实验室控制GMP实施指南

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目录

目录1 前言...............................................................................................................................................12 目的...............................................................................................................................................23 范围...............................................................................................................................................34 指南内容结构...............................................................................................................................45.质量控制实验室总体描述............................................................................................................55.1 职责....................................................................................................................................55.2 布局....................................................................................................................................55.2.1原则..........................................................................................................................55.2.2 要求.........................................................................................................................55.3 人员....................................................................................................................................65.3.1 组织架构.................................................................................................................65.3.2 资质要求.................................................................................................................65.3.3 培训.........................................................................................................................65.4 文件系统....................................................................................................................................75.4.1 分类.........................................................................................................................75.4.2 要求.........................................................................................................................76 取样.............................................................................................................................................106.16.26.36.4

定义.........................................................................................................................11应用范围.................................................................................................................12要求.........................................................................................................................126.3.1人员........................................................................................................................126.3.2取样器具................................................................................................................126.3.3样品容器................................................................................................................136.3.4取样间....................................................................................................................13流程实施.................................................................................................................136.4.1取样方案................................................................................................................136.4.2取样........................................................................................................................146.4.3标识........................................................................................................................146.4.4取样记录................................................................................................................146.4.5取样的异常处理....................................................................................................146.4.6留样........................................................................................................................157 试剂及试液的管理.....................................................................................................................177.1 定义和应用范围..............................................................................................................177.2 要求..................................................................................................................................177.2.1 采购接收和标识...................................................................................................177.2.2 储存和使用...........................................................................................................187.2.3 试剂使用效期的管理...........................................................................................187.2.4 报废.......................................................................................................................187.2.5 文件管理...............................................................................................................188 标准品/对照品............................................................................................................................198.1 定义..................................................................................................................................198.2 分类..................................................................................................................................198.3 应用范围..........................................................................................................................208.4 要求..................................................................................................................................208.4.1 接收.......................................................................................................................208.4.2 标识.......................................................................................................................208.4.3 标准溶液的稳定性研究.......................................................................................20i目录

实验室控制系统GMP实施指南8.4.4 标准品、对照品的使用、处置和贮存...............................................................218.4.5 文件管理...............................................................................................................219实验室分析仪器的确认.............................................................................................................229.1 应用范围..........................................................................................................................239.2 确认实施..........................................................................................................................249.2.1 验证总计划...........................................................................................................249.2.2 确认方案...............................................................................................................249.2.3 确认实施...............................................................................................................259.2.4 确认报告...............................................................................................................279.2.5 系统适用性试验...................................................................................................279.2.6 实验室仪器控制系统和数据处理系统的确认...................................................279.2.7 再确认...................................................................................................................2810 实验室分析仪器的校准与维护...............................................................................................3210.1定义................................................................................................................................3310.2应用范围........................................................................................................................3310.3要求................................................................................................................................3310.3.1 人员.....................................................................................................................3310.3.2 分类.....................................................................................................................3410.3.3 实施指导.............................................................................................................3410.3.4 文件.....................................................................................................................3611 分析方法的验证和确认...........................................................................................................4511.1分析方法........................................................................................................................4611.2方法验证........................................................................................................................4611.3方法确认........................................................................................................................4711.4适用范围........................................................................................................................4711.5方法验证的一般原则....................................................................................................4711.6需要验证的检验项目....................................................................................................4711.7方法验证内容................................................................................................................4911.7.1 准确度.........................................................................................................................4911.7.2精密度..................................................................................................................5011.7.3 专属性.................................................................................................................5211.7.4 检测限（LOD）..................................................................................................5311.7.5 定量限（LOQ）..................................................................................................5311.7.6 线性.....................................................................................................................5411.7.7 范围.....................................................................................................................5511.7.8 耐用性.................................................................................................................5511.8方法确认........................................................................................................................5911.9方法再验证....................................................................................................................5911.10文件管理......................................................................................................................6012 稳定性实验...............................................................................................................................6412.1定义................................................................................................................................6612.2应用范围........................................................................................................................6612.3原则................................................................................................................................6612.4稳定性分类....................................................................................................................6612.5技术要点........................................................................................................................6712.5.1 基本要求.............................................................................................................6712.5.2 样品储存.............................................................................................................6712.5.3 样品提取.............................................................................................................7312.5.4 分析.....................................................................................................................7312.5.5 简化方案设计.....................................................................................................7812.5.6 上市产品的稳定性试验.....................................................................................79ii实验室控制系统GMP实施指南

目录12.5.7 评估.....................................................................................................................8012.5.8 数据汇总.............................................................................................................8212.5.9 统计分析的程序.................................................................................................8212.6文件................................................................................................................................8312.6.1 标准操作规程.....................................................................................................8312.6.2 稳定性实验草案.................................................................................................8312.6.3 计划.....................................................................................................................8312.6.4 记录.....................................................................................................................8312.6.5 报告.....................................................................................................................8412.6.6 年度趋势分析与评估.........................................................................................8412.7稳定性超标或超趋势调查处理....................................................................................8412.7.1原则.....................................................................................................................8412.7.2 程序.....................................................................................................................8413 超出标准及超趋势的实验结果调查.......................................................................................8713.1定义................................................................................................................................8713.2重要性............................................................................................................................8713.3应用范围........................................................................................................................8713.4实施................................................................................................................................8713.4.1 一般原则.............................................................................................................8713.4.2 流程.....................................................................................................................8813.4.3 文件.....................................................................................................................9313.7.2 职责的确定：.....................................................................................................9314 原始数据的管理.......................................................................................................................9814.1实验室原始数据的范围................................................................................................9914.1.1 实验室记录要求...............................................................................................10014.1.2 数据完整性.......................................................................................................10014.1.3 数据记录形式...................................................................................................10014.2实验室记录的设计......................................................................................................10114.3实验室记录的填写和复核..........................................................................................10114.3.1 实验室记录的填写...........................................................................................10214.3.2 记录的复核.......................................................................................................10214.3.3记录更正要求...................................................................................................10314.4记录的管理..................................................................................................................10315 物料及产品的检验.................................................................................................................10515.1质量标准的管理..........................................................................................................10815.1.1 质量标准的设计与制定...................................................................................10915.1.2 质量标准的审核与批准...................................................................................11015.1.3 质量标准的分发、撤销、复制、销毁...........................................................11015.2检验..............................................................................................................................11115.2.1 检验样品：.......................................................................................................11115.3检验报告书的管理......................................................................................................11115.4委托检验......................................................................................................................11215.4.1 原则...................................................................................................................11515.4.2 应用范围...........................................................................................................11516.4.3 职责...................................................................................................................11616.4.4 受托方的选定...................................................................................................11615.4.5 合同签订...........................................................................................................11715.4.6 合同实施...........................................................................................................11715.4.7 结果评估...........................................................................................................11715.4.8 实验后样品处理...............................................................................................11816 微生物检验.............................................................................................................................119iii目录

实验室控制系统GMP实施指南16.1应用范围......................................................................................................................12016.2原则..............................................................................................................................12016.3人员资质及培训要求..................................................................................................12016.4设施..............................................................................................................................12016.4.1 无菌及微生物限度检验等实验区域...............................................................12116.4.2 菌种处理、微生物鉴别和阳性对照室...........................................................12116.4.3 抗生素微生物检定室.......................................................................................12116.4.4 培养室及其他功能间.......................................................................................12116.5设备..............................................................................................................................12216.5.1 无菌隔离器（如使用）...................................................................................12216.5.2 实验室用层流台...............................................................................................12316.5.3 培养箱...............................................................................................................12316.5.4 蒸汽灭菌柜.......................................................................................................12316.5.5 空调高效过滤器...............................................................................................12316.6灭菌消毒方式..............................................................................................................12316.7菌种的管理..................................................................................................................12416.8培养基..........................................................................................................................12516.8.1 培养基的制备...................................................................................................12516.8.2 培养基的贮藏...................................................................................................12616.8.3 培养基的质量控制实验...................................................................................12616.9实验分类......................................................................................................................12716.9.1 总菌落数检查...................................................................................................12716.9.2 控制菌检查.......................................................................................................13216.9.3 非无菌产品的实验频率...................................................................................13416.9.4 无菌检查法.......................................................................................................13516.9.5 内毒素检查.......................................................................................................138参考文献.......................................................................................................................................141术语表...........................................................................................................................................142关键词索引...................................................................................................................................144iv实验室控制系统GMP实施指南

表格索引

表格索引表1-1指南逻辑关系图...............................................................................................................1表9-1自动取样溶出仪确认测试项目示例..............................................................................29表10-1 仪器使用日志示例.........................................................................................................36表10-2校准记录示例...............................................................................................................37表10-3外部校准评估报告示例...............................................................................................38表10-4分析天平校准要求示例...............................................................................................40表10-5HPLC校准项目及周期示例.......................................................................................42表10-6HPLC年度预防性维护示例........................................................................................43表11-1检验项目和验证内容...................................................................................................48表11-2方法验证对比表...........................................................................................................48表11-3 准确度方法验证示例.....................................................................................................49表11-4精密度验证方法...........................................................................................................51表11-5中间精密度的设计方案...............................................................................................51表11-5专属性方法验证............................................................................................................52表11-6杂质测定检测限验证方法...........................................................................................53表11-7杂质定量测定验证方法...............................................................................................53表11-8 线性验证和准确度验证需涵盖的最低浓度范围..........................................................54表11-9方法耐用性影响因素示例...........................................................................................55表11-10HPLC含量方法耐用性考虑因素及变化范围示例..................................................56表11-11 分析方法验证接受标准示例.........................................................................................56表12-1四个气候带的分类表...................................................................................................67表12-2 标准贮藏条件表.............................................................................................................68表12-3温度选择性制剂的标准贮藏条件................................................................................69表12-4原料药包装分类（水蒸气渗透性）............................................................................69表12-5 原料药及制剂影响因素试验条件..................................................................................71表12-6半渗透包装标准贮藏条件...........................................................................................72表12-7密闭包装贮藏条件.......................................................................................................72表12-8拟冷藏药物的贮藏条件...............................................................................................72表12-9拟冷冻贮藏药物标准贮藏条件....................................................................................72表12-10稳定性试验点时间表.................................................................................................74表12-11 原料药及制剂稳定性重点考察项目参考表................................................................74表12-12片剂中间产品放置时间研究示例..............................................................................77表12-13转运运输条件示例.....................................................................................................78表12-14括号法方案设计.........................................................................................................79表12-15矩阵法方案设计.........................................................................................................79表16-1非无菌制剂产品类型与检验频次示例......................................................................134表16-2原料检验频次及分类标准示例..............................................