使用一次性技术的单克隆抗体生产设施--Vice President (VP) 副总裁2012.4.17

nullMAb Single Use Technology Facilities 使用一次性技术的单克隆抗体生产设施 MAb Single Use Technology Facilities 使用一次性技术的单克隆抗体生产设施 Niels Guldager Senior Technology Partner, Biopharmaceuticals 资深生物制药专家 Niels Ulrik Haxthausen Vice President (VP) 副总裁 NNE Pharmaplan 恩宜珐玛*Outline 概要Outline 概要Biotech - trends and challenges 生物技术 - 趋势和挑战 The MAb case 单克隆抗体案例 Facility of the Future– based on the ISPE guideline 未来的生产设施 – 基于ISPE准则 3 Manufaturing Operations and Activities 生产运营和活动 4 Process and Equipment 工艺和设备 5 Process support and utilities 工艺支持和公用工程 6 Facility design 厂房设计 7 Process controls + Quality by Design & ASTM E2500 工艺控制+质量源于设计 & ASTM E2500 How far can we standardize ? 我们什么时候能达到标准化？ *nullNiels GuldagerNiels is a senior consult for bioprocess and technology at NNE Pharmaplan. He has 16 years of experience with operation and design of biopharmaceutical processes. Niels has spearheaded the implementation and development of new concepts within single use technology and within the application of Quality by Design and ASTM E2500. Niels 是恩宜珐玛公司生物工艺和技术领域的高级顾问。他在生物制药工艺的设计和运营领域有16年经验。他是实施和开发一次性使用技术，质量源于设计和ASTM E2500应用的先驱。 Niels is currently engaged in collaborative writing efforts for task force and baseline guide groups. He holds the Certified Pharmaceutical Industry Professional™ certification from ISPE. 目前他负责专案组和基准指南小组的协同写作工作。 他持有ISPE认证的“制药行业专家”证书。 *nullBiotechnology - challenges 生物技术-挑战  Modern production technologies and new facility design philosophies have the potential to revolutionize the business case for Biopharmaceutical development, launch and production facilities. 现代生产技术和新建生产设施设计理念具有改革生物制药开发，上市和生产设 施的潜能。 Bringing Biopharmaceutical products from development to production introduces considerations about the long tem facility life cycle and how a pragmatic future oriented perspective can ensure project success. 生物制药产品从开发到生产要考虑生产设施的长期生命周期和实际着眼于未来的能保证项目成功的因素。 The challenge is not only process and technology driven – factors like quality system, analytical program, technology transfer and organizational competences are also part of the synthesis necessary for successful bridging from development to commercial production. 所面临的挑战不仅是工艺和技术为导向 - 质量体系，分析程序，技术转让和组织能力等因 素也是成功的从开发到商业化生产的综合必要因素。*Monoclonal Antibodies单克隆抗体Monoclonal Antibodies单克隆抗体 Facility of the FutureContinued growth in Mab – but: The paradigms will shift The market will be much more fragmented 单克隆抗体技术生产设施在未来的发展-但是 模式将变化 市场将会变得更加散乱无序*MAbs for cancer treatment - many products, smaller volumes 单克隆抗体用于癌症治疗-多种产品,小剂量 Solid tumours实体肿瘤: 12 Head/neck cancer头颈癌: 3 Leukemia白血病: 17 Lung cancer肺癌: 15 Pancretic cancer胰腺癌: 9 Colorectal cancer肠癌: 10 Kidney cancer肾癌: 5 Prostate cancer前列腺癌: 5 Sarcoma恶性毒瘤: 4 Cancer/chemotherapy 癌症/化疗 related conditions相关情况: 2 Unspecified cancers未定义的癌症: 5* *Drugs that have potential for one or more of the mentioned cancers *表示有可能治疗上述提到的一种或者几种癌症的药物 MAbs for cancer treatment - many products, smaller volumes 单克隆抗体用于癌症治疗-多种产品,小剂量Brain cancer 脑癌: 8 Breast cancer 乳腺癌: 10 Ovarian cancer卵巢癌 : 7 Liver cancer肝癌: 4 Bladder cancer膀胱癌: 1 Stomach cancer胃癌: 4 Other cancers其他癌症: 10 Multiple myeloma多发性骨髓瘤: 7 Lymphoma淋巴瘤: 22 Skin cancer皮肤癌: 3 Source: ‘Nearly 900 Medicines and Vaccines in Testing Offer Hope in the figh Against Cancer’, 2011 report from America’s biopharmaceutical research companies)887 new cancer treatment products are currently in development - approximately 200 of these are monoclonal antibodies: 目前正在研发的治疗癌症的新药有887种-其中大约200种是单克隆抗体*null*创新的生物制药可以治疗那些致命的或是十年前严重降低生活质量的疾病。但是，现实是并不是所有人都能拥有这些创新药。Continued Growth - Patent Expiries 持续增长-专利到期Continued Growth - Patent Expiries 持续增长-专利到期Source: http://seekingalpha.com/article/71375-10-pharmaceutical-stocks-and-their-patent-expiration-drugs) Top 10 pharmaceutials 2011 and their patent expiries 2011年前十位制药企业以及他们专利到期的时间MAbs indicated in grey灰色表示单克隆抗体*Mab’s: Yield Increases Changes Perspectives 单克隆抗体:提高产量改变前景 *Mab’s: Yield Increases Changes Perspectives 单克隆抗体:提高产量改变前景 Case: Crucell PER.C6: 案例: Crucell PER.C6 - Human origin cell line, human-glycosylation pattern 人原代细胞系,人糖基化模式 - Protein production platform: Therapeutic protein, MAb’s, virus 蛋白质生产平台：治疗型蛋白质,单克隆抗体,病毒 - 6-8 g/liter fed batch 6-8克/升一组 - Extreme Density process: 15 - 27 g/liter at harvest 高密度工艺:收获15-27克/升New cell lines 新细胞生产线 Media optimization and process understanding 培养基优化和对工艺的理解 MAb’s: From mgs/liter to 5 - 10 - 15 - 25 g/liter reported 单克隆抗体:从毫克/升至5-10-15-25克/升的 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 Case: LONZA GS expression system: 案例：LONZA 谷氨酰胺合成酶表达系统： - More than 100 X increase over 1990’s cell line yields 细胞株系的产量比20世纪90年代增长了100倍Converging force field 趋同的领域 Converging force field 趋同的领域 1 Many new products will compete on same market, so smaller volumes needed许多新产品在同一市场竞争，因而需要小剂量产品 200+ new MAb based products in development 超过200种单克隆抗体产品正在研发中 Bio-similar legislation in development or approved from EU, JP, US, WHO 生物仿制药的法规正在完善中或者已经获得欧盟,日本,美国和世卫组织批准 Local production capacity may be required for entry to some markets 为了进入一些市场可能需要增强本地生产能力 Investors in emerging market see a huge opportunity for “quick” entry in biotech 新兴市场的投资者在快速进入生物科技行业中发现了巨大的机会 Bioreactor yield increases 生物反应器产量增加 Single use technology and increased yields reduce the investment levels drastically 一次性使用技术和增加的产量导致投资水平急剧下降 Single use technology gives flexibility to cover variations in platform processes 一次性技术为平台工艺的多样化提供了灵活性 *A New Paradigm 新的模式 From Megafacilities to Small, Single Use Technology Units: 从大规模设施到小规模,一次性使用技术单元A New Paradigm 新的模式 From Megafacilities to Small, Single Use Technology Units: 从大规模设施到小规模,一次性使用技术单元Due to yield increases, there is a huge overcapacity in the market – so no volume growth in the existing facilities in EU/US. 由于产量增加，市场上产能过剩-所以欧盟和美国的现有设施没有增长的空间 The existing facilities are designed for low yields (< 1g/l) and stainless steel. They are very capital intensive and 现有生产设施的设计仅限于低产量 (< 1g/l）和不锈钢。而且属于资本密集型 Almost all new facilities are going for single use – and higher yields (>3g/l) 几乎所有的新设施都追求一次性使用技术-追求更高的产量(>3g/l) The shift to bio-similar, and to more or less protectionist emerging markets creates a big diversification 向仿制药的转换，而且对新兴市场或多或少的贸易保护造成了市场巨大的多元化 Result: A number of smaller units. 结果:一系列更小规模的单元6 years. 1 Bill $1-2 years < 50 mill $*nullTomorrow is today 明天源于今天Single Use MAb 次性技术单克隆抗体Other single use Biotech 其他一次性使用生物技术*2 Facility of the Future未来的生产设施2 Facility of the Future未来的生产设施Impact of single use technology 一次性使用技术的影响 * ISPE Baseline Guide volume 6: ISPE基准指南第六卷 Biopharmaceutical Manufacturing Facilities 生物制药生产设施* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 Biopharmaceutical Manufacturing Facilities 生物制药生产设施June 2004 1st edition. Scheduled for update soon. 2004年6月第一版，预计会在近期更新 Joint effort between industry and regulators 行业和监管机构之间的共同努力 Updated 2nd edition will much more on closed systems, single use technology 更新的第二版将更多关注封闭系统和一次性使用技术 Contents 内容 3 Manufaturing Operations and Activities 生产运营和活动 4 Process and Equipment 工艺和设备 5 Process support and utilities 工艺支持和公用工程 6 Facility design 生产设施设计 7 Process controls 工艺控制 …is not a list of final answers, but input for: 这不是最终 答案 八年级地理上册填图题岩土工程勘察试题省略号的作用及举例应急救援安全知识车间5s试题及答案 ，但是是为了 Careful, risk based approach 谨慎，基于风险的方法 Regulatory and quality concerns 关注的法规和质量 Safety requirements 安全要求 Points to consider 需要考虑的要点 Regional differences in requirements 要求的区域差异 Facility of the Future (1) 未来的设施(1)Facility of the Future (1) 未来的设施(1)Standard标准 Process core is standard - support functions are adaptable for local conditions 工艺核心是标准-支持功能要能适用本地条件 Equipment, documentation and procedures based on platform process 设备,文件记录和规程都基于平台工艺 Fast 快速 Ready for PQ within 12-18 months from approved concept 基于批准的概念，12-18个月内可完成性能确认之前的所有工作 Single use technology reduces validation and installation 一次性使用技术减少了验证和安装工作 Flexible 灵活 Flexibility and adaptability inherent in single use technologies 灵活性和适应性依赖于一次性技术 *Standard facility output 标准设施产量Standard facility output 标准设施产量Annual output (bulk API) 年产量 Up to 200 kg MAb in standard mode 使用标准模式生产的单克隆抗体产量达到200公斤 Up to 400 kg MAb in upgraded mode 使用升级后的模式达到400公斤 (at titer 3 g/L, 70% overall yield, 90% facility utilization) (滴定量3 g/L,总产率70%,设施利用率90%） Sufficient to meet annual demand for all but biggest selling products today 现在除了大规模销售的药品，足够满足每年的需求*Capacity 产能Capacity 产能Installed capacity 安装能力 Initial 初始阶段 2 SUB Bioreactor groups of: 1x50L + 1x200L + 2x1000L 2个一次性生物反应器组： 1x50L + 1x200L + 2x1000L Total production capacity: 4x1000L SUBs 全部产能： 4x1000L 一次性生物返应器 Upgrade 升级 Upgradeable to 4x2000L SUBs by substition 可通过替换升级到4x2000L 的一次性生物反应器 (20L-100L- 500L-2x2000L) *null* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 3 Manufacturing Operations and Activities 生产运营和活动* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 3 Manufacturing Operations and Activities 生产运营和活动Concerns 担忧： Process design is tied to facility design 工艺设计与设施设计紧密结合 Open processing places more focus on processes and people 开放式操作区更多关注工艺和人员 Huge difference between single product and multiproduct facility 单一产品和多产品生产设施之间的巨大差异 Viral clearance病毒清除 Single Use technology design impact 一次性使用技术设计影响Single Use technology design impact 一次性使用技术设计影响 Factors different from traditional technology 不同于传统技术的要素 Operators come close to process equipment, touch connections 操作人员接近工艺设备，直接接触设备 Manual operations to install, make connections and disassemble 安装，链接和卸载的手动操作 Transparency – visual contact desirable (not critical) 透明度 – 优良的虚拟式接触（不是关键因素） Limitations in pressures, flows, mass and heat transfer 压力，流量，数量和传热的限制 Transport volumes and distances become critical 传输数量和距离成为关键 Area for transport and maneuvering around - pipeless plant (for process) 传输区域和周围机动-无管式设施（工艺） Solid waste increased 固态废弃增加 Consumables storage space increased 消耗品存储空间增加*Flexibility 灵活性Flexibility 灵活性 Single use technology decouples the process from the building 一次性技术分离工艺与建筑 This means that flexibility mainly takes the form of low classification floor space! 这意味着灵活性主要采用低分类楼面空间的形式 No complex distribution matrices as connections are flexible 简单式分布矩阵作为链接是灵活的 Media and buffer supply is configured to the given process 培养基和缓冲液供应被设置为特定工艺 Can start with only eg. 500L bioreactor train and expand rapidly 能够从只有500L的生物反应器开始培养和快速扩张 2000L footprint is not drastically larger than 500L footprint 2000L占地面积不大于500L的占地面积 A lot of production power in a simple facility 在简单的生产设施里包含大量生产能力* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 4 Process and Equipment 工艺和设备* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 4 Process and Equipment 工艺和设备Concerns 担忧 Specific equipment design considerations 特定设备的设计考虑 Controlling critical process parameters 关键工艺参数控制 Equipment cleanability 设备清洁性 Equipment shared use 设备共享使用 Maintenance operations impacting production 维护操作影响生产 nullNiels Guldager, ngu@nnepharmaplan.com MAb single use technology facilities, Chinapharm 2011*Design factors: 设计要素 Trend: HTST media treatment 趋势：HTST培养基处理 Media towers 培养基存储器 Shelf life 存储期限*nullNiels Guldager, ngu@nnepharmaplan.com MAb single use technology facilities, Chinapharm 2011*Design factors: 设计要素 Transport for harvest bag 收获袋的传输 Depth filters dismantled 深度过滤器的拆除 Consider including proA step 考虑包括proA步骤* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 6 Facility design 设施设计 ISPE Baseline Guide volume 6: ISPE基准指南第六卷 6 Facility design 设施设计Concerns 担忧 Segregation and flow patterns 隔离和流向模式 Layout principles 布局原则 Area classifications 区域分类 Horizontal and vertical arrangements横向和纵向安排 *nullNiels Guldager, ngu@nnepharmaplan.com MAb single use technology facilities, Chinapharm 2011*Media towers 培养基存储器Bioreactors 生物反应器Buffer towers 缓冲液存储器Chrom skids 色谱板Waste control 废弃物控制 Side view – media/buffer prep – process interface 侧视图 – 培养基/缓冲液准备 – 工艺接口 Facility design Floor space for inspection, cleaning, transport Handling solid waste in controlled manner Extra floor space is flexibility (just add more bags) Daylight for intensive operations Process flow unidirectional *nullNiels Guldager, ngu@nnepharmaplan.com MAb single use technology facilities, Chinapharm 2011* Overall Resulting Philosophy 总体结果模式 Process support and utilities/Facility design Quality: Flow from dirty (powders) to cleaner (end product) Ergonomics: Flow from big to small volumes/loads * ISPE Baseline Guide volume 6: ISPE基准指南第六卷 5 Process support and utilities 工艺支持和公用工程* ISPE Baseline Guide volume 6: ISPE基准指南第六卷 5 Process support and utilities 工艺支持和公用工程Concerns 担忧 WFI or purified water? 注射用水或是纯净水？ Risk of contamination from shared systems 来自共享系统的污染风险 Design considerations for clean utility systems清洁公用工程系统的设计考虑 Biowaste handling生物废料的处理 Local conditions 当地条件Local conditions 当地条件 Classification approach: conservative or aggressive 洁净模式:保守还是激进 Media and water available as preproduced 可用的作为预生产的培养基和水 Fill-finish y/n:灌装 Warehouse:仓库 On site y/n:现场 Black utilities 非洁净公用工程 QC-laboratory QC实验室 R&D laboratory R&D 实验室 PD pilot plant PD中试厂 Clinical pilot plant 临床中试厂 Administration, reception 行政，前台 Standard is adaptable: Site interfaces, building levels 标准化是具有灵活性的：现场接口，建筑层数Process support and Utiltities Simplify supply infrastructure by placing big users together Separate dispensing for good housekeeping Provide structured warehouse arrangement Sufficient local storage for SU consumables*ISPE Baseline Guide volume 6: ISPE基准指南第六卷 7 Process Controls - QbD and ASTM E2500 工艺控制 – 质量源于设计和ASTM E2500 ISPE Baseline Guide volume 6: ISPE基准指南第六卷 7 Process Controls - QbD and ASTM E2500 工艺控制 – 质量源于设计和ASTM E2500 Concerns 担忧 Identify the critical parameters – based on science & risk 确定关键参数 - 基于科学和风险 Know your product specifics – but leverage the commonalities (starting point: the A-Mab study) 知道你的产品细节 - 但是要利用共性（起点：一个单抗案例研究） What needs to be qualified in the facility – and what is consumables & operations 生产设施里需要配备什么 - 什么是消耗品及营运 Leachables & extractibles 浸出和提取 *nullRaw Materials & Disposables Sourcing原材料&废弃原料Operational know how 操作技能Market Knowledge 市场知识Regulatory filing 依法申报Product & Process development 产品/工艺研发Clinical Material 临床材料Quality Systems 质量系统GMP & QbD GMP&质量源于设计Training 培训 焊锡培训资料ppt免费下载焊接培训教程 ppt 下载特设培训下载班长管理培训下载培训时间表下载 Facility Approval 设施批准Facility Design 生产设施设计Construction施工Validation验证The Road to Compliant production符合生产之路*Standard? – YES & NO. 是否要标准化？Standard? – YES & NO. 是否要标准化？A standard facility for Mab production can be defined – but:可以定义单克隆产品的标准生产设施，但是 A number of factors will drive differentiation – in increasing impact order:许多因素将导致差异 - 以下因素按影响递增排序 Size matters 尺寸因素 Specific processes & specific yields matters 具体工艺&具体产量因素 Country matters: 国家因素 Local regulations & practices 当地法规 Level of regulatory acceptance 监管机构认可的水平 Supply chain 供应链 Site matters 现场因素 Available faciltites – clean & black utilities, canteens, ... 可用的生产设施 – 洁净和非洁净公用工程，食堂 Existing functions – QC, quality systems, maintenance,...现有的功能 – QC, 质量体系，维修 Company Matters – VERY MUCH 公司因素 – 很多 Start-up or global deployment 公司启动或是全球发展 Existing company knowhow and practice 现有的公司专有技术 Internal regulations and procedures 内部 规范 编程规范下载gsp规范下载钢格栅规范下载警徽规范下载建设厅规范下载 和流程 Conservatism or risk&change preparedness 做好保守主义或是冒险变革的准备 So what stays standard? 那什么要保持标准化？ *Biotech on Demand按需设计的生物科技设施Biotech on Demand按需设计的生物科技设施Fast, affordable standard facilities 快速经济的标准设施 High predictabality in price, time and quality 价格,时间和质量的可预测性 Configurable to meet local demands, site conditions and resources 可通过配置满足当地的要求,现场情况和人员情况 Configurable to a wide range of products and production ranges 可通过配置满足各种产品和不同生产规模 Different building principles - depending on logistics, local conditions, price levels 各种建筑原则 - 基于物流，当地情况和物价水平 *Cost ranges 成本范围Cost ranges 成本范围Some functions may be available on site already 在现场可能已经具备的一些功能 Cost: 20-30…50 million USD 成本: 20-30…50百万美元 Depending on scope and geographical location 取决于范围及地理位置 *Areas 区域Areas 区域Footprints 建筑面积 Production module: 生产模块 Materials + solutions + process core + support: 1500-1800 m2 原料 + 方式 + 工艺核心 + 支持:1500-1800平方 Typical vertical layout 典型的垂直分布 Ground level 1: Bulk API 第一层: 原料药 Level 2: Fill finish and Utilities 第二层: 灌装和公用工程 Level 3: Offices, laboratories and HVAC 第三层: 办公室，实验室和暖通 Total floor area: 4500 m2 总面积： 4500平方米*Construction methods 施工方法Construction methods 施工方法Standardized, modular design ensures the right functionality 标准化，模块化设计确保正确的功能 Can be built on site能够在现场建造 Or或者 Can be constructed in a modular fashion 能够以模块化方式进行建造 Depends on local availability of skilled construction resources, import restrictions and taxes, transportation etc. 取决于本地可用的高水准施工人员,进口限制及关税,交通等 *Summary 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf Summary 总结Facility of the Future is not a product out of the box – however:未来的生产设施不是标新立异的产品，但是： The project types converge – just like the old ”6-pack” (6*20m3 stainless steel) 项目类型集中 - 像老式的“ 6个面的立方体” （6 * 20立方米不锈钢） The number of facilities is much bigger than the ”old” paradigm 新生产设施的数量比旧的“模范”设施多得多 Tha facilities are mroe similar – and more flexible 生产设施更相似 – 更灵活 The speed of decision and implementation is much larger 决策和执行的速度快得多 *