-Offs in Antibody Purification Processes. BioPharm International. Available from: geid=2 [Accessed 7 February, 2012]. Thermo Scientific (2012). Mem-PER Eukaryotic Membrane Protein Extraction Kit. Available from: [Accessed 24 February, 2012]. Vermasvuori R (2009). Production Of Recombinant Proteins And Monoclonal Antibodies Techno- Economical Evaluation Of The Production Methods. Available from: Research Methodology GBI Research s dedicated research and analysis teams consist of experienced professionals with a pedigree in marketing, market research, consulting backgrounds in the medical devices industry, and advanced statistical expertise. GBI Research adheres to the codes of practice of the Market Research Society ( and the Strategic and Competitive Intelligence Professionals ( All GBI Research databases are continuously updated and revised. The following research methodology is followed for all databases and reports Coverage The objective of updating GBI Research s coverage is to ensure that it represents the most up-to-date vision of the industry possible. Changes to the industry taxonomy are built on the basis of extensive research of company, association and competitor sources. GBI Research aims to cover all major news events and deals in the medical industry, updated on a daily basis. The coverage is further streamlined and strengthened with additional inputs from GBI Research s expert panel (see below) Secondary Research Secondary research was carried out on internal and external sources being to obtain qualitative and quantitative information relating to each market. The secondary research sources that are referred to in this report include but are not limited to: Company websites, annual reports, financial reports, investor presentations and US Securities and Exchanges Commission (SEC) filings Industry trade journals, scientific journals and other technical literature Relevant patent and regulatory databases National government documents, statistical databases and market reports News articles, press releases and webcasts specific to the companies operating in the market Page 58

14 Downstream Processing in Biopharmaceuticals Appendix Primary Research GBI Research conducts hundreds of primary interviews each year with industry participants and commentators in order to validate its data and analysis. A typical research interview fulfills the following functions: It provides first-hand information on the market size, market trends, growth trends, competitive landscape, and future outlook Helps in validating and strengthening the secondary research findings; and Further develops the analysis team s expertise and market understanding Primary research involves correspondence, and telephone interviews as well as face-to-face interviews for each market, category, segment and sub-segment across geographies. The participants who typically take part in such a process include, but are not limited to: Industry participants: CEOs, VPs, marketing/product managers, market intelligence managers and national sales managers; Hospital stores, laboratories, pharmacies, distributors and paramedics; Outside experts: investment bankers, valuation experts, research analysts specializing in specific medical equipment markets; and Key Opinion Leaders (KOLs): physicians and surgeons specializing in different therapeutic areas corresponding to different kinds of pharmaceutical drugs Expert Panel Validation GBI Research uses a panel of experts to cross-verify its databases and forecasts. GBI Research s expert panel comprises marketing managers, product specialists, international sales managers from medical device companies, academics from research universities, KOLs from hospitals, consultants from venture capital funds and distributors/suppliers of medical equipment and supplies. Historic data and forecasts are relayed to GBI Research s Expert Panel for feedback and adjusted in accordance with their feedback Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research. Page 59