바이오GMP중간범위_compressed PDF

바이오플랜트 GMP운영 2023.08.30 CURRENT 싸토리우스코리아바이오텍(유) 대표이사 싸토리우스코리아(유) 대표이사 싸토리우스코리아오퍼레이션스(유) 대표이사 건국대학교 공과대학 생물공학과 겸임교수 이화여자대학교 약학대학 겸임교수 (사)국제백신연구소 한국후원회 상임이사 김덕상 Kim Deok-sang (사)첨단재생...

바이오플랜트 GMP운영 2023.08.30 CURRENT 싸토리우스코리아바이오텍(유) 대표이사 싸토리우스코리아(유) 대표이사 싸토리우스코리아오퍼레이션스(유) 대표이사 건국대학교 공과대학 생물공학과 겸임교수 이화여자대학교 약학대학 겸임교수 (사)국제백신연구소 한국후원회 상임이사 김덕상 Kim Deok-sang (사)첨단재생의료산업협회 부회장 국제제약공학협회 (ISPE) 한국대표 한국생물공학회 부회장 한독상공회의소 이사 010.6485.2000 [email protected] EDUCATION 서울대학교 경영전문대학원 경영전문석사 Executive MBA 고려대학교 대학원 (생명공학) 석,박사 건국대학교 미생물공학 학사 강의 소개 Course Overview 본 과목은 의약품, 특히 바이오시밀러와 같은 바이오의약품의 연구개발, 허가 등록, 생산 및 이와 연관된 Regulatory Affairs의 전반을 이해 하는데 목적을 두고 있다. 현업에 종사하고 있는 관련 분야의 전문가를 초빙하여 현장의 살아 있는 내용을 바탕으로 이론과 실재를 습득할 수 있도록 옴니버 스 형식의 강의로 진행 된다. Course Objectives 바이오의약품의 연구 개발 인허가 과정 공정개발 과 Scale-Up 단위 공정의 이해 바이오플랜트 설계 및 시공에 대한 overview Contact 배정민 조교 010-2756-8449 [email protected] 강의 소개 Evaluation System ▪ 상대 평가 중간고사(35%), 기말고사 (35%), 과제물 (15%), 출석 (15%) Required Material 차수 별 강의 자료 • BIOSIMILAR - 강원도 교육청 - • Current Good Manufacturing Practice (CGMP) for Drugs & Biological Products and Related Regulations - Chung Keel Lee – • Additional Reading Material Course Schedule 구분 날짜 내용 강사 1주차 8/30 강의 Introduction - Bioindustry Overview & Project OT 김덕상/박종호 2주차 9/6 Upstream Process 하태수 3주차 9/13 Downstream Process 1 (Chromatography) 윤진욱 4주차 9/20 Downstream Process 2 (여과 및 기타공정) 김영태 5주차 9/27 완제공정 김정수 6주차 10/4 GMP 공정실무의 이해 및 GMP Utility 김영태 7주차 10/11 Validation 및 QA 이도연 8주차 10/18 중간고사 Course Schedule 구분 날짜 내용 강사 10/25 Quality Control 개론 정창건 10주차 11/1 바이오의약품 생산개발 최신 경향, Tech Transfer, MSAT 전재홍, 심원일 11주차 11/8 ICH Guidelines Q Part의 이해 김의연 12주차 11/15 GMP Engineering 오형균 13주차 11/22 바이오 공정 설계 김영태 14주차 11/29 GMP Inspection 박종천, 홍석동 15주차 12/6 Project 발표 김영태 16주차 12/13 기말고사 9주차 Source: www.chocchildrens.org medical research medicine exercise aged regenerative medicine molecular repair stem cells gene therapy aging wellness life lifespan concept youth pharmaceuticals tissue engineering wellbeing health nutrition Anti-aging Organ replacement elderly long genetics longevity extension lifestyle diet telomerase healthspan rejuvenation calorie restriction exosome 한국의 바이오산업 ▪ Korea won the 1st ranking of innovation Bloomberg Innovation Index (2021) 2021 Rank 2020 Rank YoY Change Economy Total Score 1 2 +1 S. Korea 90.49 2 3 +1 Singapore 87.76 3 4 +1 Switzerland 87.60 4 1 -3 Germany 86.45 5 5 0 Swedem 86.39 6 8 +2 Denmark 86.12 7 6 -1 Israel 85.50 8 7 -1 Finland 84.86 9 13 +4 Netherlands 84.29 10 11 +1 Austria 83.93 11 9 -2 U.S. 83.59 12 12 0 Japan 82.86 바이오 의약품 산업 1,200조 원 글로벌 100대 의약품 매출액 비중 세계 제약산업 규모 21.7조원 (1.8%) 한국 2026년(F) 45% 55% 2019년 47% 53% 2012년 61% 39% 합성 바이오 Source : Evaluate Pharma Word Preview 2020, Outlook to 2026, Evaluate Pharma, 2020.7.16 바이오 의약품 산업 규모 Source : howmuch.net, 17 July 2018 R&D Spending (PPP) Global Share Rank All Other Countries $249.8 B 13.9% 1 South Korea 4.3% 1 United States $476.5 B 26.4% 2 Israel 4.2% 2 China $370.6 B 20.6% 3 Japan 3.4% 3 Japan $170.5 B 9.5% 4 Switzerland 3.2% 4 Germany $109.8 B 6.1% 5 Finland 3.2% 5 South Korea $73.2 B 4.1% 6 Austria 3.1% 6 France $60.8 B 3.4% 7 Sweden 3.1% 7 India $48.1 B 2.7% 8 United Kingdom $44.2 B 2.5% 8 Denmark 2.9% 9 Brazil $42.1 B 2.3% 9 Germany 2.9% 10 Russia $39.8 B 2.2% 10 United States 2.7% Rank Country Country As a % of GDP Current Status of K-Pharma 11th (2022) About 19th (2021) Exports 5th (2022) 13th (2021) Market Size 25.4 trillion won $9.4 billion Source: Statista.com, Korea Biomedical Review, Ministry of Health and Welfare, Oec.world.com, Informa.com 2023 Development of new drugs Clinical Trials Seoul 3rd FDA approvals Among cities in the world 4대 시중은행과 3대 통신사 시가총액 국내 벤처캐피털(VC) 바이오· 의료분야 투자 1조 6770억원 2023년 8월 29일 기준 삼성바이오로직스 53조 6700억원 셀트리온 21조 4600억원 4대 시중은행 59조 8258억원 KB금융신한지주하나금융우리금융 3대 통신사 SK텔레콤KTLG유플러스 26조 8833억원 1조 1058억원 8000억원 3,788억원 2017 2018 2019 2020 2021 2022 한국벤처캐피탈협회 2023.02. Number of newly established Bio ventures in Korea 바이오 중소/벤처기업의 전국 분포도 500 1992년 ~ 2018년 400 경기 국내 바이오 중소/벤처기업 수 : 2,519곳 서울 인천 47개 300 507개 360개 충남 경북 96개 92개 200 대구 광주 32개 전남 80개 100 강원 143개 47개 부산 51개 제주 0 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 Source: Korean Venture Capital Association 80개 Source: 2018년 국내 바이오 중소· 벤처기업 현황 통계, 국가생명공학연구정책센터 Regen Medicine Market Trend in Korea Cell Therapy Market Korea Stem Cell Market Korea 단위: 억 원 단위: 조 원 9.6 ▪ Established National Center for Stem Cell and Regenerative Medicine (2016) CAGR 25 % 780 7.6 CAGR 26.67 % 468 4.7 338 3.7 1.2 1.5 16' 17' 2.3 # of Clinical Trials for Stem Cell treatment 618 6.0 1.8 ▪ Enacted Advanced Regenerative Medicine Act to accelerate the development of new and innovative treatment Others, 19% 361 Spain, 5% India, 5% China, 10% 18' 19' USA, 46% 2.9 20' 21' 22' 23' 24' Source: Global Stem Cell market Forecast 2017-2025 published by InkWood 25' 2015 2016 2017 2018 Source: 식품의약품안전처, 2020 2019 Korea, 15% #1 in Asia #2 in Global Source: Korea Ministry of Food and Drug Safety Licensing out in 2020 UK JAPAN USA Licensing-out : 13 cases (10.1 조 원) To : UK, USA, France, China, Japan From : Yuhan, Hanmi, Alteogen, Legochem etc. CHINA Facility Expansion Samsung – USA (CDO R&D) Celltrion – China (Manufacturing Plant) CMO Capacity Worldwide Chemical Expected Market Size 2014 2020 Bio 18.3 58.6 77조 원 27.8 75.1 103조 원 Source: Evaluate Pharma 단위: K ℓ 1,620 620 600 360 190 Samsung Biologics Celltrion 303 Lonza 275 Boehringer Ingelheim CMO Capacity in Korea Major CMO customers in Korea 단위: K ℓ 2,622 880 Current 1,295 2025 2030 세계 최대 바이오클러스터로 떠오른 인천 송도 아시아경제 2023-02-08 중앙경제 2023-08-16 매일경제 2022-11-25 한국경제 2023-01-13 파이낸셜뉴스 2023-03-22 매일경제 2023-06-28 파이낸셜뉴스 2023-08-18 파이낸셜뉴스 2023-06-14 매일경제 2023-01-12 TRENDS Personalized Medicine & Precision Medicine Cell Therapy With 180 Drugs in Development, T-cell Immuno-therapies may emerge as next Blockbusters CAR-T Therapy CAR-T Therapy Stem Cell Therapy Gene Therapy Tissue Engineering 'Mouse With Ear' Scientist's Research Vindicated Source: www.shanghai.gov.cn Tissue engineering is a set of methods that can replace or repair damaged or diseased tissues with natural, synthetic, or semisynthetic tissue mimics. These mimics can either be fully functional or will grow into the required functionality. 바이오닉스 : Bio+Nano+Electronics 바이오 프린팅 기술과 접목 The Second Decade of Synthetic Biology 2010-2020 Source: www.nature.com Digital HealthcareFuture trends Bio-pharmaceutical Products Biologics Medicines containing substances derived or derived from living organisms. examples: Blood Products, Toxins or Anti-toxin, Vaccine What are Bio-pharmaceuticals? Biopharmaceuticals Chemical drugs Active Agent Small molecules Manufacturing Chemical synthesis Administration Mainly oral Advantages • First-time or improved treatment of serious illnesses, such as cancer, multiple sclerosis, rheumatism • Targets only diseased cells; fewer side effects • New vaccines Large molecules > 20,000 atoms Cell culture processes with living cells Mainly intravenous Complexity challenges Similarity OH HO HO HO N H CH3 Example: Secondary Metabolite Acarbose 645 D O OH HO HO O O HO Valienamin OH HO 4,6-Didesoxyglucose O O HO OH HO Maltose Example: Monoclonal Antibody IgG approx. 150 kD Antigenbinding site Fab unit Fab unit Antigenbinding site Fc unit Carbohydrate chain Characteristics of Proteins • High molecular weight • Complex three-dimensional structure • Various functional groups (e.g. -OH, -NH2, -S-S) • Soluble only in aquous systems in high dilution • Denaturation leads to loss of activity • Sensitive to chemical, proteolytic, thermal degradation and to shear forces • Microheterogeneities lead to complex mixtures of closely related compounds • Analytical characterization difficult • A fully validated process with strict control of all critical parameters and detailed documentation of all steps is vital for biological products • The basic philosophy of cGMP-production is identical for chemical and biological drugs Biopharmaceuticals vs Chemical Drugs Biopharmaceuticals Chemical Drugs High molecular weight Low molecular weight Made with/from live cells/organisms - Inherent & contamination risk Organic or chemical synthesis Many critical process steps Fewer critical process steps Less easily characterized Well-characterized Structure may or may not be completely defined or known Known structure Heterogeneous mixture - May include variants Homogeneous drug substance Immunogenic Not immunogenic Top 200 Pharmaceuticals by Retail Sales in 2021 Compiled and Produced by the Njarðarson Group (The University of Arizona) 2019 Best Selling Drugs Source: www.pharmacompass.com Protein Based Therapeutics Modalities Muromonab-CD3 for transplant rejection treatment (1986) Recombinant Peptides Lixisenatide for diabetes type II Bi- / MultiSpecifics Removab® for malignant ascites Recombinant Proteins (incl. fusion proteins) Enbrel (Amgen) for rheumatoid arthritis (1998) Antibody Drug Conjugate Kadcyla® (Genentec/Roche), Herceptin for breast cancer Recombinant Enzymes Kanuma for lysosomal acid lipase (LAL) deficiency (2015) Protein-Based Vaccines (incl. recombinant & subunit) Cholera, diptheria, Novavax COVID-19 Plasma-Derived Proteins (FVIII, FIX, Globulins) Naked mAbs Modalities mAb Process Development CLD/Cell Banking Clone Screening Process Development Clarification Capture/Polish Viral Clearance UF/DF Sterile filtration Clarification Capture (Protein A) Virus Inactivation UF/DF UF/DF Sterile filtration Conjugation Reaction(s) Impurity Removal | DAR Refinement ADC Bulk Formulation Sterile filtration Alkaline Cell Lysis Clarification UF/DF Capture & polishing UF/DF Sterile filtration In vitro transcription (IVT) UF/DF Capture & polishing UF/DF LNP * Formulation Sterile filtration Viral vector Cell lysis Clarification UF/DF Capture & polishing Sterile filtration mAb Cell expansion (CHO) Polishing 1/2 Viral Clearance ADC mAb Preparation Plasmid DNA Fermentation (E-coli) mRNA / LNP IVT Process Development AAV Cell expansion (HEK 293) Page / 52 Patent Expiration of Blockbusters Patent expiration time-line for blockbusters leads biosimilar development trend 2012 2014 2016 2018 2020 2022 2024 2026 2028 바이오시밀러란? Biosimilar A biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and has no clinically meaningful differences in terms of safety, purity and potency (safety and effectiveness) from the reference product. Unlike small-molecule generic drugs, these large, complex protein molecules cannot be absolutely identical to the original Biosimilars are similar to the reference....but not identical to the reference Biopharmaceutical Products Biosimilar / Biobettter • Biosimilar Drugs that have proven to be comparable in quality and nonclinical and clinical equivalence to items already approved for manufacturing or selling. • Biobetter Drug products that have improved safety, efficacy, or usefulness compared to already licensed biopharmaceuticals, or that have improved drug technology. Making Monoclonals 1974: Small Volumes, Low Concentrations César Milstein © The Nobel Foundation 1984 From murine to human: Evolution of monoclonal Antibodies Steven Chamow BioProcess Consultant A 1000 fold productivity increase in Fermentation of MAb Data adapted from: F. Wurm Production of recombinant Protein Therapeutics in Cultivated Mammalian Cells. Nature Biotechnology 22, 1-6 (2004) Drug Development Process IND Submission Drug Discovery Research NDA Submission IND Approval NDA Approval Clinical Studies Pre-Clinical Studies 100 ~ 300 patient volunteers Phase 1 Candidate Development * Pharmacokinetics * Dose-ranging Pharmacology 20 ~ 100 healthy volunteers Toxicity (Short-Term) Marketing 1000 ~ 3000 patient volunteers Phase 2 * Efficacy, Safety Phase 3 * Efficacy, Safety Candidate Selection Commercial Drug Toxicity (Long-Term) IDEA Post-Marketing Safety Monitoring Quality Specification Establishment FDA Review Quality Toxicity FDA Review Efficacy Regulated Un-Regulated mAb Lifecycle from Drug Discovery to Manufacturing Bio 의약품 연구개발 과정 Drug Discovery Preclinical Development • Novel Mab Discovery • Discovery Biology & Drug Screening • Cell Line Engineering & Construction • In-Life & Toxicology Study • Bioanalytical Services Clinical Development • Assay, Formulation & Process Development • Identification of Process-Related Impurities • Raw Materials Testing & Supply Chain Assessment • Product Analytical Characterization • GMP Cell Banking & Storage and Cell line Characterization • Viral Clearance Validation • rProtein/ Mab & Cellular Therapeutics Manufacture (GMP/non-GMP) • • Lot Release Testing • Stability Studies Formulation, Fill & Finish • Clinical and Regulatory Services Commercialization Early Phase Drug Discovery Preclinical Development • Novel Mab Discovery • Discovery Biology & Drug Screening • Cell Line Engineering & Construction • In-Life & Toxicology Study Clinical Development Commercialization Early phase • Understanding the molecule • Creating a basic manufacturing process • Small number of batches for animal studies Intensive Phase Drug Discovery Preclinical Development • Novel Mab Discovery • Discovery Biology & Drug Screening • Cell Line Engineering & Construction • In-Life & Toxicology Study • Bioanalytical Services Clinical Development • Assay, Formulation & Process Development • Identification of Process-Related Impurities • Raw Materials Testing & Supply Chain Assessment • Product Analytical Characterization • GMP Cell Banking & Storage and Cell line Characterization • Viral Clearance Validation Commercialization Intensive phase • many processes being developed • DS and DP characterization • GMP in place Production processes for biopharmaceuticals are highly complex Biologics Development & Manufacturing Monoclonal Antibody Manufacturing Process Cell Clarification Media Preparation Diafiltration / Buffer Exchange / Final concentration Disposable Virus Filter Fermentation Polishing Step Clarification Concentration Volume reduction Appropriate Scale Up is challenging The Renaissance of Protein Purification Michelangelo de Lodovico Buonarotti Source: 2005 David Gaya, Wikimedia Commons Up- and Downstream Processing is Following Different Rules Biosynthesis Fermentation Cell Culture Transgenics Tissue Harvesting TCF Cell lysate Milk “Green Juice“ Tissue Extract Biology driven Capturing Purification/ Polishing Form./ Filling Clarification/ Isolation Concentration Selectivity/ HCP, DNA, EE/ Virus safety Delivery Engineering driven Downstream Processing of BioPharmaceuticals Microorganisms Pyrogens Protein Raw Material (rDNA) Cell Host cell culture proteins medium CIP Downstream Process Bulk Ligand Leakage Cells Nucleic acids Viruses Pure Bulk Product (Therapeutic) Nucleic Leakage Viruses Pyrogens acids DSP: From High Dilution to High Purity Polishing high Purity Intermediate Purification Capturing low Step Monoclonal Antibody Production Process Major Process derived Contaminants in MAb Production - Virus safety concept FDA PTC 1997 Monoclonal Antibody Manufacturing Plant Monoclonal Antibody Manufacturing Plant Monoclonal Antibody Manufacturing Plant Monoclonal Antibody Plant (Multi Use) Page 1 Monoclonal Antibody Plant (Multi Use) Monoclonal Antibody Plant (Single Use) Engineering Workflow based on Platforms Info from Customer Pre-Concept Definition of URS Process Block Diagram Concept Design Preparation of URS Generic PFD Basic Design Finalization of URS Process Simulation P&ID draft Detail Design and Construction 2D-CAD, P&ID, Dimensioning, ... Seed Bioreactor Production Bioreactor Detailed PFD Generic Equipment List Depth Filtration Process Schedule 3D-CAD Detailed Equipment List and Description, Qualification Model Protein A Pool Bag ... PFD Generic Layout - Mass Balance - Yield - Parameter - ... Free of Charge Quotation 1 +/- 25% Quotation 2 +/- 10% Quotation 3 +/- 0% Main Parameters in Drug Development Innovation … to Clinic Regulatory Compliance Quality Time … to Proof of Concept … to Partnering Risk “Fail fast, fail cheap” … to Market “The name of the game is speed” Money Return on Investment Risk in Drug Development Safety & Efficacy Product Market Share Reimbursement Patents Demand Production Market Feasibility Economy Quality Risk Personnel Structures Procedures Organizational Regulat. Compl. Financial IND/IMPD BLA Risk in Biologicals Development Demand Product Feasibility Production Market Economy Quality Risk Organizational Regulat. Compl. Financial Diligent planning of production strategy Production Risk Small Molecules (NCE) vs. Biologicals (NBE) Production Costs (COGS) Process Development & Production Scale-up Tech-transfer Reproducibility Robustness Analytics & Product Characterization Comparability NCEs Biologicals <10% 3-30% less complex complex & & less critical critical no concern major concern The product is defined by the process Production risk is considerably higher for Biologicals Key Drivers of Biologicals Production Infrastructure & Capacity Process Performance & Scalability Product Characterization & Formulation Technical Feasibility Economic Biologicals Viability Clinical Proof & Demand Regulatory Compliance Key Drivers of Biologicals Production Technical Feasibility Economic Viability Biologicals Clinical Proof & Demand Consistent Product Quality Regulatory Compliance Process Validation Documentation Key Drivers of Biologicals Production Technical Feasibility Economic Biologicals Viability Market Size & Share Number of Indications and/or Studies Clinical Proof & Demand Regulatory Compliance Activity & Dosing: Amounts, Cycles, Duration Number of Patients Key Drivers of Biologicals Production Technical Feasibility COGS Timelines Economic Biologicals Viability Investments Clinical Proof & Demand Regulatory Compliance What is the market demand, really… 6 ton-scale products Most products at 10s to 100s kg scale Planning Production Enabling preclinical and clinical material supply: ▪ ▪ ▪ ▪ Which productivities and yields are required? Which production scale is needed? Time for process development, pilot runs and GMP production? Availability of resources for development & production: In-house or external? ➔ How much material is required? Demand per Patient Treatment for IgGs on the Market Per Dose • Raptiva • Humira • Remicade • Avastin • Rituxan • Erbitux • Synagis • Herceptin 53/75 mg 40 mg 225 - 375 mg 375 mg 750 mg 800/500 mg 1100 mg 300/150 mg Schedule weekly… x 12 bi-weekly… bi-monthly x 6 bi-weekly… x 8 weekly x4 weekly… x 8 monthly x5 weekly… Per patient treatment 1 g 1 g p.a. 1.2 - 2.3 g 3 g 3 g 4.3 g 5.5 g 7.8 g p.a. ➔ Primarily triggered by indication and/or mechanism of action Extrapolation of Clinical Demand IgG : Focus on Phase I/II Supply Low dosing and treatment demand per patient 0.5 g/pat. 500 0 CTM demand [g] 1000 High dosing and treatment demand per patient 5 g/pat. 1000g 500g 250g 10g 25g 50g 100g 100g 20 pat. 50 pat. 100 pat. 200 pat. 20 pat. 50 pat. Phase I Phase II Phase I Phase I: Phase II: 20* - 250 g 50 - 1000 g 100 pat. 200 pat. Phase II ~ 10x variability ~ 20x variability *= incl. retains etc. Extrapolation of Clinical Demand IgG : for Phase III & Market Supply Low dosing and treatment demand per patient 0.5 g/pat. 25kg 300 High dosing and treatment demand per patient 5 g/pat. 250kg 200 20 100 10 50kg 5kg 0.25kg 1kg 3kg 10kg 0 0 500 2000 pat. Phase III Phase III: Market: 10000 50000 pat. Market 500 2000 pat. Phase III 0.25 - 10 kg 5 - 250 kg 10000 50000 pat. Market ~ 40x variability ~ 50x variability CTM demand [kg] CTM demand [kg] 30 Material Demand vs. Bioreactor Scale Required volumes at given productivities Harvest Titer [g/L]: Demand Preclin. Phase I Phase II Phase III [g]: [g]: [g]: [g]: [g]: [g]: [g]: [g]: 5 50 20 250 50 1000 250 10000 0.25 0.5 1 Volumes required [L] [L] [L] 40 20 10 400 200 100 160 80 40 2000 1000 500 400 200 100 8000 4000 2000 2000 1000 500 80000 40000 20000 (DSP Yield at 50%) Material Demand Phase I & II Required runs at given scale and productivities Demand Preclin. Phase I Phase I Phase II Phase II [g] Bioreactor Volumes [L] 50 250 250 1000 1000 100 100 250 250 1000 Harvest Titer [g/L] 0.25 0.5 1 Number of Runs 4 2 1 20 10 5 8 4 2 32 16 8 8 4 2 (DSP Yield at 50%) Material Demand Phase III & Market Required runs at given scale and productivities Demand Phase III Market [kg] Bioreactor Volumes [L] 10 250 10000 10000 Harvest Titer [g/L] 0.25 0.5 1 8 200 4 100 2 50 (DSP Yield at 50%) Benchmarking Process Performance Typical performance figures & factors of optimization (IgG) Fermentation [g/L] 0.25 0.5 1 5 2 ~ 20-fold Recovery [%] 40 60 80 80 1.5 ~ 2-fold Net yield [g/L] 0.1 0.3 0.8 4 3 ~ 40-fold Manufacturing Trends Continuous Bioprocessing Hybrid System (Current) • A continuous unit operation with zero or minimal internal hold volume. ✓ Consistent Product Quality ✓ Low Process Cycle Times ✓ High Equipment Utilization • Key Components ✓ Single-Use System ✓ Perfusion System ✓ Continuous Multi-column Chromatography Fully Continuous Process (Future) Manufacturing Trends Singe-Use Systems • Bioprocess system composed of disposable fluid path components to replace reusable stainless steel components. ✓ Reduced Cleaning Requirements ✓ Reduced Risk of Cross-contamination ✓ Improved Process Efficiency Single-Use System Conventional Stainless Steel System Manufacturing Trends Singe-Use Systems ✓ Various Single-Use Technologies Filtrations Bioreactors Mixing System Containers Sampling System Tubing System Single-Use Technologies reduce Production Costs by up to 40% 70-80% CAPEX reduction Faster production Higher flexibility 30-40% 10-20% Market Penetration of Single-use1) No crosscontamination Reduced water consumption Reduced energy consumption Past Present Future Overcoming the Valley of Death ?? Stupid! It’s Time to Market! Other Business Trends Outsourcing Services Outsourcing activities as a strategy to stay competitive and flexible in a world of exponentially growing knowledge, increasingly sophisticated technologies and an unstable economic environment Source: American Pharmaceutical Review Other Business Trends CMO Organization providing services in the pharmaceutical industry from drug development through drug manufacturing CDMO (Contract Development and Manufacturing Organization) Organization providing comprehensive services from drug development through drug manufacturing 2.4조 원 2조 원 1.9조 원 Source: Frost&Sullivan Changes to Strategy Management Strategies Open Innovation • Licensing • M&A • Joint Venture Strategies Open Innovation • Business Concept • Acquiring outside sources or releasing inside sources to improve product lines and shorten the time to market Scientometrics (2020) 125:1801–1832 한국바이오협회 www.koreabio.org 한국바이오의약품협회 www.kobia.kr 한국제약바이오협회 www.kpbma.or.kr 바이오스펙테이터 biospectator.com ISPE www.ispe.org ISPE – Baseline Guides ISPE - Publications ISPE Korea Affiliate https://www.ispe.or.kr/ispe.html PDA(Parental Drug Association) www.pda.org 한국제약교육기술원(KPTEC) www.kptec.or.kr Sure GMP www.suregmp.com Pharmaceutical Technology www.pharmaceutical-technology.com Drug Development Technology https://www.clinicaltrialsarena.com/ RAPS www.raps.org 125 국내 바이오헬스케어산업 동향 2023년 대한민국의 현재와 미래산업의 중심 박종호 2023. 08. 30. 국내 바이오테크기업의 위치(2021년평가) Page / 2 국내 바이오테크기업의 위치(2021년평가) Page / 3 국내 바이오테크기업의 위치(2023년평가) Page / 4 국내 바이오테크기업의 위치(2023년평가) http://www.samsungactive.co.kr/main.do https://blog.naver.com/1_stepmore/223173464200 Page / 5 바이오헬스케어산업의 분류 바이오헬스케어산업의 분류 ▪ Red / White / Green Biotechnology ▪ Product based / Platform based company ▪ First in Class / Best in Class / Me too Drug ▪ 기술의 진보에 따른 구분(Red 바이오 중심) 신약개발 의 영역 (Value creation / Cost reduction) ▪ small molecule drug ▪ Protein / antibody drug ▪ (stem)cell therapy ▪ gene therapy / RNAi therapy Page / 6 바이오헬스케어분야 기초 key word ▪ 세포 (원핵 / 진핵) ▪ 유전정보 (DNA / RNA ; 핵산) ▪ 단백질 (기능, 구조, 신호전달), 펩타이드(Aa 30개미만) ▪ Target vs Marker ▪ Proliferation(분열) vs Differentiation(분화) ▪ CRO / CMO OTC / ETC(일반의약품/전문의약품) ▪ 크기 : chemical molecule < Peptide < Protein < Antibody < Cell < Tissue < Organ Page / 7 일반적인 신약개발의 단계 일반적인 신약개발 단계(신약개발 회사의 주요업무) ▪ Discovery 후보물질탐색 및 발굴 ▪ Development 비임상 임상1상 임상약리 임상2상 치료적탐색 임상3상 치료적확증 ▪ 상용화 규격화, 생산 및 시판후 임상 Page / 8 신약개발과정 자료: PhRMA, 하나금융투자 Page / 9 신약개발 단계별 성공확률 자료: Nature Biotechnology, 하나금융투자 Page / 10 신약개발단계별 수행주체 자료: 하나금융투자 Page / 11 바이오의약품 vs 화학합성의약품 자료: 언론 및 학술 자료, 한화투자증권 리서치센터 바이오의약품이란? 유전자재조합, 세포배양, 세포융합 등 생물공학 기술을 이용해 생산되는 의약품을 말하며 기존 화학합성의약품에 비해 더 복잡한 생물공정을 거치며 살아있는 유기물을 바탕으로 하기에 고가이나 질환 별 표적치료제 개발이 가능하고 희귀성이나 난치성 치료제개발이 가능하여 고성장중임 Page / 12 바이오의약품의 분류(I) 바이오의약품 및 제약산업의 범위 자료: 한화투자증권 리서치센터 Page / 13 바이오의약품의 분류(II) 바이오의약품의 분류 자료: 한화투자증권 리서치센터 Page / 14 세부신약개발 분야별 현황 형태 합성 의약 단백질 의약 항체 의약 세포 치료제 例 아스피린, 비아그라, 리피토, 성장 단계 완숙 글리벡, 타미플루, 택솔 등 EPO, 성장호르몬, 인슐린, GCSF 허셉틴, 아바스틴, 레미케이드, 낮은 임상개발 성공률 → 고비용 다국적 제약사들이 철수 중 완숙 대형 개발 타겟 고갈 높은 타겟 선택성 → 안전성 Good 중간 리툭산, 휴미라, 엔브렐 카티스템 비고 현재의 고성장 분야 질병 타겟 고갈 → 성장성 한계 초기성장 광대한 재활 의약 수요 미래의 고성장 분야 RNA 표적/ 유전자 치료제 Page / 15 무궁무진한 신규 질병 타겟 Mipomersen (고지혈증) 초기성장 높은 타겟 선택성 → 안전성 Good 미래의 고성장 분야 국내 주요바이오의약품 분야의 분류 상위제약사 유한양행, 한미약품, 종근당, 녹십자, 동아에스티 바이오시밀러/CMO 셀트리온그룹, 삼성바이오로직스, 에이프로젠제약, 이수앱지스, 폴루스 보톨리눔 톡신 생산기업 메디톡스, 휴젤, 대웅제약, 휴메딕스, 제테마 단백질신약 개발기업 제넥신, 에이비엘바이오, 인트론바이오, 알테오젠, 앱클론, 펩트론, 유바이오로직스 유전자치료제(핵산치료제) 신라젠, 헬릭스미스, 올릭스, 올리패스 세포치료제 메디포스트, 차바이오텍, 안트로젠, 녹십자셀 합성신약 에이치엘비, 메지온, 레고켐바이오, 오스코텍 면역항암제(T세포억제저해 제, 활성제, 증폭제) 박셀바이오, 제넥신, 네오이뮨텍, 메드팩토 Page / 16 국내기업동향 참고 사이트 금융감독원 전자공시 시스템 dart.fss.or.kr 기업정보 한국거래소 기업공시 kind.krx.co.kr(IR자료실) 기업IR정보 한국예탁결제원 증권정보 포털 www.seibro.or.kr 주식발행 및 유통정보 paxnet.moneta.co.kr 팍스넷 www.38.co.kr 38커뮤니케이션 기타 참고 사이트 Page / 17 (기술)창업의 성공요건 ▪ 창업의 3대 구성요건 : 인력, 기술, 자본 ▪ 회사가 성장함에 따라 인력/기술/자본의 비중은 변한다. ▪ 지적재산권에 대한 이해와 권리확보 방안 ▪ 초기자본구성 및 핵심기간인력 확보의 중요성 ▪ 인력구성원간 비전공유의 중요성 ← 주주간 계약서(동업계약서) 반드시 필요 Page / 18 자본조달에 대한 예시(벤처자본증가사례)-1 Page / 19 자본조달에 대한 예시(벤처자본증가사례)-2 ▪ 2021.9 자본금 1억원으로 회사설립 (설립자보유지분율100%) ▪ Page / 20 2022.9 엔젤투자유치(5억원) ▪ 10배수 할증투자유치 ▪ 회사가치 15억원으로 평가 ▪ 자본잉여금 4.5억원 전액 무상증자시행 ▪ 무증후 창업자 투자단가 5,000 → 1,250 ▪ 엔젤투자자 투자단가 50,000 → 12,500 ▪ 창업자지분율 100% → 66.7%로 감소 자본조달에 대한 예시(벤처자본증가사례)-3 ▪ Page / 21 2023.9 벤처투자유치(10억원) ▪ 20배수 할증투자유치 ▪ 회사가치 130억원으로 평가 ▪ 자본잉여금 중 3.25억원 무상증자시행 ▪ 무증후 창업자 투자단가 최초5,000 → 833 ▪ 1차엔젤투자자 최초 50,000 → 8,333 ▪ 2차벤처투자자 최초 100,000 → 66,667 ▪ 창업자지분율 66.7% → 61.5%로 감소 자본조달에 대한 예시(벤처자본증가사례)-4 ▪ Page / 22 2024.9 pre-IPO투자유치(100억원) ▪ 30배수 할증투자유치 ▪ 회사가치 392.5억원으로 평가 ▪ 창업자지분율 61.5% → 45.9%로 감소 자본조달에 대한 예시(벤처자본증가사례)-5 ▪ 2025.9 코스당 상장공모증자 ▪ 40배수 할증투자유치 ▪ 회사가치 523억원으로 평가 ▪ 창업자의 지분가치 변화 ▪ 1억원 투자 → 240억원의 가치 (연수익율IRR 294%) Page / 23 바이오헬스케어기업 IPO 동향(2023/2022년) 첫날종가 21/4/16 4/16시총 (단 주가 위:억원) 업종 상장일 큐리옥스바이오시스템즈 파로스아이바이오 프로테옴텍 큐라티스 에스바이오메딕스 지아이이노베이션 바이오인프라 바이오노트(유) 인벤티지랩 디티앤씨알오 샤페론 선바이오 알피바이오 에이프릴바이오 루닛 보로노이 바이오에프이엔씨 애드바이오텍 툴젠 지니너스 차백신연구소 바이오플러스 에이비온 바이젠셀 HK이노엔 큐라클 에스디바이오센서㈜ SK바이오사이언스(유) 네오이뮨텍(Reg.S) 프레스티지바이오로직스 프레스티지바이오파마(유, DR싱가 포르) 의료용기기제조업 연구개발업 의료용품제조업 연구개발업 의약품제조업 연구개발업 연구개발업 의료용품제조업 의약품제조업 연구개발업 기초의약물질. 생물학적제제 의약품제조업 의약품제조업 연구개발업 (의료)소프트웨어개발업 연구개발업 기초의약물질. 생물학적제제 동물용약품 유전자교정플랫폼 생물정보분석 백신 및 면역증강제 히알루론산제제전문 표적항암제 면역세포치료제 전문의약품, 숙취해소음료 혈관질환치료제 진단키트 백신, 바이오의약품 신약(면역항암제, IL-7) 바이오위탁생산(CMO, CDO) 2023-08-10 2023-07-27 2023-06-16 2023-06-15 2023-05-04 2023-03-30 2023-03-02 2022-12-22 2022-11-22 2022-11-11 2022-10-19 2022-10-05 2022-09-29 2022-07-28 2022-07-21 2022-06-24 2022-02-21 2022-01-24 2021-12-10 2021-11-08 2021-10-22 2021-09-27 2021-09-08 2021-08-25 2021-08-09 2021-07-22 2021-07-16 2021-03-18 2021-03-16 2021-03-11 13,000 14,000 4,500 4,000 18,000 13,000 21,000 9,000 12,000 17,000 5,000 11,000 13,000 16,000 30,000 40,000 28,000 7,000 70,000 20,000 11,000 31,500 17,000 52,700 59,000 25,000 52,000 65,000 7,500 12,400 17,330 8,730 5,210 5,850 18,830 20,250 29,400 10,650 14,950 13,850 8,630 10,600 18,300 21,850 40,000 29,350 22,200 5,950 91,100 13,400 13,000 32,450 15,700 59,500 68,500 30,650 61,000 169,000 14,350 14,300 24,150 16,700 3,580 3,220 9,300 26,500 13,700 5,100 21,700 5,010 4,165 10,440 9,950 22,800 152,900 74,800 13,000 3,525 36,000 4,370 5,790 8,010 7,770 5,590 36,250 12,800 11,600 75,800 2,030 4,725 1,935 2,157 461 1,243 1,050 5,844 657 5,201 1,824 636 961 1,286 862 2,437 18,931 9,461 1,130 322 2,851 1,441 1,545 4,640 1,505 1,067 10,270 1,773 14,436 58,202 2,007 2,887 9,320 146,200 13,700 10,150 23,500 11,850 34,900 54,500 25,800 53,300 236,000 10,550 11,500 717 9,966 1,489 2,683 3,375 2,109 3,293 15,753 3,504 55,044 180,540 10,395 5,429 132,000 12,900 18,850 100,980 12,693 8,440 신약(항체의약품) 2021-02-05 32,000 32,800 11,300 6,791 25,100 15,084 32,300 19,411 Page / 24 공모가 23/08/18 08/18시총 21/11/18 11/18시총 주가 (단위:억원) 주가 (단위:억원) 회사명 바이오헬스케어기업 IPO 동향(2020년) 첫날종가 21/4/16 4/16시총 (단 주가 위:억원) 업종 상장일 지놈앤컴퍼니 신약(마이크로바이옴) 2020-12-23 40,000 68,800 13,700 1,932 36,150 4,879 51,600 6,939 프리시젼바이오 의료기기(체외진단) 2020-12-22 12,500 32,500 6,570 763 10,800 1,224 16,950 1,906 엔젠바이오 NGS기반 진단서비스 2020-12-10 14,000 25,650 6,410 809 13,550 1,684 19,750 2,442 퀀타매트릭스 의료기기(체외진단) 2020-12-09 25,500 24,100 5,080 840 12,100 1,800 17,550 2,596 고바이오랩 신약(마이크로바이옴) 2020-11-18 15,000 31,300 9,460 1,785 22,300 3,628 34,100 5,371 미코바이오메드 의료기기(체외진단) 2020-10-22 15,000 13,700 4,090 749 8,850 1,619 12,700 2,319 피플바이오 혈액진단(퇴행성뇌질환) 2020-10-19 20,000 23,400 8,760 1,095 16,200 1,822 43,050 2,431 박셀바이오 신약(항암면역치료제) 2020-09-22 30,000 21,300 30,200 4,597 60,000 9,134 103,100 15,695 압타머사이언스 신약(압타머기반, 폐암진단) 2020-09-16 25,000 27,750 3,685 626 17,400 1,473 23,750 2,011 셀레믹스 NGS기반 바이오서비스 2020-08-21 20,000 25,800 4,330 354 13,700 1,118 22,400 1,829 제놀루션 생물학적제제(RNAi관련사업) 2020-07-24 14,000 24,750 4,400 844 13,250 1,268 17,850 854 소마젠 유전체분석서비스 2020-07-13 11,000 15,100 5,720 1,100 8,180 1,565 13,550 2,570 SK바이오팜(유) 신약(CNS질환 뇌전증 외) 2020-07-02 49,000 127,000 86,500 67,741 99,600 78,000 111,500 87,319 젠큐릭스 의료용품(유방암예후진단 외) 2020-06-25 22,700 21,650 4,350 577 16,350 1,072 19,350 1,251 에스씨엠생명과학 신약(성체줄기세포치료) 2020-06-17 17,000 36,100 4,755 583 16,000 1,923 34,000 4,050 드림씨아이에스 임상시험수탁기관(CRO) 2020-05-22 14,900 30,500 14,000 830 10,600 600 18,700 1,046 Page / 25 공모가 23/08/18 08/18시총 21/11/18 11/18시총 주가 (단위:억원) 주가 (단위:억원) 회사명 바이오헬스케어기업 IPO 동향(2019/2018년) 회사명 업종 상장일 CJ바이오사이언스(천랩) 브릿지바이오테라퓨틱스 메드팩토 신테카바이오 티움바이오 제테마 라파스 녹십자웰빙 올리패스 압타바이오 수젠텍 지노믹트리 셀리드 이노테라피 비피도 유틸렉스 에이비엘바이오 전진바이오팜 엠아이텍 티앤알바이오팹 네오펙트 싸이토젠 디알젬 파멥신 노바렉스 셀리버리 엘앤씨바이오 옵티팜 바이오솔루션 올릭스 아이큐어 제노레이 오스테오닉 엔지켐생명과학 동구바이오제약 신약(마이크로바이옴) 신약(NRDO, 궤양성대장염치료제BBT-401 외) 신약(유전체분석,면역항암제 백토서팁 외) 유전체분석 신약개발지원 신약(합성, 바이오) 의료용품(히알루론산, 보톨리눔독소) 신약(경피전달기술기반) 의약품(수액제 등), 건기식 신약(PNA기반인공유전자기술) 신약(Apta-DC기술,유전자전달체) 체외진단용의료기기 의료용품(체외암조기진단) 항암면역치료백신개발 의료용지혈제(홍합, 생체모방) 건기식(프로바이오틱스) 면역항암치료(T세포치료제) 이중항체(항체치료,면역관문) 유해동물/해충피해감소제 의료기기(비혈관용스텐트 외) 조직공학 및 재생의학(3D바이오프린팅) 의료기기(뇌졸증재활기기 외) CTC기반 Liquid Biopsy응용사업 의료기기(진단용엑스선촬영장치 외) 항체신약 건기식 약리물질 생체내전송기술 의료기기(인체조직기반 외) 이종장기 외 세포치료제 개발 RNA간섭플랫폼기술 경피약물전달시스템기반 X-ray영상진단장비 골접합용 판 및 나사 원료의약품(항결핵제 외) 전문의약품(피부과, 비뇨기과치료제) 알리코제약 제네릭의약품 2019-12-26 2019-12-20 2019-12-19 2019-12-17 2019-11-22 2019-11-14 2019-11-11 2019-10-14 2019-09-20 2019-06-12 2019-05-28 2019-03-27 2019-02-20 2019-02-01 2018-12-26 2018-12-24 2018-12-19 2018-12-14 2018-11-29 2018-11-28 2018-11-28 2018-11-22 2018-11-22 2018-11-21 2018-11-14 2018-11-09 2018-11-01 2018-10-26 2018-08-20 2018-07-18 2018-07-12 2018-05-28 2018-02-22 2018-02-21 2018-02-13 2018-02-12 Page / 26 공모가 첫날종가 23/08/18 08/18시총 21/11/18 11/18시총 주가 (단위:억원) 주가 (단위:억원) 40,000 60,000 40,000 12,000 12,000 21,000 20,000 11,300 20,000 30,000 12,000 27,000 33,000 18,000 18,000 50,000 15,000 10,000 4,500 18,000 11,000 17,000 6,500 60,000 19,000 25,000 24,000 10,000 29,000 36,000 65,000 23,000 7,700 56,000 16,000 38,500 54,300 35,900 16,700 13,450 22,450 18,050 12,500 24,800 38,900 10,150 27,300 51,100 19,350 36,500 78,100 13,650 12,750 4,770 12,500 7,700 15,600 6,760 63,600 20,100 28,700 26,950 11,700 28,500 65,600 60,600 37,350 13,100 85,200 41,600 20,100 5,490 14,580 15,570 7,290 20,400 23,500 6,870 1,745 10,190 6,980 26,950 6,330 8,950 6,700 3,510 18,500 5,680 9,550 11,720 1,165 15,730 10,740 2,140 10,440 1,182 1,101 3,074 2,323 1,785 3,637 2,034 1,220 525 2,272 1,143 6,269 616 567 548 1,290 8,853 423 3,067 2,485 268 2,895 1,216 550 1,958 6,680 2,449 35,450 7,190 9,720 14,950 2,550 6,490 6,320 1,650 5,280 12,000 23,500 6,270 21/4/16 4/16시총 (단 주가 위:억원) 8,042 1,055 792 2,053 958 945 1,306 1,404 1,503 43,100 11,900 56,400 10,300 18,700 23,000 44,500 10,500 8,820 52,500 13,400 12,100 52,200 12,800 10,300 21,600 21,350 4,750 5,080 56,700 2,965 63,500 12,200 7,060 33,850 48,950 34,450 25,100 22,650 33,950 36,000 9,590 3,770 57,300 7,830 2,528 2,342 11,568 1,390 4,455 4,086 3,825 1,864 2,278 11,653 2,062 2,460 5,080 646 843 3,344 10,061 301 1,599 5,863 561 3,691 1,382 1,813 3,048 8,485 7,815 1,415 1,837 4,652 3,425 1,396 632 4,774 2,229 35,750 14,450 89,600 17,200 19,050 28,850 31,900 13,250 9,340 61,400 21,900 14,900 71,300 16,350 12,050 39,450 26,450 10,800 4,520 46,550 3,260 65,900 14,450 18,200 42,650 121,600 33,000 12,100 30,000 44,400 46,400 10,450 4,640 156,800 10,300 1,398 2,825 18,353 2,305 4,531 5,068 2,689 2,352 2,386 6,812 3,350 2,978 6,919 825 493 5,979 12,464 653 1,409 3,944 616 3,723 1,637 2,592 3,840 20,093 7,219 1,751 2,427 6,084 4,191 1,521 748 13,005 2,932 961 7,130 1,093 12,450 1,282 바이오헬스케어기업 IPO 동향(2017/2016년) 회사명 업종 상장일 공모가 첫날종가 23/08/18 08/18시총 21/11/18 11/18시총 21/4/16 4/16시총 19/3/14 주가 (단위:억원) 주가 (단위:억원) 주가 (단위:억원) 주가 코오롱티슈진 세포치료제 개발 2017-11-06 27,000 42,700 9,560 6,951 8,010 4,896 8,010 4,896 39,200 앱클론 항체치료제 2017-09-20 10,000 26,000 15,950 2,449 15,700 2,399 29,750 4,545 54,700 셀트리온헬스케어 항체치료제 유통 2017-07-28 41,000 50,300 68,600 112,823 84,700 131,309 132,600 201,514 73,100 아스타 미생물검사 및 진단 2017-03-20 8,000 12,600 8,850 1,149 5,210 599 4,865 559 8,300 덴티움(유) 임플란트 외 치과용기기 2017-03-15 32,000 34,500 120,100 13,294 59,700 6,608 62,700 6,940 64,300 에스디생명공학 화장품제조 2017-03-02 12,000 12,200 349 149 3,520 789 4,885 1,095 10,350 신신제약 의약품제조 2017-02-28 4,500 8,020 4,840 734 6,770 1,027 8,350 1,267 8,230 피씨엘 체외진단용의료기기 2017-02-23 8,000 9,160 6,300 754 40,050 4,113 58,400 5,886 9,380 유바이오로직스 백신개발 및 제조 2017-01-24 6,000 5,070 7,720 2,814 35,000 12,680 29,750 10,406 6,700 애니젠 펩타이드소재 제조 2016-12-07 18,000 12,600 14,190 795 13,550 759 15,350 772 15,900 신라젠 펙사벡(항암백신) 2016-12-06 15,000 12,850 4,815 4,953 12,100 8,666 12,100 8,666 68,300 퓨쳐켐 방사성의약품 2016-12-01 15,000 11,050 12,840 2,838 18,200 2,484 17,750 2,422 15,200 삼성바이오로직스(유) 바이오시밀러 2016-11-10 136,000 144,000 771,000 548,752 841,000 556,448 831,000 549,831 356,000 로고스바이오시스템스 (얼라인드) 세포계수 등 측정장비 2016-11-03 25,500 21,350 8,130 584 8,580 617 8,860 637 14,000 비엘(바이오리더스) r-PGA신약 및 식품개발 2016-07-07 15,000 14,200 2,990 940 8,000 1,173 5,200 1,425 15,300 녹십자랩셀(지씨셀) 진단 2016-06-23 18,500 48,100 37,200 5,878 104,100 16,447 112,300 11,852 49,850 팬젠 세포주 개발 2016-03-11 16,500 22,300 5,750 614 7,720 824 9,500 916 13,350 큐리언트 NRDO 신약개발 2016-02-29 21,000 39,000 7,090 880 30,300 2,692 31,250 2,764 28,800 안트로젠 줄기세포 치료제 2016-02-15 24,000 39,100 14,640 1,425 54,300 5,116 56,700 5,156 94,700 Page / 27 바이오헬스케어기업 IPO 동향(2015~13년) 회사명 업종 상장일 공모가 첫날종가 11/18시 23/08/1 08/18시총 21/11/18 21/4/16 4/16시총 19/3/14 총 (단위: 8 주가 (단위:억원) 주가 주가 (단위:억원) 주가 억원) 휴젤 보톨리눔 톡신 치료제 2015-12-24 150,000 14,739 142,000 강스템바이오텍 줄기세포 치료제 2015-12-21 6,000 168,300 119,000 9,360 1,924 730 3,330 17,729 189,800 1,263 7,070 23,697 401,700 1,807 22,150 씨트리 (HLB제약) 신약개발 2015-12-21 6,500 12,000 12,510 3,703 1,640 1,494 15,500 3,465 4,765 뉴트리바이오텍 (코스맥스엔비티) 건강기능식품제조 2015-12-16 21,000 29,000 5,060 1,044 6,170 1,273 8,830 1,821 17,550 DXVX(엠지메드;캔서롭, 마크로젠) 분자진단 2015-11-20 40,000 36,300 7,140 2,158 7,740 2,221 7,740 1,786 8,450 케어젠 펩타이드화장품 2015-11-17 110,000 107,000 203,000 아이진 안과용신약 2015-11-13 13,500 에이티젠(엔케이맥스) NK세포치료제 2015-10-23 파마리서치(프로덕트) PDRN치료제 2015-07-24 펩트론 항체치료제 코아스템켐온 제노포커스 21,808 66,900 7,187 68,900 7,402 76,500 13,100 3,635 781 18,650 3,993 30,250 3,549 16,000 17,000 25,800 13,490 5,452 20,700 7,646 18,300 6,341 14,900 55,000 114,500 22,800 927 75,600 7,645 72,100 7,291 39,500 2015-07-22 16,000 41,600 35,500 7,323 10,100 2,083 14,750 3,042 23,750 줄기세포치료제 2015-06-26 16,000 41,600 6,650 2,186 18,400 2,920 18,150 2,853 14,350 효소개발전문 2015-05-29 11,000 25,300 3,630 818 7,700 1,732 8,340 1,868 9,360 휴메딕스 히알루론산제제전문 2014-12-26 28,000 39,200 39,650 4,336 23,950 2,388 35,750 3,565 30,500 하이로닉 피부, 비만미용기기 2014-12-17 51,000 73,300 10,240 1,571 6,630 935 6,210 876 5,120 녹십자엠에스 진단 2014-12-17 6,000 10,350 4,305 909 7,380 1,558 11,900 2,513 13,950 랩지노믹스 진단 2014-12-16 13,200 14,250 5,060 1,878 23,700 2,714 22,350 2,559 7,670 비씨월드제약 제약 2014-12-15 15,700 17,550 6,550 582 15,300 1,361 17,700 1,574 22,800 알테오젠 단백질 운반체기술 2014-12-12 26,000 21,500 44,150 22,827 69,000 29,162 93,000 39,176 42,650 테고사이언스 세포치료제 개발 2014-11-06 13,500 31,050 9,640 782 21,700 1,760 26,900 2,181 42,850 메디아나 의료기기 2014-10-07 6,200 5,850 5,500 880 5,060 810 15,550 1,345 7,850 인트로메딕 의료기기 2013-12-19 6,000 5,700 5,850 2,237 6,230 2,382 2,785 890 3,510 에이씨티(협진) 화장품 소재 2013-11-08 8,100 10,200 975 337 4,480 1,551 4,480 1,551 5,460 내츄럴엔도텍 건강기능식품제조 2013-10-31 40,000 84,700 2,460 781 4,725 1,473 2,525 612 9,800 아미코젠 효소개발전문 2013-09-12 25,000 57,500 17,290 3,416 29,150 5,758 38,000 7,302 35,100 진단 2013-05-30 4,500 10,350 7,650 2,778 16,250 5,901 20,050 7,281 4,225 의약화학(ADC)신약개발 2013-05-10 15,500 17,500 35,350 9,364 50,600 12,263 59,200 14,277 57,500 엑세스바이오 레고켐바이오사이언스 코렌텍 정형외과용의료기기 2013-03-05 16,000 15,550 11,710 1,494 12,450 1,473 20,450 2,377 707 아이센스 당뇨진단 2013-01-30 19,000 25,950 29,750 8,187 30,150 4,142 29,300 4,025 25,200 Page / 28 THANK YOU UPSTREAM PROCESS 1. 1.1 Cell Culture Technology 1.2 Batch, Fed Batch, Continuous Culture 1.3 대량 생산을 위한 Scale Study의 이해 하태수 2023. 09. 06. CONTENT Lecture note Page / ▪ Biopharma Industry in Modalities ▪ Global Challenge from COVID-19 ▪ Cell Culture of Suspension Cells by Using Bioreactors ▪ Type of Cell Culture Processing ▪ Cell Metabolite Analysis ▪ In Example ▪ Data Analytics Solutions for Bioprocessing ▪ Scale Study for Large Scale Bioproduction Biopharma Industry in Modalities Page / 3 Biopharma Industry in Modalities Biopharma Industry: Modalities for Different Indications Infectious Diseases Cancer Treatment and Prevention Protein-Based Vaccines Gene-Modified Cell Therapy Virus | Viral Vector mRNA & Bioconjugate mRNA / pDNA Vaccines (Protein, Viral, mRNA / pDNA) Chronic Inflammatory(만성염증), Genetic and Other Diseased Cell Therapy Page / 4 Gene-Modified Cell Therapy Gene Therapy Recombinant Protein Biopharma Industry in Modalities Protein-Based Therapeutics (PBT) Modalities Naked mAbs Recombinant Peptides Bi- / Multi Specifics Recombinant Proteins Antibody Drug Conjugate Recombinant Enzymes Protein-Based Vaccines Plasma-Derived Proteins 2022 Global Market Size: 2600억 달러 Page / 5 2025 Global Market Size: 4600억 달러 Biopharma Industry in Modalities Viral-Based Therapeutics (VBT) Modalities Gene Therapy* Typical Vector Gene Therapy Marketed Products Adeno Associated Virus (AAV) Luxturna 2017, Roche Zolgensma 2019, Novartis Vaccine** Gene-modified Cell Therapy (making vv*) Nucleic Acid Vaccine Viral Vector Vaccines Lentivirus, Retrovirus mRNA, pDNA Adenovirus, MVA (천연두) Kymriah Zynteglo 2017, Novartis 2019, Bluebird bio mRNA Covid mRNA Covid Vaccine 2021 Vaccine 2021 BioNTech & Pfizer Moderna Gene Therapy Explained - YouTube * Other gene therapies including mRNA therapy, exosome, other RNA therapies ** Other vaccines including inactivated / attenuated virus vaccine, microbial Vaccines Page / 6 Adenovirus Covid Vaccine 2021 Astrazenca Adenovirus Covid Vaccine 2021 Cansino Biopharma Industry in Modalities Advanced Therapy Modalities Gene-Modified Cell Therapy Immune Cell PBMC, CAR-T, TCR-T, CAR-Treg, TIL, NK, CAR-NK Kymriah | Novartis FDA Approves First CAR T-Cell Therapy – The evolution of CAR-T Cell Therapy Abecma | Bluebird bio FDA Approves BCMA-Targeted CAR T-Cell Therapy for Multiple Myeloma Page / 7 Cell Therapy Stem Cell BM-MSC, UC-MSC, AT-MSC, IPSC(유도 만능 줄기 세포), HSC (조혈모 줄기 세포) Prochymal | Osiris Prochymal – First Stem Cell Drug Approved Alofisel | Takeda Alofisel (darvadstrocel) for the Treatment of Complex Perianal Fistulas in Crohn’s Disease Global Challenge from COVID-19 Page / 8 Global Challenge from COVID-19 A Global Effort to Bring a Vaccine to the Market: COVID 19 Cell banking & Characterization Page / 9 Protein, Viral Vectors & Virus Testing Media Optimization Process Development Lot Release Testing Single Use Manufacturing Global Challenge from COVID-19 Strategies for COVID-19 Vaccine Development The scientific community has made tremendous efforts to understand the disease, and unparalleled efforts are ongoing to develop vaccines and treatments. Studying antibodies generated from COVID-19 infections and vaccines can provide invaluable information towards therapeutic antibody development and engineering. Kinetics, affinity and epitope interrelationships are important factors in vaccine and therapeutic design. Page / 10 Global Challenge from COVID-19 Upstream Process in Platform WCB | Cell Type Small Scale Production Scale Page / 11 Media & Buffer Preparation Cell Culture Harvest & Purification Formulation | Fill Cryopreservation | Storage ❖ Recombinant protein platform ❖ Viral vector platform ▪ What: Recombinant antigen produced in various expression system ▪ What: Viral vector coding for an antigen gene ▪ CHO, Inset, E.coli.. ▪ Adenoviruses, MVA, Measles(홍역)… ▪ Progress: a well proven process platform with a long track record ▪ Progress: a new fast and highly productive platform ❖ mRNA platform ❖ Virus platform ▪ What: mRNA encoding antigen genes of an infectious agent ▪ What: Traditional viral vaccines are made of inactivated or live-attenuated SARS-CoV-2 ▪ E.coli (Plasmid) ▪ ▪ Progress: the fastest development and production process platform Progress: a traditional approach leveraging previous MERS and SARS pipeline Global Challenge from COVID-19 How Vaccines are Made and Manufactured Viral Vector Platform Adenovirus-Based Vaccine for COVID-19 - YouTube Page / 12 mRNA Platform Example AAV process optimization Optimization of Critical Process Parameters for Transfection and Production Phase for HEK293 Culture Screen to get the right set point in a controlled manner comparing with shake flask – pH and stirring speed were identified to be critical process parameters – One experiment and cultivation over 5 days in the Ambr 15 already leads to identification of optimal and robust HEK293T culture conditions via design space Range Stirring speed 400 – 800 rpm pH 6.9 – 7.3 DO 30 – 70 % Responses VCC, viability Page / 13 Comparison fold expansion 10 7.5 fold expansion Parameter 5 2.5 0 0 1 days 2 3 4 Example AAV process optimization Optimization of HEK293T Culture (Cell Growth) Parameters High throughput platform Parameters Cell line Medium Transfection reagent type Plasmid ration(pH:pV) Transfection reagent to DNA ratio Volume of transfection reagent Cell density Total plasmid Complex time(min) Page / 14 DoE | MODDE Key factors | Parameters The linear regression coefficients from the screening design was used to assess the importance of the different factors. As a result, we were able to select the factors having the bigger impact on the titer increase, and then narrow down the scope to further optimize the AAV productivity. Screening Optimization The titer regression coefficients obtained from the optimization design are more accurate compared to the model from the screening design and supports both linear and none linear terms. Positive coefficients increase titer while negative ones decrease the response. Medium7 and ATCC Cell line are factors that have the highest impact on the titers. Cell Culture of Suspension Cells by Using Bioreactors Page / 15 Cell Culture Technologies Overview the Steam for Bioprocessing Cell Culture Process Upstream Production of the desired drug Culture Media Preparation Cell Banking Seed Train Production Centrifugation | Clarification Downstream Isolation and filling of the desired drug Page / 16 Final Filling Cryopreservation Sterile Filtration Concentration Virus Removal Filtration Viral Clearance Capture Chromatography Cell Culture Technologies About Cell Culture Process ▪ 세포 배양 공정은 단일 세포주가 충분한 성장,분열 기간을 거쳐 타겟이 되는 물질을 대량으로 생산할 수 있도록 배양하는 과정 입니다. 세포주 (Cell Line) 단계별 스케일 업 대규모 항체 생산 Page / 17 Cell Culture Technologies Bioprocessing Optimization ▪ 최적화된 세포 배양 공정 개발 과정 소형 바이오리액터에서 다양한 배양 조건 실험 Page / 18 품질, 생산량 극대화를 위한 각 변수 별 최적 범위 도출 Lab-scale 바이오리액터에서 생산결과 추가 검증 Main parts for cell cultivation Main Parts for Cell Culture Process Cell Culture by using Bioreactors ▪ Optimal operating conditions in design space ▪ Seed (Sub-Culture) to main cultivation ▪ Control for pH, DO, Mixing and Temp. etc. 2 Analysis of Culture Conditions by offline Sampling ▪ Intracellular metabolic observers ▪ Cell health state observers ▪ Concentration of nutrients inside 3 Yield and Quality of Product from Big Data ▪ Increasing of product yield and quality ▪ Advanced data analytics ▪ Validate of bioprocessing in QbD Scale Study ▪ Process development from small scale to production scale 1 Bioprocessing 4 Page / 19 Main parts for cell cultivation Main Parts for Cell Culture Technologies BIOREACTOR ▪ ▪ ▪ ▪ ▪ ▪ pH DO Stirrer Temp etc kLa P/V IPC (In Process Control) ▪ ▪ ▪ ▪ ▪ Online Glucose, Lactate Online O2, CO2 Gas Online Viable Cell Density Online Total Cell Mass Spectroscopy etc Data Analytics ▪ ▪ ▪ ▪ ▪ ▪ Page / 20 PAT Sensors Glucose Lactate Glutamine Ammonium Cell Viability pCO2 etc ▪ DoE (Design of Experiment) ▪ MVDA (Big Data) ▪ Correlation from law material to product ▪ Influencing factors on bioprocessing for quality Main parts for cell cultivation Step 1: Cell Culture by Using Bioreactors Agitation ▪ Mixing by Impeller Control Parameter of bioreactor ▪ pH ▪ DO ▪ Temperature ▪ Stirrer ▪ Pump to add a solution ▪ Gassing (Air, O2, N2, CO2) Aeration ▪ Supply of gassing for pH, DO Page / 21 Main parts for cell cultivation Main Parts to Control of Bioreactor ▪ pH & DO Control ▪ Temp Shift ▪ Important in Process ▪ Type of vessel for temp control Cell Culture By bioreactors Page / 22 ▪ Shear Force ▪ Feeding Strategy ▪ Scale Study ▪ Correct Volume and Continuous Feeding Main parts for cell cultivation Bioreactor Parameters From Glass Vessel Exhaust of Gas Exhaust of Gas Stirrer by Motor pH Mixing by stirrer DO Temp Supply of Gas (Air, O2, N2, CO2) For CC For MO Pumps Impeller Temperature module Sparger Ring Sparger Micro Sparger Weight pH, DO & Temp Sensors Page / 23 Main parts for cell cultivation Advanced Data Analysis Single Use Exhaust Cooler ▪ Design of Impeller Classical pH, DO sensors Mettler and Hamilton Flexible of Impeller (2x 3 blade or 1x 3 blade, 1x 6 blade) SU optical pH, DO sensors Defined pore size for micro, Ring sparger Page / 24 Connection of Viamass Sensor ▪ Flexible ▪ Classical design Main parts for cell cultivation Page / 25 Main parts for cell cultivation Step 2: Offline Analysis of Process from Culture Sample Analysis of culture conditions ▪ Cell Analysis Cell Density, Cell Viability, Cell Diameter etc Sampling Analysis ▪ Chemical Analysis Gluc, Lac, Gln, Glu, NH4+, Na+, K+, Ca++ ▪ Gas Analysis pH, pCO2, pO2 Offline Sample Page / 26 ▪ Osmolality Main parts for cell cultivation Step 3: Data Analysis Data from Bioreactor, Initial Conditions, IPC, Batch Quality Initial batch conditions Start Process parameters Start IPC data Start Batch quality attributes End B1 End End B2 B3 B4 Recipe, raw material char… Page / 27 pH, Temp, flows, pressure… Nutrient levels, Yield, cell properties, quality… product amounts.. Study for Design Space & Process Optimization Type of Cell Culture Processing Page / 28 Type of Cell Culture Processing Type of Cell Culture Processing 회분식 배양 (Batch Culture) 유가식 배양 (Fed-Batch Culture) 연속식 배양 (Continuous Culture) ▪ 회분식 배양(Batch Culture): 초기 배