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MODULE 3: QUALITY3.1 TABLE OF CONTENTS OF MODULE 3MODULE 3: QUALITY -13.1 TABLE OF CONTENTS OF MODULE -13.2 BODY OF DATA-33.2.S DRUG SUBSTANCE-33.2.S.1 General Information-3 一般信息3.2.S.1.1 Nomenclature -3 命名3.2.S.1.2 Structure-4 结构3.2.S.1.3 General Properties-5 一般性质3.2.S.2 Manufacture-6 生产3.2.S.2.1 Manufacturer-6 生产商3.2.S.2.2 Description of Manufacturing Process and Process Controls-16 生产过程描述和过程控制描述3.2.S.2.3 Control of Materials-27 物料控制3.2.S.2.4 Controls of Critical Steps and Intermediates-38 关键步骤控制和关键中间体控制3.2.S.2.5 Process Validation and Evaluation-51 工艺验证和评估3.2.S.3 Characterization-61 定性3.2.S.3.1 Elucidation of Structure and Other Characteristics-61 结构和其他特性阐述3.2.S.3.2 Impurities-63 杂质3.2.S.4 Control of Drug Substance-73 原料药控制3.2.S.4.1 Specification and Routine Test Method -73 质量标准和常规检测方法3.2.S.4.2 Analytical Procedures-75 检测操作规程3.2.S.4.3 Validation of Analytical Procedures-78 检测操作规程验证3.2.S.4.4 Batch Analyses -102 批分析3.2.S.4.5 Justification of Specification-103 质量标准的论证3.2.S.5 Reference Standards or Materials-104 参照标准品或参照物质3.2.S.5.1 Classification and control-104 类别和控制3.5.S.5.2 Standard Materials List-105 标准品一览表3.2.S.6 Container Closure System-106 包装密封系统3.2.S.6.1 Packaging Materials Specification-106 包装材料质量标准3.2.S.6.2 Packaging Type-109 包装类型3.2.S.7 Stability-110 稳定性3.2.S.7.1 Stability Summary-110 稳定性总结3.2.S.7.2 Post-approval Stability Protocol-110 批准后的稳定性方案3.2.S.7.3 Stability Data-113 稳定性数据3.2.A APPENDICES-119 附录3.2.A.1 Facilities and Equipment-119 设施和设备3.2A.2 Material Safe Data Sheet-122 原料安全数据表3.3 LITERATURE REFERENCES-126 文献参考3.2 BODY OF DATA3.2.S DRUG SUBSTANCE (3.2.S.1 General Information3.2.S.1一般信息3.2.S.1.1 Nomenclature 3.2.S.1.1 命名 United States Adopted Name美国名称 Pharmacopoeia Name of Product （Compendial Name）药典名称Ph.Eur.4th Edition BP2002 USP26 Active Component Chemical Name of Product （CAS，IUPAC）产品活性成份的化学名（CAS，IUPAC的命名） Company Name or laboratory codes公司名称或实验室代号 Other nonproprietary names(e.g., International Nonproprietary Name(INN), British Approved Name(BAN), Japanese Accepted Name(JAN)其他非专用名称（INN名称，英国名称，日本名称） Chemical Abstracts Service(CAS) Registry Number化学文摘号3.2.S.1.2 Structure 3.2.S.1.2 结构 Structural Formula结构式 Molecular Formula分子式 Molecular Mass分子量 3.2.S.1.3 General Properties3.2.S.1.3一般性质 Physical chemical properties理化性质 A general description ( appearance, color, physical state) 综述(外观、颜色、物理状态) Melting or boiling points 熔点或沸点Solubility profile(aqueous and nonaqueous)溶解度（水溶液或非水溶液） UV maximum absorption最大紫外吸收Particle size颗粒度Density密度Tap density堆密度，Bulk density松密度Solution PH 溶液PH3.2.S.2 Manufacture3.2.S.2 生产3.2.S.2.1 Manufacturer3.2.S.2.1 生产商 Manufacturer Name and Address生产商名称和地址 Production Site Address生产场地地址 Name, telephone number, fax number and e-mail address of a contact person联系人姓名、电话号码、传真号码、E-mail 地址 Manufacturing responsibility生产商职责 Commitment承诺 Organizational Chart and Key Person组织机构图及关键人员 Buildings and Facility建筑和设施 A. Buildings OverviewA. 建筑综述说明厂房占地面积，建筑物数量及建筑面积。提供厂房平面布置图，图中关键建筑物均有标识（仓储、生产、质量控制、维护等）B. Product Manufacturing Site B. 产品生产场所应说明每个生产车间的面积及任何特殊的建筑结构特点（几层楼、总高度、占地面积、建筑面积、共有多少岗位、每层楼有几个岗位，每层楼面积为多少、有无有洁净级别要求的岗位，面积多少） a. Clean Area a. 洁净区b. Utilities b. 公用系统 C. Warehouse Facilities C. 仓储设施 应说明面积及任何特殊的建筑结构特点（几层楼、总高度、建筑面积、房间数等）原料、中间体、成品分别储存在何处，有无调节风扇排风，有无温湿度计。 D. Q. C. Building D. Q. C. 大楼 应说明面积及任何特殊的建筑结构特点（几层楼、总高度、建筑面积、房间数等），E. Equipment E. 设备a. Production Equipmenta. 生产设备 Production Equipment Layout Diagram with Equipment Code Numbers 带有设备编号的生产设备平面布置图 List of Major Production Equipment主要生产设备一览表Manufacturing Equipment List生产设备一览表No.序号Equipment No.设备编号Name 名称Mode型号lMaterial of Construction结构材质Volume (m3)体积(m3)Quantity数量Motor Power (kW)电机功率 Production Equipment Maintenance and Calibration生产设备维护和校验说明生产设备及辅助设备（计量仪表、计量罐等）常规检查、维护及校验的内部程序 b. 实验室设备 b. Laboratory Equipment List of Major Laboratory Equipment主要实验室设备一览表Laboratory Equipment List 实验室设备一览表No.序号Name名称Model No.型号Quantity数量Supplier供应商 Laboratory Equipment Maintenance and Calibration 实验室设备维护和校验描述关键实验设备常规检查、维护及校验的内部程序3.2.S.2.2 Description of Manufacturing Process and Process Controls 生产工艺描述和工艺控制描述 A Flow Diagram( r)流程图A. Synthetic route化学合成路线B. Flow Diagram of Process 工艺流程图 注：1）说明起始材料、中间体、结构复杂的试剂、合成后材料及原料药的化学结构和生物学方面的鉴定2）描述起始材料、中间体、合成后材料和原料药的分子式及分子量3）说明关键的工艺控制及实施这些控制的控制点4） 对中间体是以原样使用还是分离后使用以及何种中间体被认为是最终中间体的说明 Description of Process Step工艺步骤描述A. 溴化反应a. 原材料消耗（原材料配比表）b. 所使用的设备类型（说明关键设备的材料和结构）c. 操作步骤B. 胺化反应a. 原材料消耗（原材料配比表）b. 所使用的设备类型（说明关键设备的材料和结构）c. 操作步骤 C. 成盐反应a. 原材料消耗（原材料配比表）b. 所使用的设备类型（说明关键设备的材料和结构）c. 操作步骤 D. 精制 a. 原材料消耗（原材料配比表）b. 所使用的设备类型（说明关键设备的材料和结构）c. 操作步骤E. 干燥，磨粉F. 包装和贴签G. 成品储存 H. 再加工 对各中间体及成品不合格情况进行的再加工分别进行描述J. 其他操作例对老化材料的提纯以降低降解产品的含量注：1）列出每个步骤中使用的起始材料或中间体的化学或生物名称和使用量，每个步骤中使用的溶剂、试剂和辅料的化学或生物名称和使用量，每个步骤由新的一页开始2）所使用的设备类型且说明关键设备的材料和结构。3）每步反应详细描述应包括反应条件及理论和预期收率，标示关键生产步骤，标示所有工艺控制及其相关数字范围、限制或验收标准（重点突出关键过程控制），对使用recycling 滤液（母液）以回收反应物、中间体或原料药的生产步骤包括获得、分离二次结晶物（二次收割物）的步骤进行标示，对使用回收溶剂或辅料的生产步骤进行标示，对涉及馏分收集及其过程控制、未使用馏分的处理（例如回收）等生产步骤进行标示。说明每个过程检验所用的分析方法，说明对中间体、合成后材料和已检验的非成品原料药的鉴别。应有体现每步反应的批生产记录3.2.S.2.3 Control of Materials 3.2.S.2.3 物料控制 Raw Materials List, Retest date and Supplier原材料一览表，再检测及供应商Raw Materials List , Retest date and Supplier 原材料一览表，再检测及供应商No.编号Code No.代码Grade级别Name名称Retest date再检测日期Manufacturer 生产商 Raw Materials Specification原材料质量标准The COA of raw materials see appendix XXX .原材料的质量分析报告见附件XXX. 1 Material Name : Code No.: 1 原材料名称 : 代码:Grade: 等级Purpose: 用途Item项目Specifications指标Test Methods检测方法See SOP No. .见SOP 编号XXXXXRefer to USP26. 参照USP26Purified Water Code No.:502 纯水 代码.:502Grade: USP26等级：USP26Purpose: 用途：Specifications质量标准Item 项目 Specifications指标TOC总有机碳500ppbWater Conductivity (25)水电导率1.3s/cmTotal CFU总CFU80 CFU/mlBacterial endotoxins细菌内毒素0.25 EU/mlTest Method 检测方法See SOP XXX见 SOP XXXRefer to USP26参照USP263.2.S.2.4 Controls of Critical Steps and Intermediates3.2.S.2.4 关键步骤和关键中间体的控制 Controls of Critical Steps关键步骤的控制A. B.C.D.E.*. Holding Times and Storage Conditions for Materials at Each Step *. 物料在每一步骤中的停留时间和储存条件Name of Step步骤名称Name of Equipment设备名称Temperature()温度()Pressure (MPa)压力(MPa)pHMax. Holding Time (h)最长停留时间 1213*. Water Quality Monitoring & Handling Means When Out-of-specification水质监控和超标时处理方式Water Quality Monitoring & Handling Means When Out-of-specification水质监控和超标时处理方式Item项目NormalRange正常范围AlarmLimits警戒限TestMethods测试方法Period周期Handling whenOut-of-specification超标时的处理Sampling Place取样地点Notes注意事项Potable Water饮用水Purified Water纯化水TOC(ppb)总有机碳(ppb)Conductivity(s/cm)电导率(s/cm)Total CFU/mL总CFU/mlEndotoxin (EU/mL)内毒素(EU/mL)注：对关键步骤，论证其数值范围、限制或验收标准，应包括论证的支持数据、 描述分析方法90 Controls of Intermediates中间体控制A. Intermediates Sampling ProcedureA. 中间体取样程序 B. Intermediates Specification B. 中间体质量标准No.序号 Name of Process过程名称 Name of Material物料名称Item项目Quality Standards质量标准Test Methods检测方法C. Test methods C. 检测方法 3.2.S.2.5 Process Validation and Evaluation 3.2.S.2.5 工艺验证和评估 #List of Major Validation Protocols for the Manufacturing System 生产系统主要验证方案一览表No.序号Name of Protocol方案名称 Utilities?A. Validation on Purified Water SystemA. 纯化水系统验证 B. Validation on Compressed Air System B. 压缩空气系统验证 Environment环境A. Validation on HVAC System A. 空调系统验证 3.2.S.3 Characterisation3.2.S.3 定性 3.2.S.3.1 Elucidation of Structure and Other Characteristics 3.2.S.3.1 结构和其他特性阐述 Physical-chemical Characteristics物理-化学性质A. Characteristics A. 特性B. Melting or boiling points 熔点或沸点C. Solubility profile(aqueous and nonaqueous)溶解度（水溶液或非水溶液） D. UV maximum absorption最大紫外吸收E. Particle size颗粒度F. Tap density堆密度G. Bulk density松密度H. Solution PH 溶液PH Evidence of Chemical Structure化学结构证明A. Infrared Spectra A. 红外光谱 B. Nuclear Magnetic Resonance Spectra B. 核磁共振光谱 C. Mass Spectra C. 质谱 D. X-ray Powder Diffraction Patterns D. 粉末X-光衍射E. Ultraviolet SpectraE. 紫外光谱3.2.S.3.2 Impurities3.2.S.3.2 杂质A complete impurity profiles is available on site, which is summarized on the following pages.有关所有可得到的杂质描述 Impurities Introduction杂质介绍A. Organic Impurities A. 有机杂质 B. Residual SolventsB. 残留溶媒C. Inorganic ImpuritiesC. 无机杂质 Test procedures, results and conclusions检测方法、结果和结论 A. Organic impurities A. 有机杂质Instruments and Reagents:仪器和试剂 Impurity reference solution:杂质参照溶液：Name名称Concentration (g/ml)浓度(g/ml)Solvent溶剂Detect Limit检测限度Testing result: 检测结果： In order to compare the impurities in different batches of the same species of products, we give serial number to the impurities in following table:为比较同类产品中不同批间的杂质，下列表中给出杂质的系列批号：Substance Name: 物质名称The Ret. time and resolution of all impurities and major components: (detailed chromatogram see figure I-1 to figure I-12 of Appendix IV)所有杂质和主成份的保留时间和分离度：（详细的图谱见附录IV的I-1 至 I-12）Name名称Ret. time(min)保留时间Half Width(min)半峰宽(min)Resolution分离度Testing sample introduction:检测样品介绍： Batch No.批号Date of manufacture生产日期Site of manufacture生产地点Manufacturing Process生产工艺Use of batches采用的批Batch size批的大小Reference to analytical procedure used所用的检测方法参照Testing results: (detailed chromatogram see figure 检测结果：（详细的色谱图见图No. of impurities杂质序号Impurities distribution1Ret time(min)保留时间Area (%)面积Name of impurities杂质名称2Ret time(min)保留时间Area (%)面积Name of impurities杂质名称3Ret time(min)保留时间Area (%)面积Name of impurities杂质名称4Ret time(min)保留时间Area (%)面积Name of impurities杂质名称5Ret time(min)保留时间Area (%)面积Name of impurities杂质名称Total amount of impurities (%)杂质总量(%)Note: - 注意：Conclusion: 结论：B. Residual solventB. 残留溶媒Instrument and examine conditions:仪器和检测条件 Reagents: 试剂：Limit of Quantitative定量限Suitability of system testing results 系统适用性试验结果Item项目Specification指标n-butanol正丁醇Ethyl acetate乙酸乙酯Precision精密度Linearity线性Conclusion: 结论：Samples testing results:样品测试结果：(detailed chromatogram see figure )详细图谱见图Batch No.批号 Solvent Name溶剂名称Conclusion for residual solvent analysis: 残留溶媒分析结论：C. Inorganic impurities C. 无机杂质Testing of heavy metals:重金属检测：Methods: see Ph. Eur. 4th Edition 2.4.8方法见Ph. Eur. 4th Edition 2.4.8Result:结果 Name名称Batch No.批号Result结果Conclusion: 结论：Testing of * item项目XXX的检测Methods: s 方法：sResult:结果Name名称Batch No.批号Result结果Conclusion: 结论：Testing of XXXX的检测Methods: see P 方法见PResult:结果Name名称Batch No.批号Result结果Conclusion: 结论 Total conclusion for impurity analyses:杂质分析的总结论：3.2.S.4 Control of Drug Substance3.2.S.4 原料药的控制3.2.S.4.1 Specification and Routine Test Method3.2.S.4.1 质量标准和常规检测方法Item项目Specifications指标Test Methods检测方法Tested by检测者Refer to参照xx药典第xx版，xx药典xx版3.2.S.4.2 Analytical Procedures3.2.S.4.2 检测规程3.2.S.4.3 Validation of Analytical Procedures3.2.S.4.3 检测规程验证 Method方法 Instruments and testing conditions仪器和检测条件 Validation items and results 验证项目及结果Accuracy:准确度： Table for Recovery rate 回收率表 Level of concentration浓度Serial No.系列号Content of XXX含量Content of XXX含量 Recovery rate of XXX回收率Recovery rate回收率 Conclusion: The range of * is from 98.77% to 99.90%, the range of the * is from 99.75% to 101.08%. All of the deviation range is between 100 + 2, so the accuracy is good. 结论：Precision: 精密度Repeatability:重复性：Inject standard solution and sample solution respectively, calculate the content of * 6 times parallel test is conducted. The following table is for the changes of the peak area, which can meet the requirements of RSD2.0%( Ph.Eur.4th Edition).将标准溶液和样品溶液分别进样，计算*6次平行实验的结果。下表列出了峰面积的变化，可满足RSD2.0%( Ph.Eur.4th Edition)的要求。The result is in the following table. ( 结果列于下表：No.序号Content of Pen-PPen-P含量Content of Pro-HPro-H含量123456Average平均RSD相对标准差 Conclusion: From the above result, the repeatability is good. 结论：由上述结果得出，重现性佳 Intermediate Precision: 中间精密度（重现性） Inject standard solution and sample solution respectively, calculate the content of There are 3 times parallel test every day and continuous 3 days(in 3days,one standard and sample are used).Person and instrument may be changed randomly, which can meet the requirements of RSD2.0%(the precision of one day)and RSD3.0%(the precision of different day). 将标准溶液和样品溶液分别进样，计算*含量。每天进行3次平行试验，持续3天（在3天中，只采用一个标准溶液和一个样品）The result is in the following table: (结果如下表Time时间No.序号Content of Pen-PPen-P含量Content of Pro-HPro-H含量The first day第一天123Average平均RSDTime时间No.The second day第二天123Average平均RSDTime时间No.The