Stability(cGMP培训系列7)
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cGMP培训
浙江省食品药品监督管理局培训中心 ZJFDA
SIX SYSTEM APPROACH
TO GMP IN MANUFACTURING
OF SOLID DOSAGE FORM 固体制剂的六大体系
Presented by sFDA & Alliance Pharm
on
浙江省药监局& 美国洲际药业
17, 18 March 2006 Hangzhou, China
manufacturing通过减少生产可变性 得到
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.7 What is a Process什么是过程?
Changing low-value INPUT into high-value OUTPUT把低价值的输
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.5 The Race of Quality质量的赛跑 –
1970s
After WWII, Deming taught Japanese industry methods and techniques of quality management & improvement.
入变成高价值的输出
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.8 Knowledge is Power 知识就是力量
Alvin Toffler托夫勒 – The THIRD WAVE 第三次
浪潮-1980
SIX SYSTEM APPROACH
TO GMP IN MANUFACTURING
OF SOLID DOSAGE FORM 固体制剂的六大体系
Presented by sFDA & Alliance Pharm
on
浙江省药监局& 美国洲际药业
17, 18 March 2006 Hangzhou, China
manufacturing通过减少生产可变性 得到
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.7 What is a Process什么是过程?
Changing low-value INPUT into high-value OUTPUT把低价值的输
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.5 The Race of Quality质量的赛跑 –
1970s
After WWII, Deming taught Japanese industry methods and techniques of quality management & improvement.
入变成高价值的输出
Simon Rusmin
March 17 and 18, 2006
浙江省食品药品监督管理局培训中心 ZJFDA
1.8 Knowledge is Power 知识就是力量
Alvin Toffler托夫勒 – The THIRD WAVE 第三次
浪潮-1980
CGMP(中英对照)
目录A．总则 (1)211．1 范围 (1)211．3定义 (1)B组织与人员 (2)211．22质量控制部门的指责 (2)211．25人员资格 (3)211．28人员职责 (4)211.34顾问 (4)C．厂房和设施 (5)211．42设计与建造特征 (5)211．44照明 (7)211．46通风、空气过滤、空气加热与冷却 (7)211．48管件 (8)211.50 污水和废料 (8)211.52 洗涤和洗设备 (8)211.56环境卫生 (9)211.58 保养 (10)D. 设备 (10)211．63 设备的设计、尺寸及位置 (10)211．65 设备制造 (10)211．67 设备清洁与保养 (11)211．68 自动化设备、机械化设备和电子设备 (12)211．72 过滤器 (13)E. 成分、药品容器和密封件的控制 (13)211．80 总要求 (13)211．82 未检验的成份、药品容器和密封件的接收与贮存 (14)211．84 成分、药品容器和封口物品的试验、批准或拒收 (14)211.86 获准的成份、药品容器和密封件的使用 (17)211.87 获准的成份、药品容器＆密封件的复检 (17)211.89 拒收的成份、药品容器＆封口物品 (17)211.94 药品密容器和密封件 (18)F. 生产和加工控制 (18)211.100 成文的规程，偏差 (18)211.101 成份的进料 (19)211.103 产量计算 (20)211.105 设备鉴别 (20)211.111 生产时间限制 (21)211.113 微生物污染的控制 (21)211.115返工 (21)G、包装和标签控制 (22)211．122材料的检查和使用标准 (22)211．125标签的发放 (23)211．130包装和标签操作 (24)211．132人用非处方药（OTC）保险包装的要求 (25)211．134药品检查 (29)211．137有效期 (29)H．贮存和销售 (30)211．150 销售程序 (30)I 实验室控制 (31)211．160 总要求 (31)211．165 销售要求的检验与发放 (32)211．166 稳定性试验 (34)211．167 特别检验要求 (35)211．170 样品保存 (36)211．173 实验动物 (38)211．176 青霉素污染 (38)J．记录和报告 (39)211．180 总要求 (39)211．182 设备清洁和使用记录 (41)211．184 成份、药品容器、密封件及标签的记录 (41)211．186 主要生产和控制的记录 (42)211．188 批生产和控制记录 (44)211．192 产品记录复查 (45)211．194 实验室记录 (45)211．196 销售记录 (47)211．198 投诉档案 (48)K．退回的药品和回收处理 (50)211．204 退回的药品 (50)211．208药品的回收处理 (51)Subpart A-General Provisions§211.1 Scopea)The regulations in this part contain theminimum current good manufacturing practice for preparation of drug products for administration to humans or animals.b)The current good manufacturing practiceregulations in this chapter, as they pertain to drug products, and in parts 600 through 680 of this chapter, as they pertain to biological products for human use, shall be considered to supplement, not supersede, the regulations in this part unless the regulations explicitly provide otherwise. In the event it is impossible to comply with applicable regulations both in this part and in other parts of this chapter or in parts 600 through 680 of this chapter, the regulation specifically applicable to the drug product in question shall supersede the regulation in this part.c)Pending consideration of a proposedexemption, published in the Federal Register of September 29, 1978, the requirements in this part shall not be enforced for OTC drug products if the products and all their ingredients are ordinarily marketed and consumed as human foods, and which products may also fall within the legal definition of drugs by virtue of their intended use. Therefore, until further notice, regulations under part 110 of this chapter, and where applicable, parts 113 to 129 of this chapter, shall be applied in determining whether these OTC drug products that are also foods are manufactured, processed, packed, or held under current good manufacturing practice.§211.3 Definitions.The definitions set forth in §210.3 of this chapter apply in this part. A．总则211．1 范围（a）本部分的条例包含人用或兽用药品制备的现行最低限度的药品生产管理规范（GMP）。
美国药品分析实验室CGMP的实施和操作
建立和管理CGMP的分析实验室
• 一套全面和适用的SOP • SOP-9.标准规定的建立 ，批准和管理
• 产品的标准规定是保证产品质量的证书. 必须建立制定原材料,原料药 和产品标准规定的程序. 列出建立USP, EP, BP和CP标准规定的程序 和要求, 尤其是对建立本厂产品的标准规定, 要对这一程序有明确的规 定并列出详细的要求. 对标准规定的格式和编号也应规格化. 制定标准 规定正式化的过程, 正式启用的要求, 进行修订的程序和文件管理的规 定. 这样才能保证产品的测试项目的标准规定不会因人为的意愿而改 变. • 在研发阶段的标准规定是允许定为<报告结果>或将指标范围定得很宽, 留有余地.
建立和管理CGMP的分析实验室
• 建立一套全面和适用地SOP • SOP的格式和内容 • 质保部门应颁布其SOP规定该公司的SOP格式, 编号的定义, 内容中各段节的排列及SOP审核和批 准的责任。 • 通常SOP含有: 标题, 所涉及的部门, 序号,编号, 应 用范围, 责任部门管理人, 程序, 有效之日, 页数, 审核人签名和审批人签名. 必须有专栏列出修改 SOP的原因。
建立和管理CGMP的分析实验室
• 一套全面和适用的SOP • SOP-11.验证分析方法的程序, 批准和 管理
• 测试GMP产品的分析方法必须是经过验证的. FDA是要求 按照ICH的指导文件来进行分析方法的验证. 因此应对其 过程制定标准操作程序. 建立方法验证方案的程序、针对 各类分析方法, 列出对各项验证实验的要求, 制定验证报告 的格式, 修订验证报告的要求和文件管理的规定. • 这一内Байду номын сангаас将专题介绍.
建立和管理CGMP的分析实验室
• 一套全面和适用的SOP • SOP-7. 使用和管理测试仪器的使 用记录本
Production and Process Controls(cGMP培训系列6)
பைடு நூலகம்
Sec. 211.100 Written procedures; deviations. (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.
Sec. 211.100 Written procedures; deviations. (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.
ICHQ7(中英文)
精心整理INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH H ARMONISED T RIPARTITE G UIDELINEG OOD M ANUFACTURING P RACTICE G UIDE FOR A CTIVE P HARMACEUTICAL I NGREDIENTSQ7Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 10 November 2000, this guideline is recommended for adoption to the three regulatory parties to ICHTable of Contents 目录1. INTRODUCTION 1. 前言1.1 Objective 1.1 目的1.2 Regulatory Applicability 1.2 法规的适用性1.3 Scope 1.3 范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1 总则2.2 Responsibilities of the Quality Unit(s) 2.2 质量部门的责任精心整理2.3 Responsibility for Production Activities 2.3 生产的职责2.4 Internal Audits (Self Inspection) 2.4 内部审计（自检）2.5 Product Quality Review 2.5 产品质量回顾3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.1人员资格3.2 Personnel Hygiene 3.2 个人卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和建造4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 特殊限制4.5 Lighting 4.5 照明5.3 Calibration7.4 Storage8.2 Time Limits9.1 General9.3 Label Issuance and Control 9.3 标签发放与管理9.4 Packaging and Labeling Operations 9.4 包装和贴签管理10. STORAGE AND DISTRIBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 入库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室管理11.1 General Controls 11.1通则11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的检测11.3 Validation of Analytical Procedures 11.3 分析方法的验证11.4 Certificates of Analysis 11.4 检验报告11.5 Stability Monitoring of APIs 11.5 原料药的稳定性考察11.6 Expiry and Retest Dating 11.6 有效期和复验期11.7 Reserve/Retention Samples 11.7 留样12. VALIDATION 12.验证精心整理12.1 Validation Policy 12.1 验证方针12.2 Validation Documentation 12.2 验证文件12.3 Qualification 12.3 确认12.4 Approaches to Process Validation 12.4 工艺验证的方法12.5 Process Validation Program 12.5 工艺验证的程序12.6 Periodic Review of Validated Systems 12.6 对已验证的系统的定期回顾12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析方法的验证13. CHANGE CONTROL 13.变更控制14. REJECTION AND RE-USE OF MATERIALS 14.物料的拒收和再利用14.1 Rejection 14.1 拒收14.2 Reprocessing 14.2 返工14.3 Reworking 14.3 重新加工14.5 Returns17.5 Stability18.1 General19.1 General19.2 Quality19.5 Production19.6 Validation19.7 Changes20. Glossary1. INTRODUCTION 1. 简介1.1 Objective 1.1 目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.本文件旨在提供在适当的体系下为了控制生产原料药的质量而实施的药品生产质量管理规范（GMP）的指南。
CGMP文件_稳定性试验研究程序SOP
4.0 责任 Responsibility :
4.1 QC 负责进行稳定性研究样品的分析。 The responsibility of performing the analysis of stability samples lies with Quality control.
4.2 QA 负责监督稳定性计划的执行，负责稳定性数据的审核和评估。
3.2 复验日期 Retest Date:
签名/日期 Sign / Date
名字 Name 职务 Designation
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
Page No.: 4 of 13
5.1.2.5 返工/重新加工的批次 Reprocessed/Reworked batches
标准操作程 序
Standard Operating Procedure
文件编码 Doc. No.: 颁发日期： Issue Date:
替代： Supersedes:
标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
生效日期： Effective Date: 复审日期： Review Date: 页码：第 1 页共 13 页 Page No.: 1 of 13
4.1 QC 负责进行稳定性研究样品的分析。 The responsibility of performing the analysis of stability samples lies with Quality control.
4.2 QA 负责监督稳定性计划的执行，负责稳定性数据的审核和评估。
3.2 复验日期 Retest Date:
签名/日期 Sign / Date
名字 Name 职务 Designation
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
制定人 Prepared by
审核人 Reviewed by
批准人 Approved by
文件编码 Doc. No.: 标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
Page No.: 4 of 13
5.1.2.5 返工/重新加工的批次 Reprocessed/Reworked batches
标准操作程 序
Standard Operating Procedure
文件编码 Doc. No.: 颁发日期： Issue Date:
替代： Supersedes:
标题：稳定性研究程序 TITLE: PROCEDURE FOR STABILITY STUDIES
生效日期： Effective Date: 复审日期： Review Date: 页码：第 1 页共 13 页 Page No.: 1 of 13
ICH-Q7(中英文对照)【范本模板】
Q7a（中英文对照）FDA原料药GMP指南Table of Contents 目录1。
INTRODUCTION 1。
简介1.1 Objective 1.1目的1.2 Regulatory Applicability 1。
2法规的适用性1.3 Scope 1。
3范围2。
QUALITY MANAGEMENT 2.质量管理2。
1 Principles 2。
1总则2。
2 Responsibilities of the Quality Unit（s) 2。
2质量部门的责任2。
3 Responsibility for Production Activities 2。
3生产作业的职责2。
4内部审计（自检）29589 7395 玕€32268 7E0C 縌21637 5485咅-26995 6973 楳2。
4 Internal Audits （Self Inspection)2.5 Product Quality Review 2。
5产品质量审核3. PERSONNEL 3。
人员3。
1 Personnel Qualifications 3。
人员的资质3.2 Personnel Hygiene 3.2 人员卫生3.3 Consultants 3。
3 顾问4。
BUILDINGS AND FACILITIES 4。
建筑和设施4.1 Design and Construction 4。
1 设计和结构4.2 Utilities 4.2 公用设施4。
3 水ct[？d＃37711 934F 鍏4。
3 Water4。
4 Containment 4.4 限制4。
5 Lighting 4.5 照明4。
6 Sewage and Refuse 4。
6 排污和垃圾4。
7 Sanitation and Maintenance 4.7 卫生和保养5. PROCESS EQUIPMENT 5。
工艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and Cleaning 5。
cGMP条款培训课件
10
组织与人员（二）
• 211.25人员资格 • （a） 每位从事药品生产、加工、包装或仓贮工作人员，应接受培训、
教育及有实践经验，完成委派的各项职务。培训是按照现行GMP（包 括本章中的现行GMP条例和这些条例要求的成文程序）中涉及雇员的 内容。邀请合格人员指导，并连续多次培训，保证雇员熟悉现行GMP 对他们的要求。 • （b） 负责监督药品的生产、加工、包装或仓贮工作的每一个工作人 员，应受教育、培训及有经验，完成委派的各项职务。以此作为提供 药品具有安全性、均一性、效价或含量、质量及纯度的保证。 • （c） 有足够量监督每种药品的生产、加工、包装或仓贮的合格人员。
（d） 任何人，在任何时间，明显地表现出现有影响药品安全性和质量 的疾病或开放性损伤，应避免接触各种成份、药品容器、包装设备、 密封件、中间体，直至病愈或经医学测定认为对药品安全性及质量 无危害性时为止。教育所有人员，报告监督人员对药品有不利影 响的健康情况。
• 211.34顾问：为了对问题提出意见，聘请顾问。顾问应对药品生产、 加工、包装或仓贮提出建议，他们受过足够的教育、培训，且有丰富 的实践经验。保留他们的姓名、地址、任何的顾问资格及服务形式等 履历资料。
• (b) 凡是在药品生产、加工、包装或贮存过程中存在任何不符合本部分 及21CFR 211—226部分中陈述的法规的药品，依据联邦食品、药品及 化妆品法501 (a)(2)-(B)，该药应被视为劣药，同时导致该事故发生的 负责人应受相应的法规的制裁。
PPT学习交流
3
定义（一） • (1) 法(Act) 指联邦食品、药品及化妆品法，修订版(21 U.S.C 301 et seq.)。 • (2) 批(Batch) 指在规定限度内，按照某一生产指令在同一生产周期内生产出来的， 具有同一性质和质量的一定数量的药品或其它物料。 • (3) 组分(Component) 指用于药品生产的所有成份，包括那些未在药品中出现的成份。 • (4) 药品(Drug Product) 指成品制剂(如：片剂、胶囊剂、口服液等)，通常含有一种活性成份 并伴有非活性成份(但不是必需的)。本术语也包括不含有活性成份但 作为安慰剂使用的成品制剂。 • (5) 纤维(Fiber) 指长度大于其宽度的3倍的任何微粒状污染物。
ICHQ7(中英文)
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH H ARMONISED T RIPARTITE G UIDELINEG OOD M ANUFACTURING P RACTICE G UIDE FOR A CTIVE P HARMACEUTICAL I NGREDIENTSQ7Current Step 4 versiondated 10 November 2000This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.中英文对照Q7Current Step 4 versionG OOD M ANUFACTURING P RACTICE G UIDE FOR A CTIVE P HARMACEUTICAL I NGREDIENTSICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 10 November 2000, this guideline is recommendedfor adoption to the three regulatory parties to ICHTable of Contents 目录1. INTRODUCTION 1. 前言1.1 Objective 1.1 目的1.2 Regulatory Applicability 1.2 法规的适用性1.3 Scope 1.3 范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1 总则2.2 Responsibilities of the Quality Unit(s) 2.2 质量部门的责任2.3 Responsibility for Production Activities 2.3 生产的职责2.4 Internal Audits (Self Inspection) 2.4 内部审计（自检）2.5 Product Quality Review 2.5 产品质量回顾3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.1人员资格3.2 Personnel Hygiene 3.2 个人卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和建造4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 特殊限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 污物和废弃物4.7 Sanitation and Maintenance 4.7 卫生和维护5. PROCESS EQUIPMENT 5. 工艺设备5.1 Design and Construction 5.1 设计和建造5.2 Equipment Maintenance and Cleaning 5.2 设备维护和清洁5.3 Calibration 5.3 校验5.4 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECORDS 6. 文件和记录6.1 Documentation System and Specifications 6.1 文件系统和质量标准6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使用记录6.3 Records of Raw Materials,Intermediates, 6.3 原料、中间体、原料药的标签和包装材料的记录API Labeling and Packaging Materials6.4 Master Production Instructions 6.4 主生产指令（主生产和控制记录）(Master Production and Control Records)6.5 Batch Production Records 6.5 批生产记录（批生产和控制记录）(BatchProduction and Control Records)6.6 Laboratory Control Records 6.6 实验室控制记录6.7 Batch Production Record Review 6.7 批生产记录审核7. MATERIALS MANAGEMENT 7. 物料管理7.1 General Controls 7.1 一般要求7.2 Receipt and Quarantine 7.2 接收和待验7.3 Sampling and Testing of Incoming Production Materials 7.3 来料的取样与检测7.4 Storage 7.4 储存7.5 Re-evaluation 7.5 再评价8. PRODUCTION AND IN-PROCESS CONTROLS 8. 生产管理和生产过程控制8.1 Production Operations 8.1 生产管理8.2 Time Limits 8.2 时限8.3 In-process Sampling and Controls 8.3 生产过程中的取样和控制8.4 Blending Batches of Intermediates or APIs 8.4 中间体或原料药的混批8.5 Contamination Control 8.5 污染控制9. PACKAGING AND IDENTIFICATION 9. 原料药和中间体的包装和贴签LABELING OF APIs AND INTERMEDIATES9.1 General 9.1 通则9.2 Packaging Materials 9.2 包装材料9.3 Label Issuance and Control 9.3 标签发放与管理9.4 Packaging and Labeling Operations 9.4 包装和贴签管理10. STORAGE AND DISTRIBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 入库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室管理11.1 General Controls 11.1通则11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的检测11.3 Validation of Analytical Procedures 11.3 分析方法的验证11.4 Certificates of Analysis 11.4 检验报告11.5 Stability Monitoring of APIs 11.5 原料药的稳定性考察11.6 Expiry and Retest Dating 11.6 有效期和复验期11.7 Reserve/Retention Samples 11.7 留样12. VALIDATION 12.验证12.1 Validation Policy 12.1 验证方针12.2 Validation Documentation 12.2 验证文件12.3 Qualification 12.3 确认12.4 Approaches to Process Validation 12.4 工艺验证的方法12.5 Process Validation Program 12.5 工艺验证的程序12.6 Periodic Review of Validated Systems 12.6 对已验证的系统的定期回顾12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析方法的验证13. CHANGE CONTROL 13.变更控制14. REJECTION AND RE-USE OF MATERIALS 14.物料的拒收和再利用14.1 Rejection 14.1 拒收14.2 Reprocessing 14.2 返工14.3 Reworking 14.3 重新加工14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收14.5 Returns 14.5 退货15. COMPLAINTS AND RECALLS 15.投诉与召回16. CONTRACT MANUFACTURERS 16.协议生产商（包括实验室）(INCLUDING LABORATORIES)17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, 17.代理商、经纪人、贸易商、经销商、重新包装者REPACKERS, AND RELABELLERS 和重新贴签者17.1 Applicability 17.1 适用性17.2 Traceability of Distributed APIs and Intermediates 17.2 已分发的原料药和中间体的可追溯性17.3 Quality Management 17.3 质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4 原料药和中间体的重新包装、重新贴签和待检17.5 Stability 17.5 稳定性17.6 Transfer of Information 17.6 信息的传达17.7 Handling of Complaints and Recalls 17.7 投诉和召回的处理17.8 Handling of Returns 17.8 退货的处理18. Specific Guidance for APIs Manufactured by Cell 18. 用细胞繁殖/发酵生产的原料药的特殊指南Culture/Fermentation18.1 General 18.1 总则18.2 Cell Bank Maintenance and Record Keeping 18.2 细胞库的维护和记录的保存18.3 Cell Culture/Fermentation 18.3 细胞繁殖/发酵18.4 Harvesting, Isolation and Purification 18.4 收取、分离和精制18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤19. APIs for Use in Clinical Trials 19. 用于临床研究的原料药19.1 General 19.1 总则19.2 Quality 19.2 质量19.3 Equipment and Facilities 19.3 设备和设施19.4 Control of Raw Materials 19.4 原料的控制19.5 Production 19.5 生产19.6 Validation 19.6 验证19.7 Changes 19.7 变更19.8 Laboratory Controls 19.8 实验室控制19.9 Documentation 19.9 文件20. Glossary 20. 术语1. INTRODUCTION 1. 简介1.1 Objective 1.1 目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.本文件旨在提供在适当的体系下为了控制生产原料药的质量而实施的药品生产质量管理规范（GMP）的指南。
CAPA(cGMP培训系列2)_2
• Nonconformities are cited during inspection,
and corrective action plan required.
• Warning Letter– more serious, available
to the public
• Fines, stop product
4
What are the symptoms of an eCAfPfAecstyisvteem? 好的预防纠偏系统有 那些特征？
• A reduction in quality i•sAsureesduction in the severity of i•sMsourees preventive actions over t•iMmoere consistent p•rIomdpurcotvse/dprcoucsetsosmeesr s•aBteitstfearctbiuosniness results
auodbistervations, ianutdeirtnsaland external audits
• Quality Records
▫ Periodic r▫evPireowcess c▫onTtersotling results, trends,
• Peotsct Market
dat▫a Frequency and
used
• Document
▫ Dates of i▫nvDeasttaigraetviioenwed (data
sources, records, dates)
Cause and Effect, 6 M’s 5 Why’s, etc.
▫ Corrections or
and corrective action plan required.
• Warning Letter– more serious, available
to the public
• Fines, stop product
4
What are the symptoms of an eCAfPfAecstyisvteem? 好的预防纠偏系统有 那些特征？
• A reduction in quality i•sAsureesduction in the severity of i•sMsourees preventive actions over t•iMmoere consistent p•rIomdpurcotvse/dprcoucsetsosmeesr s•aBteitstfearctbiuosniness results
auodbistervations, ianutdeirtnsaland external audits
• Quality Records
▫ Periodic r▫evPireowcess c▫onTtersotling results, trends,
• Peotsct Market
dat▫a Frequency and
used
• Document
▫ Dates of i▫nvDeasttaigraetviioenwed (data
sources, records, dates)
Cause and Effect, 6 M’s 5 Why’s, etc.
▫ Corrections or
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• Microbial微生物
– Understand impurities/degradation products
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Stability Testing适用范围
• Stability Testing
– Drugs and Cosmetics – Combination Drug/Devices where the drug component is the regulating factor
– Package Integrity – Color, odor, taste, etc
• Chemical化学性能
– Active ingredient – pH, specific gravity, viscosity, etc – Adhesive, polymer residuals, etc
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QP 101 – Cosmetics
• Cosmetic products requiring stability studies will be allowed to proceed to market after a minimum of 3 months testing has been successfully achieved at accelerated conditions (as per Section 5.1). The stability study protocol will continue to its planned conclusion. Freeze/thaw studies may be a part of the stability protocol.
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ICH Guidelines ICH纲要
• Three production lots or scalable pilot lots that simulate the conditions of production.三批次 • ICH Guidelines温度和湿度 – International Committee on Harmonization • Accelerated - 40º C/75% RH – 3 months = 1 year – 6 months = 2 years • Real Time - 25º C/60% RH • Intermediate - 30º C/65% RH
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Why Perform Stability Testing or Aging Studies?为什么要做稳定性测试
•Shelf life (Expiration Date) determination – Maintain acceptance criteria properties保质期
• Physical物理性能
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QP 101 – Cosmetics
• Expiration dated cosmetic products will require two pilot or production lots for stability study purposes. If production lots are not used for stability study, one primary batch can be submitted for study using pilot batch manufacturing equipment. The remaining pilot batch is to be made at a minimum of 10% of the production batch volume.
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QP 101 – Medical Devices医疗器械
• The initial stability study samples will be taken from the OQ validation run. Additional stability study samples that are needed as indicated by the study protocol will be taken from the PQ validation runs. • Where only the physical characteristics of the device (appearance, color, etc) are being evaluated, ASTM procedure F1980-02 on aging can be followed. The study author will establish the conditioning temperature and conditioning time to achieve the desired theoretical shelf does Medline have for stability study ?美联怎么做的？
QP101
10
QP 101 – Basics基础
• Applies to all to Over the Counter (OTC) and prescription pharmaceuticals, cosmetic formulations, medical devices (requiring formulation) and other products requiring stability studies to establish a shelf life or expiration date. • Protocol • Enough samples to perform all tests during each time period • Progress Reports • Report with analysis of data
药 化妆品 含药医疗器械
6
Accelerated Aging
• Rapidly determine the effects due to the passage of time and environmental effects on the sterile integrity of packages and the physical properties of their component packaging materials. • Subjecting the package to severe stress for a short period of time to simulate stress over a longer period of time. • Performed in a controlled temperature environment.
16
QP 101 – Final Items成品
• At least one production lot per year will be submitted for long term real time study for the lifetime of its established dating or the expected time the product will remain in distribution. Testing of production lots will follow the requirements of the original stability study protocol. Temperature and humidity measurements of the real time storage area will be performed daily. 每年每产品取一批次持续进行稳定性测试，与最初的稳 定性测试计划相同。
7
Stability (211.166) FDA规定
• Must be a written program designed to assess the stability characteristics of drug products.测试计划 • Evaluate samples using pre-determined specifications at pre-determined test intervals衡量标 准 • Adequate number of batches tested样品数目 • Can be marketed with accelerated at risk but must be confirmed with real time加速稳定性 • Initial (prior to marketing) and On-Going (annual lots)初始测试 年试 • Follow ICH Guidelines for accelerated and real time conditions以ICH为准
1
Stability
GMP Training Module 6
2
ICH Q 1A (R2) guideline for stability study制药业国际协调会规定
According to ICH Q1A (R2) guidelines “the purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light”. 简而言之，就是质量随外界影响
11
QP 101 – Protocols/Reports 试验计划和报告
• A protocol will be established and approved before initiation of stability studies. • At any analysis time interval where a stability study has fallen outside accepted analysis limits or physical characteristic parameters, a study summary will be issued and the approvers of the protocol will be required to approve the summary report. • At the conclusion of a stability study, a summary report will be issued by the study coordinator with a discussion of the results and a recommendation of the apparent shelf life of the item.