WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO药品药品GMPGMP管理概述管理概述 WORKSHOPWORKSHOP ON GOOD MANUFACTURING PRACTICES ON GOOD MANUFACTURING PRACTICES ( (GMPsGMPs) INSPECTION) INSPECTIONWORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO介绍疫苗的质量管理和GMP的基本要素生产中的GMP 要求在检查中要寻找的内容培训班的目的培训班的目的WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP失败的教训- 案例分析“神奇的药物”投入使用。作为小儿科的万能药上市。是一种悬于液体工业溶剂双烯乙二醇中的芳香溶液.通常被认为是以酒精为基础的产品,但特殊配方为双烯乙二醇.摄取后,乙烯乙二醇代谢为草酸. 358 中毒中毒 107 死亡死亡 251 发病但存活发病但存活1938 磺胺磺胺,一种一种甘香洒剂（甜的芳香的酒精与水的溶液，用作药物的赋形剂）甘香洒剂（甜的芳香的酒精与水的溶液，用作药物的赋形剂）WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO1955 脊灰疫苗脊灰疫苗 (Cutter Labs, USA) (Lambert, E.C., Medical Mistakes, Indiana University Press, 1978)案例分析51 51 儿童麻痹儿童麻痹10 10 死亡死亡几个可能的原因几个可能的原因: :病毒灭活过程批间存在差异病毒灭活过程批间存在差异. . 未经适当的病毒灭活工艺验证而急于放大生产未经适当的病毒灭活工艺验证而急于放大生产 现行的活病毒生产工艺采用热灭活步骤现行的活病毒生产工艺采用热灭活步骤. . 对于病毒对于病毒; ; 加热灭活步骤的放大可能并不充分加热灭活步骤的放大可能并不充分WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP的历史WH0-GMPEC-GMPFDA-无菌加工无菌加工FDA-cGMPFDA-GMPPIC-GMP德国国家法律德国国家法律强制实施强制实施GMP1968197119781983198519871989WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP的历史PIC-改编的改编的 GMP根据根据 EC-GMPWHO-修订的修订的 GMPWHO-生物制品的生物制品的GMPWHO-检查指南检查指南附件附件 1的修订的修订 EC-GMPWHO-无菌药品的无菌药品的GMP1992199219921996199720022003WHO-修订的修订的 GMPWORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO什么是什么是GMP?WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO世界卫生组织将 GMP 定义为: “质量保证的一部分质量保证的一部分。 确保制品按照适合确保制品按照适合拟使用拟使用目的的目的的质量标准质量标准进行进行一致性一致性生产和质量控制生产和质量控制,并且满足并且满足市场市场许可许可的要求的要求”WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP确保产品生产和控制一致性减少那些不能通过制品检定来控制的风险交叉污染混淆WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP的基础WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量管理质量管理制定和贯彻 “质量方针”基本要素是:适当的基础或“质量体系”，包括程序, 步骤和资源 确保对产品(或服务)符合既定的“质量”要求有足够信任所必需采取的总体行为.这些行为总称为这些行为总称为 “质量保证质量保证”WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量管理质量管理 定义为管理功能中制定和贯定义为管理功能中制定和贯彻质量方针的方面彻质量方针的方面质量方针质量方针 是公司上层管理对其有关质是公司上层管理对其有关质量的总体意图的说明量的总体意图的说明, 以总体方针正式以总体方针正式表达表达. WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量关系质量关系质量管理质量管理质量控制质量控制GMP质量保证质量保证管理方面管理方面质量体系质量体系质量方针质量方针人员人员培训培训验证验证自检自检质量目标质量目标质量手册质量手册取样取样标准标准检测检测WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量管理的基本基础质量管理的基本基础WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO在一个组织内在一个组织内, QA 是一个管理的工具。在是一个管理的工具。在契约（合同）情况下，它提供对供应商的契约（合同）情况下，它提供对供应商的保证保证.QA 不是公司内某一部门单独的责任，不是公司内某一部门单独的责任， 而而是所有可能影响制品质量的员工的责任是所有可能影响制品质量的员工的责任质量管理要素质量管理要素 1) 质量保证质量保证WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量保证体系要求质量保证体系要求 I1.确保产品正确生产2.区分管理职责3.为生产和质控提供SOPs4.组织供应和使用正确的原材料5.规定生产和包装所有环节的质量控制WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOQA体系的要求体系的要求 II6.确保成品进行正确加工，并在放行前进行检查（检验）7. 确保制品经授权者审核后放行8. 储存储存和分发9. 组织自检WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP的基本要求的基本要求 I1. 明确定义并系统审核生产过程2. 关键步骤的验证3. 适当的资源： 人员，建筑，设备，材料4. 明确的书写程序 5. 经培训的操作者WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOGMP的基本要求的基本要求 II6. 完整的记录, 差错调查7. 正确的保存和分发 8. 制品召回系统9. 投诉的处理WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量控制部门质量控制部门(QC) 每个有生产许可证的企业都应该有QC部门独立于生产和其它部门是最基本的要求由一个授权的有资格的经验丰富的人员管理， 包括一个或几个质控实验室WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量控制的基本要求质量控制的基本要求资资 源源足够的设施培训的人员经验证并批准的程序WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量控制的基本要求质量控制的基本要求 - I对象对象起始材料包装材料中间产品半成品成品环境条件WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量控制的基本要求质量控制的基本要求 II1. QC部门批准的取样2. 经验证的实验方法3. 记录4. 对生产记录进行审查和评估5. 对所有偏差的差错原因调查 6. 所有成分符合市场准入的要求WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质量控制的基本要求质量控制的基本要求 III7. 成分达到要求的纯度8. 正确的容器9. 正确的标签10. 由授权人签发11. 原材料和成品的留样WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO质控部门的其它职责质控部门的其它职责1. 建立质控程序2. 参考标准品3. 正确的标签 4. 稳定性实验5. 投诉调查6. 环境监测WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO成品的评价成品的评价应包含所有相关因素，如:生产条件生产过程的检测结果生产文件符合成品标准对最终包装的检验WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO如何对企业进行检查?申请许可证的新企业: 检查所有GMP必须的要素是否有现场主文件(SMF)?是否有企业主文件(FMF)?是否有质量手册? 该手册是否包含 GMP所有的要素以及 如何用于衡量操 作？如何处理不符合的情况? 该手册是否详细描述了质量管理问题?是否有产品概要文件( Product Summary File)?WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHO通过 GMP 认可的企业: 在一个常规检查期间，由于时间有限，并不能对要素的所有方面进行检查。但是，有些方面必须结合审核进行检查。WORKSHOP ON GOOD MANUFACTURING PRACTICES (WORKSHOP ON GOOD MANUFACTURING PRACTICES (GMPsGMPs) INSPECTION FOR VACCINES) INSPECTION FOR VACCINESWHOReferences1.Good Manufacturing Practices for pharmaceutical products. In: WHO ExpertCommittee on Specifications for Pharmaceutical Preparations. Twenty-secondreport. Geneva, World Health Organization, 1992 Annex 1 (WHO TechnicalReport Series, No. 823).2. Validation of analytical procedures used in the examination of pharmaceuticalmaterials. In: WHO Expert Committee on Specifications for PharmaceuticalPreparations. Thirty-second report. Geneva, World Health Organization, 1992:Annex 5 (WHO Technical Report Series, No. 823).3. Good manufacturing practice for medicinal products in the EuropeanCommunity. Brussels, Commission of the European Communities, 1992.4. Pharmaceutical Inspection Convention, Pharmaceutical Inspection CooperationScheme (PIC/S). In: Guide to good manufacturing practice formedicinal plants, Geneva, PIC/S Secretariat, 2000.5. Quality assurance of pharmaceuticals. A compendium of guidelines andrelated materials. Volume 2. Good manufacturing practices and inspection.Geneva, World Health Organization, 1999.6. Model certificate of analysis. In: WHO Expert Committee on Specifications forPharmaceutical Preparations. Thirty-sixth report. Geneva, World HealthOrganization, 2002, Annex 10 (WHO Technical Report Series, No. 902).