Global Regulatory Policy and New Considerations · Centralized Procedures 欧盟：欧洲委员会...
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www.pptaglobal.org Global Regulatory Policy and New Considerations 全球监管政策和新思考 Mary Gustafson Vice President, Global Regulatory Policy, PPTA PPTA全球监管政策副总裁 Beijing, China 中国北京 September 7, 2017 2017年9月7日
Transcript of Global Regulatory Policy and New Considerations · Centralized Procedures 欧盟：欧洲委员会...
www.pptaglobal.org
Global Regulatory Policy and New Considerations
全球监管政策和新思考
Mary GustafsonVice President, Global Regulatory Policy, PPTA
PPTA全球监管政策副总裁
Beijing, China 中国北京September 7, 2017 2017年9月7日
www.pptaglobal.org
The Myth虚构的事
• There is no “Global Regulatory Policy”没有“全球监管政策”
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www.pptaglobal.orgSeptember 7, 2017 Beijing, China
• Regulation of Plasma Protein Therapies is regional 血浆蛋白疗法的监管是地区性的
– Legal structure 法律结构– History 历史– Risk perception 风险感知– Social mores 社会观念
The Myth虚构的事
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Plasma-Liquid Portion of Blood after Cells Removed 血浆-细胞去除后血液的液体部分
Transfusion 输血- FFP新鲜冰冻血浆
- Cryo 冷沉淀- PF 24 24小时冰冻血
浆- Plasma血浆
Transfusion 输血- aFFPRecovered
回收
Source 原料
Fractionation 分离
Whole Blood 全血 Apheresis 血浆分离
x x
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Plasma Protein Therapies血浆蛋白疗法
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Legal/Regulatory Structures法律/监管结构
• The legal and regulatory structures are as varied as the geography! 法律和监管结构因地域不同而存在差异！
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United States美国
• Players 参与者
– Food and Drug Administration 食品药品监督管理局1. Statutes (FDCA and PHS Act) 法令（《联邦食品、药品和化妆
品法案》和《公共健康服务法》）
2. Regulations (Standards and cGMP) 法规（标准和cGMP）3. Guidance documents and blood memos 指导文件和血液备忘录
– States 州1. No Federal pre-emption 无联邦优先采买权2. Some specific plasmapheresis requirements 一些特殊的单采血
浆要求
– Centers for Medicare and Medicaid Sciences 医疗保险和医疗补助科学中心1. Clinical Laboratory Improvement Act 临床实验室改进修正法规2. Total Protein Test for Source Plasma 单采血浆总蛋白检测
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US Regulatory Structure 美国监管结构
US Food, Drug and Cosmetic Act美国食品、药品和化妆品法案
Law法律
Regulations条例
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Interpretation解释
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Europe欧洲
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• Players 参与者
– European Union/European Commission (EU/EC) 欧盟/欧洲委员会
– Council of Europe/European Directorate for Quality of Medicines/European Pharmacopeia (CoE/EDQM/Ph.Eur.) 欧洲委员会/欧洲药品质量管理局/欧洲药典
– European Medicines Agency (EMA) 欧洲药品管理局– National Competent Authorities (NCA) 国家主管机构
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EU Law欧盟法
• Regulations法规
Europe is complex slide欧洲非常复杂
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Industry 产业• Feedback 反馈• Concept papers 概念论文• Subject to audits 接受审计
Institutions 机构• EU Parliament 欧盟议会• EU Commission 欧盟委员会• EU Court of Justice 欧盟法院• Council of Ministers 部长理事会
EMA/ Nat. Regulatory AgenciesEMA/国家监管机构• Evaluate medicines 评估药品• Issue Licences 颁发许可证
• Products MA 产品MA• Manufacture GxP 生产GxP
Industry representative Bodies行业代表• Exchange info between
industry and authorities行业和当局交换信息
How things work in Europe 欧洲是如何运作的
European Parliament欧盟议会
EU Guidance欧盟指南
• EU GMP Guide 欧盟GMP指南
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• Plasma as a starting material is regulated very differently in the two regions 血浆作为原料在两个地区的监管差异很大
• US control of plasma is centralized 美国对血浆集中控制– FDA controls plasma for the nation FDA控制全国的血浆
• EU control of plasma is more decentralized (shared with Member States) 欧盟对血浆的控制更为分散（与成员国共享）
– EMA coordinates plasma as starting material EMA协调原料血浆
– NCA controls plasma collection NCA控制血浆采集
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EU/US Differences Re: Plasma欧盟/美国监管差异：血浆
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• Plasma products for manufacturing 生产用血浆产品– Recovered Plasma 回收血浆
1. “recovered” from Whole Blood从全血中回收
2. By-product of WB component PreparationWB成分制备的副产品3. Expired trans fusible plasma失效的可输入血浆
– Source Plasma 单采血浆1. Frequent 频繁的2. Infrequent 不频繁的
• Source Plasma is US licensed product/recovered used via contract 单采血浆是美国许可产品/根据合约回收使用
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United States美国
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Source Plasma单采血浆
• Licensed biologic product: Standards in Title 21, Code of Federal Regulations, Part 640 注册生物产品：21 CFR Part 640标准
– “. . .defined as the fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use.” [21 CFR 640.60] “……定义为血浆置换采集的人血流动部分，预期作为进一步生产使用的原材料。”
• Additional Donor Requirements beyond WB requirements 除全血要求外，对捐献者的额外要求
– Physical examination (PE), initially and annually 体检（PE），首次和每年一次
– Total Protein (TP) > 6.0 g/dL at each donation 每次捐献的总蛋白（TP）> 6.0 g/dL– Serum electrophoresis (SPE) verified every 4 months 每4个月检查一次血清蛋白电泳（
SPE）
• Donation intervals 捐赠间隔– Frequent 频繁
1. No more than 2 times/7 day week 一周7天不超过2次2. Maximum 104 times/year 一年最多104次3. Maximum 625 – 800 mls/donation depending on weight of the donor 每次捐献最多625 – 800 mls，
取决于捐献者体重
– Infrequent – exemptions to PE/TP/SPE if no more frequent than every 4 weeks (28 days) 不频繁 – 如果频率低于每4周（28天）一次，则不需要进行PE/TP/SPE
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Presenter
Presentation Notes
@
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Europe欧洲
• EU legislative acts— 欧盟法律– Regulations: binding for member states; must be
applied as is. Exp. Orphan medical products, pharmacovigilance 法规：约束成员国；孤儿医疗必须采用的用品，药物警戒
– Directives: goal that member states must achieve. “How” left to member states.
– 指令：成员国必须达成此目标。“如何达成”留给成员国决定– Decisions: binding on member state addressed
决定：约束列出的成员国
– Recommendations: not binding建议：非约束
– Opinions: not binding意见：非约束
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EU Directives欧盟指令
• Substances of human origin—directives for blood, tissues/cells, organs 人源成分—针对血液、组织/细胞、器官的指令
• Blood Directive (2002/98/EC) Setting standards of quality and safety for blood and blood components (Mother) 血液指令（2002/98/EC )设立血液和血液成分的质量和安全性标准（母指令）
• Daughter Directives 子指令– 2004/33/EC. Certain technical requirements. Annex III. Donor
eligibility requirements. 特定的技术要求。附录III，捐献者资格要求。
– 2005/62/EC. Community standards and specs for quality system. 质量体系的社区标准和规范。
– 2005/61/EC. Traceability/notification of serious adverse reactions. 严重不良反应的追溯/通知。
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Plasma for fractionation分离用血浆
• Not licensed at European level— 欧洲未注册– NCA control of blood components 国家主管机构对血液
成分的控制
– NCA responsible for GMPs 国家主管机构负责GMP• Directive that links to plasma to final therapies via
Plasma Master File (PMF) 通过血浆主文件 (PMF)将血浆连接到终端治疗的指令
– Commission Directive 2003/63/EC amending 2001/83/EC; Annex I (III., section 1.1) 委员会指令2003/63/EC修订了2001/83/EC；附录I（III.，第1.1节）“Information related to the starting and raw materials”, for starting materials made of human blood/plasma may be replaced by a PMF certified. . . .“关于起始和原材料的信息”，以人血/血浆作为起始原材料的，可以由PMF认证取代……
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European Medicines Agency (EMA)欧洲药品管理局（EMA）
• A decentralized agency of the EU 欧盟的分散机构
• Responsible for the scientific evaluation, supervision & safety monitoring of medicines used in the EU. 负责欧盟内药品的科学评估、监督和安全性监控。
• EMA works closely with national CAs in a regulatory network. EMA与国家主管机构密切合作构成监管网络
• Responsible for scientific review of products seeking market entry in EU 负责对寻求进入欧盟市场的产品进行科学审核
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European Medicines Agency欧洲药品管理局
• Operates through committees/working parties with representation from NCAs 通过委员会/工作组与国家主管机构代表进行运作
• Responsible for scientific review of products seeking marketing authorization via centralized procedure负责通过集中程序寻求销售授权的产品的科学评审
• Various other functions, including inspections 其他各项功能，包括视察
• Issues scientific guidance 发布科学指南– Not mandatory 非强制性– “strongly encouraged” “强烈建议”
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• Link to plasma as a starting material 连接血浆原料– Guideline on plasma-derived medicinal products
(EMA/CHMP/BWP/706271/2010) 血浆医用制品指南1. Manufacture of plasma-derived medicinal products starts at plasma pool 血浆医用制品的生产从血浆库开始2. Starting material concerns 原料问题
a. Risk factors 风险因素b. Selection and exclusion criteria 选择和排除标准c. Testing 检测d. Traceability 可追溯性
e. Post-collection measures/lookback 采集后措施/回顾
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European Medicines Agency欧洲药品管理局
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Plasma Protein Therapies血浆蛋白疗法
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Albumin 白蛋白Shock, Burns, Adult Respiratory Distress Syndrome, Cardiopulmonary Bypass Surgery 休克、烧伤、成人呼吸窘迫综合征、心肺旁路手术
Alpha-1 Antitrypsin α-1抗胰蛋白酶Alpha-1 Antitrypsin deficiency (Genetic COPD)
α-1抗胰蛋白酶缺乏症（遗传COPD）
Clotting Factors 凝血因子Bleeding Disorders, FVII, FVIII, FIX, FXIII, ATIII, Protein C, Prothrombin Complex 出血性疾病、 FVII、FVIII、FIX、FXIII、ATIII、蛋白C、凝血酶原复合物
Immunoglobulin 免疫球蛋白Bleeding Disorders, FVII, FVIII, FIX, FXIII, ATIII, Protein C, Prothrombin Complex 出血性疾病、 FVII、FVIII、FIX、
FXIII、ATIII、蛋白C、凝血酶原复合物
Miscellaneous 其他Bleeding Disorders, FVII, FVIII, FIX, FXIII, ATIII, Protein C, Prothrombin Complex 出血性疾病、 FVII、FVIII、FIX、FXIII、ATIII、蛋白C、凝血酶原复合物
Plasma Protein Therapies & The Diseases They Treat 血浆蛋白疗法&可治疗的疾病
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Plasma Protein Therapies血浆蛋白治疗
• Licensing Agencies 授权机构– US: US Food and Drug Administration (FDA), Center for
Biologics Evaluation and Research (CBER), Office of Tissues and Advanced Therapies (OTAT)美国：美国食品与药品管理局(FDA)、生物制品评估和研究中心(CBER)、组织与先进疗法办公室(OTAT)
– EU: European Commission (EC) authorizes products under Centralized Procedures欧盟：欧洲委员会(EC)根据集中程序授权产品1. Scientific evaluation and recommendation from EMA
EMA的科学评估和推荐2. Product testing and release by EDQM, Official Control Authority
Batch Release (OCABR) Network for Biological ProductsEDQM进行产品检测和放行，生物制品的官方控制授权批次放行(OCABR) 网络
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GMP compliance遵守药品生产质量管理规范(GMP)
• US 美国
– 21 CFR 210, 211: Drug GMPs 药品GMPs– 21 CFR 606: Blood GMPs 血液GMPs
• Inspectorate 检查员– Office of Regional Affairs—”field” 地区事务办
公室——“现场”1. Team Biologics—GMP 团队生物制品—— GMP2. Blood cadre—GMP 血液制品骨干队伍—— GMP
– Center for Biologics Evaluation and Research 生物制品评估和研究中心1. Product specialists—Pre-License/Approval
inspections 产品专员——许可/批准前审查2. Policy experts 政策专家
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遵守药品生产质量管理规范
• EU 欧盟– Commission Regulation (EC) No. 1252/2014欧委会法
规(EC) 编号1252/2014– Directive 2003/94/EC 指令2003/94/EC– Directive 2001/83/EC 指令2001/83/EC– EU GMP guidelines 欧盟GMP指南
• EMA has coordinating role for inspections and harmonizing GMP activities at EU EMA具有在欧盟协助检查和协调GMP活动的职责
– NCAs responsible for inspecting NCA负责检查1. Within territories 领域内2. Some (eg. Germany, Italy) responsibility at state/region
国家/地区内的某些职责（如德国、意大利）
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Global Initiatives全球计划
• The Plasma Protein industry is global. 血浆蛋白产业是全球性的。
• While risk perceptions are regional, solutions need to be global. 当风险感知为区域性时，解决方案需要是全球的。
• Seek regulatory convergence when possible. 可能的情况下寻求监管融合。
• Examples: 例如：
– WHO– ICH– PIC/S– MRA
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WHO世界卫生组织
• Blood Regulators Network (BRN) established in 2006 血液监管网络(BRN)成立于2006年
– Leading international authorities in regulation of blood 血液监管方面领先的国际权威机构
– Forum for exchange of information 信息交换论坛
• Expert Committee on Biological Standardization (ECBS) established in 1947 生物标准化专家委员会(ECBS)成立于1947年
– Regulatory scientists, academia, public health bodies 监管科学家、学术界、公共卫生组织
– WHO Biological Reference Materials WHO生物参考材料
– Guidance and Recommendations 指导和推荐
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WHO Publications世界卫生组织出版物
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ICH人用药品注册技术要求国际协调会
• Congratulations for Joining ICH! 祝贺加入ICH！
• ICH established in 1990 ICH成立于1990年– Facilitate international collaboration for harmonization
of regulatory practices 协助监管实践统一化的国际合作– Initially, US, Europe and Japan plus pharmaceutical
association 最初为美国、欧洲和日本加医药协会– Restructured in 2015 for broader participation 2015年重
组，参与范围更广– Standards (Quality, Safety, Efficacy) adopted by drug
makers and regulatory authorities 标准（质量、安全性、疗效）被医药制造商和监管部门采用
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PIC/S - Pharmaceutical Inspection Convention and Pharmaceutical Inspections Co-operation Scheme 药品检查协定和药品检查合作计划
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• Non-binding, international cooperative arrangement between CAs for GMPs of medicinal products
主管机构间针对医药制品GMP的非约束、国际合作安排
• Goals 目标– To harmonize inspection procedures
worldwide by developing common GMP standards 通过开发共同的GMP标准统一全球检查程序
– Facilitate cooperation & networking between CAs 协助主管机构间的合作和沟通
• Activities 活动– Standard & Guidance Documents 标准和指导文件– Training 培训– Seminars 讲座– Coached inspections 指导检查
PIC/S国际药品检查合作计划
Presenter
Presentation Notes
49 Participating CAs
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• PIC/S Guide to inspections of source plasma establishments and plasma warehouses (Inspection Guide) 单采血浆建立和储存的PIC/S指南 （检查指南）
– September 2007 2007年9月– Provides guidance for GMP inspectors 为GMP
检查员提供指导– Available to facilities collecting and/or storing
plasma for fractionation 为用于分离的血浆的采集和/或储存提供帮助
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PIC/S国际药品检查合作计划
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MRA互认协议
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• Generally bilateral agreements between two countries 一般指两国间的双边协议
• Scope and content of agreements vary 协议的范围和内容不同• Pharmaceutical between EU and US 欧盟和美国制药业
– Initiated in 1998 but not fully implemented 起始于1998年，但未完全实施1. GMP not agreed upon 未达成GMP协议2. Inspection provisions not added 未加入检查规定
– MRA for drug GMP agreed March 2017 2017年3月达成
药品GMP的互认协议1. Allows mutual recognition of GMP inspections
达成GMP检查的相互认同2. Does not include plasma protein sector yet
尚未包含血浆蛋白领域3. Marks progress towards harmonization 标志着走向统一的进展
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Summary总结
THANK YOU 谢谢Blood is local. Plasma is global.
血液是地方的，血浆是全球的。
Mary [email protected]
September 7, 2017 Beijing, China
