As process development and manufacturing (cmc) for biologics development-an overview 26 nov09
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As process development and manufacturing (cmc) for biologics development-an overview 26 nov09



This is a high level overview presentation which was made for Academia Sinica audience as a special invitation by the President

This is a high level overview presentation which was made for Academia Sinica audience as a special invitation by the President



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  • informative overview, hoping it would say a little more about trends in CMC and regulation
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    As process development and manufacturing (cmc) for biologics development-an overview 26 nov09 As process development and manufacturing (cmc) for biologics development-an overview 26 nov09 Presentation Transcript

    • November 26 2009 Academia Sinica NanKang, Taiwan, R.O. China
    • -  Biologics – definition & applications -  Process is the Product -  Monoclonal antibodies & vaccines as growth opportunities -  Changes in global biopharmaceutical industry -  Paradigm shift in development process for bioloigcs -  Effective process development and manufacturing strategy -  Integrated CMC team -  Select/establish cell line(s) critically -  Establish knowledge-based process for commercialization -  Pursue revolutionary manufacturing technologies -  Summary
    • Biologics •  Include a wide range of medicinal products such as vaccines, blood/components, allergencis, somatic cells, gene therapy, tissues & recombinant therapeutic proteins created by biological processes (as opposed to chemically) •  Composed of sugars, proteins or nucleic acids or complex combinations of all, or living entities such as cells and tissues •  Isolated from a variety of natural sources – human, animal or microorganism, or produced by biotechnology methods and other technologies (e.g. recombinant DNA)  Gene-based and cellular biologics promise to treat a variety of medical conditions for which no other treatments are available Quotes from Wikipedia 6 July 2009
    • Glucophage® 166 Rituxan® Taxol® 854 145,000 Chemical Biologics Size (M.W.) < 500* 20,000 - 200,000+* Complexity Low High Process Conditions (T/P) High Ambient In-Process Concentration Concentrate (~100g/L) Dilute (.5 -5g/L) Reactor Volume < 8,000 L ~20,000+L Reaction Steps Multiple chemical Complex product reactions/isolations made by living cells Production Solvents Organic Aqueous Isolation/Purification Crystallization Chromatography Product Definition Few simple assays Many complex assays Process Changes Equivalency Comparability maybe clinical trials Patent/IP Molecules Process Knowhow IP Expiration Threat Generics dominant Biosimilars evolving  PROCESS is the product
    • •  Global pharmaceutical market Before global financial crisis…   Revenue US$ 773 bn in 2008   Projected growth rate of 5% •  Global biopharmaceutical market   Revenue US$75 bn in 2008   Projected growth rate 12% •  Growth in biopharmaceutical market to reach US$138 bn by 2014   dominated by products from mammalian cell cultures (>75%) •  Opportunities in biopharmaceuticals   Novel & biosimilar r-proteins   Vaccines Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
    • Therapeutic Proteins = Biopharmaceuticals •  75 FDA approved therapeutic proteins •  > 500 additional proteins under development •  Broad applications:   Cancers & autoimmune diseases (treated by monoclonal antibodies and interferons)   Heart attacks, strokes, cystic fibrosis and Gaucher's disease (treated by Enzymes and blood factors)   Metabolic diseases: diabetes (treated by insulin)   Blood diseases: anemeia (treated by erythropoietins), hemophilia (treated by blood clotting factors). •  Worldwide sales approximately $57 billion in 2006 with projected growth of 13% , or >$90 bn by 2010. •  Monoclonal antibodies (Mabs) ~32bn in 2008, growing rapidly to 30% global biologics market Piribo, “Global Protein Therapeutics Market Analysis", ProLOG Feb 13, 2008
    • Best Selling Monoclonal Antibodies 2006-2008 ($33 billion) FDA Sales ($ billion) Genetic Name Brand Companies approval 2006 2007 2008 1 Infliximab c Remicade 1998 J&J 4.2 5.04 6.5 2 Rituximab c Rituxan 1997 Roche 4.7 5.01 5.6 3 Trastuzumab hz Herceptin 1998 Roche 3.14 4.4 4.8 4 Bevacizumab Avastin 2004 Roche 2.4 3.93 4.7 5 Adalimumab h Humira 2002 Abbott 2.04 3.06 4.4 6 Cetuximab c Erbitux 2004 Bristol Myers Squibb, Merck KgA 1.1 1.35 2.0 7 Ranibizumab hz Lucentis 2006 Novartis, Roche 0.38 1.2 1.5 8 Palivizumab hz Synagis 1998 Astra Zeneca 1.1 0.62 1.2 9 Omalizumab hz Xolair 2003 Roche, Novartis 0.52 0.64 0.85 10 Natalizumab, hz Tysabri 2004/2006 Biogen Idec, Elan 0.06 0.46 0.6 11 Panitumumab h Vectibix 2006 Amgen 0.04 0.21 0.3 12 Abciximab c ReoPro 1994 J&J, Lilly 0.28 0.29 0.29 13 Efalizumab hz Raptiva 2003 Genentech, Merck Serono 0.16 0.21 0.28 14 Certolizumab TNFα Cimzia 2008 UCB 0.10 15 Tocilizumab Actemra Japan 2008 Roche Canada 2008 16 Ustenkinumab Stelara J&J EMEA 2009 12 approved and marketed monoclonal antibodies with low sales (<$100 million) are not included Source: Krishan Maggon, Global Monoclonal Antibodies Market Review 2008 (World Top Ten mAbs)
    • •  Global vaccines market will grow to over a USD $23.8 bn by 2012, growing at ~11% per year •  Novel and improved vaccines growing at 58% p.a. Traditional and combinations Include mostly pediatric & partially adult vaccines Novel and therapeutic vaccines include both adult & therapeutic Global Vaccine Market US$ bn Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
    • •  Pandemic & seasonal Flu vaccines: to reach $7.1 bn in 2010 with 19.8% growth rate, driven by pandemic flu vaccine global supply shortage (H5N1, H1N1) •  Driven by bird flu (2005) and swine flu (2009), government spending worldwide on Pandemic Influenza Preparedness tripled to $7 bn in 2009 ($2.2 bn in 2004, 17% CAGR), reaching ~ $10 bn by 2015 (5% CAGR) •  Global Pandemic Influenza Preparedness Market: estimated @$52 bn in 2010-2015 (5% CAGR)   Novel cell-based process & manufacturing technology reaching the market:   Baculovirus system/Insect cells (Protein Sciences, Novavax)   Mammalian cells: Vero (Baxter), MDCK (Novartis)   Per.C6 (Sanofi/Crucell); in serum-free media   Avian cells: EB66, duck embryonic stem cell line by Vivalis   DNA vaccines: VGX Pharma (IND) early development Global Pandemic Influenza Preparedness Market Forecast 2010-2015, Publication: 04/2009 by Market Research Media.
    • •  Concerns over global Economy  Increasing global price regulations   Implement a protectionist and nationalist policies   Strengthen the local pharmaceutical industry by implementing more stringent price regulation on foreign manufacturers •  Shift in growth from mature markets to emerging markets   Emerging economies could generate up to a fifth of global pharmaceutical sales by 2020   Changing growth dynamics from the West to emerging economies shift developer interest in patient groups   Increasing trend in outsourcing manufacturing and R&D cost-effectively •  Cost containment pressures in major markets worldwide   Escalating healthcare costs have put pressure on payers to contain pharmaceutical expenditure   Multiple stakeholders in the R&D/Product Development process including payers, patients and pharmacists (for pricing considerations) Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
    • Global Pharmaceutical Sales Global Pharmaceutical: 2009 Market Sizes* Growth Rate 4.5-5.5% Emerging, 115 US, 302 Japan, 88 * All values 2008 2009 are in US$, EU, 172 Billions 15% Growth Rate in Sales (%) 10% Growth in emerging country markets:  Far outstrip growth in the US & EU 5% US EU Japan Emerging Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
    • Discovery Phase Development Phase Commercialization Phase (3-6 years) (5-10 years) (8-12 years - Patent Expiration) Basic Manufacturing Full Early Stage Late Stage - Full Product Research Sales Discovery Development Development Management Distribution ECN IND BLA LAUNCH Generics Biosimilars 10,000 -30,000 ~250 5-10 2-5 2 1 Preclinical Phase I Phase IIa, IIb Phase III Testing Clinical Trial Clinical Trial Clinical Trial (lab & animal testing) Small Biologics Molecules Drug Development Outsourcing to CROs, CMOs Process Tech Transfer earlier Manufacturing Outsourcing to External Facilities
    • Molecular Biology Preclinical Filing, Regulatory & Clinical Launch & Cell Line & Process Review & Approval Development Commercialization Development 2-3 years 3-4 years 1-2 years Full Drug Development Capabilities and Infrastructure Required -  CMC: Process development & biologics Manufacturing -  Preclinical and Clinical: Toxicity, Phases 1 and III, comparability studies -  Filing and regulatory challenges High Barriers to Entry -  $50M – $500M long term investment required -  Competition with existing brands (low price differentials) -  Complexity of products (not API) and manufacturing facilities Highly Competitive Markets -  Large pharmaceutical companies moved in: Merck, Novartis, Aztrazeneca -  Major generics companies formed alliance: Teva & Lonza
    •  Chemistry, manufacturing and control (CMC) •  Manufacturing Information “pertaining to the composition, manufacture, stability and controls used for manufacturing the drug substance and the drug product” •  Information “ensure that the company can adequately produce and supply consistent batches of the drug”  Early development stage   Evaluate current technology to produce product, begin cell line and process development, and product characterization   Supply GLP material for preclinical toxicology study & produce GMP material for clinical trials   Begin developing process with end in mind
    • New cell line? Process changes? Formulation changes? Process Devt Biologics Process Commercial & Medium Scale Research scale production Fill & Finish production <10L 2000lL – 20,000L 10L-500L •  New cell line •  Process development, •  Process scale up •  Vial filling, packing development optimisation, scale-up •  DS Manufcturing •  Lyophilization, •  Expression •  Productivity enhancement facility operations •  Supply chain operations engineering •  QbD, PAT implementation •  COGS improvement •  COGS improvement •  Media design •  Product quality & stability •  Lean manufacturing •  Lean manufacturing •  Novel product FUNCTIONAL EXCELLENCE ONE CMC TEAM CELL CULTURE ANALYTICS PURIFICATION FORMULATION • Molecular Biologists • Analytical Biochemists• Chromatographers • Formulation chemists • Microbiologists • Biophysical Chemists • Protein Biochemists • Protein Biochemists • Cell Biologists • Protein Biochemists • Biochemical Engineers • Engineers • Virologists
    • Source:
    • 1981 - HER2 gene cloned 1985 - Axel Ullrich and Art Levinson clone HER2 gene 1990 - Creates anti-HER2 monoclonal Antibody (Herceptin) 1992 - Files Herceptin IND, Phase I trials initiated (25-50 patients) 1993 - Herceptin Phases II trials begin (250-200 patients) 1995 - Initiates Phase III, 3 trials (500-1,000 patients) 1996 - Partners with DAKO for commercial diagnostic testing kits 1997 - Completes Phase III enrollment 1998 - Presents Phase III data demonstrating effect with chemotherapy and increase time to disease progression 1998 - Herceptin approved by FDA  Fully integrated high performance team delivers a mAb in <10 years
    • •  All key expertise critical for product development available in country •  Government support for infrastructure and high risk investment •  Early development focus Clinical Commercial Regulatory hospitals Manufacturing Consultant? or CMOs Clinical Institutes Or CROs Discovery Novel drug or Marketing (internal & external) Consultant? Biosimilars Early Development CMC Preclinical Institutes Institutes Legal/IP or CMOs or CROs Consultants   Integrate in-country project team with core elements   Fill gaps in various support areas by appropriate consultants   Form oversight committee to support Project Team
    •   Selection of cell lines – product specific & IP sensitive   Many matured cell line platforms to choose from (e.g. mAbs: CHO, NSO, per.C6)   Cell line selection and construction in early basic research stage without considering manufacturing may result in challenges/ delays in commercialization   Select cell line critically with END in mind: titer, stability, product glycosylation & manufacturability   change of cell line post phase I clinical trials undesirable   process changes post phase II to be minimized Process is Product  Cell line dictates process
    • Selective to infection; reduces risk to adventitious agents   Swine cell lines: EB66 duck embryonic stem cell line by Vavilis shows promises A-Bio notes: process information is gathered from EPAR sources and published literature; CELVAPAN information is from Baxter
    • •  Product design & selection in early basic research stage without considering manufacturing may result in challenges/delays in commercialization •  Characterization of desired product driven by clinical needs impacts significantly downstream •  Product characterization requires advanced analytics •  Product complexity presents challenges in consistent supply to patients (eg. blood factors, live virus vaccines)   Multiple cell hosts developed at early stage for strategic decision including manufacturability Process is Product  Product quality challenges process (eg. glycosylation pattern)
    •   Glycan homogenity •  Large statistical population of variants •  Difficult to achieve due to macro and microhetergenity •  Achievable via process design and manufacturing consistency   Immunogenicity - injection site reactions/threat of anaphylaxis   Change in efficacy – ADCC response (Rituxin, tumor killing)   Product incomparability after scale up (Lumizyme, Genzyme) •  Myozyme (160L) = Lumizyme (2,000L) •  New BLA requested submission over carbohydrate structure changes   CMC comparability issues (Erbitux, Imclone) •  pre-clinical PK issues: sBLA for non-small lung cancer withdrawn •  Additional PK requested by FDA for Erbitux 1st line head & neck cancer Biopharm Bulletin. March 13, 2009
    • Traditional Approach (fixed controls) Failures; variation detected late Variability in raw materials, High variability in conditions product; Possible recalls; Product safety concerns Dynamic Control Strategy (multidimensional) Rapid correction of Characterized Space process parameters Design Space Variability in PAT Product Adaptive raw materials, Adaptive Control Space consistency; conditions Control Space Lower failures Acceptable Operating Space
    •   Genentech has built a deep knowledge base for Quality by Design (QbD) approaches: • 5 licensed & 26 mAbs in active development • 6 licensed sites for mAb DS production & 9 successful DS site transfers • 7 successful major version changes • 13 major Drug Substance Comparability Protocols approved   40 planned comparability efforts through 2010 based on QbD   Expanded Comparability Protocols: to bundle ‘like’ changes within a single submission   Successful transfer to Singapore: Lucentis DS plant (microbial 1,000L) late 2006-2010 FDA license   Avastin DS plant (Cell culture, 80,000L) Early 2007 -2010 FDA license (~37 mths) “The Progress of Biotechnology manufacturing and Process Sciences” Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.
    • High Cell Process Facility Productivity Simplification Efficiencies Current mAb platform Using disposable systems improvement: Higher reduces SIP and CIP capacity resins, One column requirements TREND: process, No Protein A Higher cell productivity and Reduction of Process Chromatography Alternatives process optimization result Equipment Size Crystallization, Ppt, Q filters in smaller and less complex manufacturing facilities Chemical Process like - Process and facility (20,000L vs. 2,000L) Continuous Processing modularization reduces construction time Automated sampling and monitoring with new sensors Moving of process equipment into gray space Equipment with Integrated reduces cleanroom space. instrumentation for real time control and release “The Progress of Biotechnology manufacturing and Process Sciences” Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.
    • Upstream Process Downstream Process  Disposable Technology: Eliminates CIP, SIP, utilities  Controlled Environment Modules: Gowning , operator mobility , protects product & people  Advantages: 60%++ reduction in capital investment, 40% less space needed, 85% reduction in water and waste, 32% reduction in COGS  Faster deployment: 12-18 months vs. 4+ years
    •   For biologics, Process is the Product – effective process development for manufacturing critical for product quality and consistency, hence commercialization.   Monoclonal anitbodies and vaccines present significant opportunities among future biologics being developed – advanced manufacturing platform available to improve productivity and reduce COGS.   Emerging market will enjoy significant growth in biopharmaceuticals driven by global changes   Drug development process paradigm shift towards earlier tech transfer around phase I for biologics – integrated cross functional CMC team, formed early to guide process development with END manufacturing ability in mind essential for successful commercialization.