制剂产品工艺验证 模版 - 图文

甲苯咪唑片工艺验证草案

Process Validation Protocol

甲苯咪唑片100mg制造工艺验证

Process validation of Mebendazole 100mg Tablets

目录CONTENT TABLE

目录CONTENT TABLE ........................................................................................................................ 2 1.

1.1 1.2 1.3 1.4

背景介绍INTRODUCTION .......................................................................................... 4

验证产品基本信息BASIC INFORMATION OF VALIATIONED PRODUCT ................. 4 背景Background ........................................................................................................................ 4 目的Purpose ............................................................................................................................... 4 范围Scope ................................................................................................................................... 5

2. 3.

3.1 3.2 3.3 3.4

责任RESPONSIBILITY ................................................................................................ 7 方法APPROACH ........................................................................................................... 8

工艺验证与验证批释放Process validation and release of the validation batch .................. 8 Comparison to biobatch ............................................................................................................. 8 稳定性研究Stability study to this process validation ............................................................. 8 与工艺验证相关的清洁验证Cleaning validation related to this process validation ........... 8

3.5 分析方法与IPC/释放标准Analytical method overview including IPC /release specifications ...................................................................................................................................................... 9 3.6

结果记录与评估的方法Methods for recording & evalusting results ................................... 9

4.

4.1

工艺介绍PROCESS ..................................................................................................... 10

产品处方Product Formulation ............................................................................................... 10

4.1.1 处方Formulation............................................................................................................. 10

4.1.2 原材料合格供户清单Qualified suppliers List of raw materials ................................. 11

4.2 4.3 4.4 4.5

接触容器Immediate containers .............................................................................................. 12 生产设备和设施Manufacturing Equipment and Facility .................................................... 12 工艺流程图Process Flow Diagram ......................................................................................... 13 关键工艺参数与变量Critical Process Parameters and Variables ...................................... 14

5

5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9

工艺验证过程PROCESS VALIDATION .......................................................................... 15

粘合液制备Prepare binding solution ..................................................................................... 15 干混工序Dry-mixing (Pre-mixing) ......................................................................................... 17 湿法制粒和干燥工序Wet Granulation and Drying ............................................................. 19 整粒工序Breaking .................................................................................................................... 22 不加硬脂酸镁的混合Mixing without Magnesium stearate ................................................. 23 加硬脂酸镁的混合Mixing with Magnesium stearate ........................................................... 25 中间体桶料In drums ............................................................................................................... 29 压片工序The tableting process ............................................................................................... 31 贮存时间Holding time study ................................................................................................... 35

6 验证中偏差/变更处理DEVIATION AND CHANGE HANDLING...................................... 37

7 8

培训TRAINING ............................................................................................................... 37 参考文献REFERENCE ..................................................................... 错误！未定义书签。

1. 背景介绍INTRODUCTION

1.1 验证产品基本信息BASIC INFORMATION OF VALIATIONED PRODUCT

产品名称 PRODUCT NAME: 剂量 STRENGTH: 标示重量 NORMAL WEIGHT 批记录编号 BPR CODE 本次验证工艺步骤 PRODUCTION STEP: 甲苯咪唑片 Mebendazole Tablets 物料编码 MATERIAL CODE: 亚批次 SUB-BATCHES 批量 BATCH SIZE: 变更控制 编号 CCN: 制粒/整粒/混合/压片Granulating/Breaking/Mixing/Compressing 1.2 背景Background

生产的甲苯咪唑100mg口服片剂的主要成分是甲苯咪唑，自1988年投放到生产后，先后进行了三次工艺验证，详细情况参见下表。

次数No 1 时间 Time 报告号 Report code 验证内容 Content 结果 Results 合格 Pass 合格 Pass 合格 Pass 2 3 自2001年验证完成后，A的生产工艺和生产设备均没有发生变更，未出现与工艺相关的不符合事件。依据中国cGMP第七章/第58条、工艺验证管理程序SMP-VMP006有关周期性再验证的规定，在2001年成功实施工艺验证后在2006年需要对A100mg口服片剂的制造工艺再次进行全面的验证，确保现行的工艺流程可以继续稳定、持续的生产出合格的产品。 1.3 目的Purpose

该方案的目的是The purpose of this protocol is to:

?

确认所需验证的工艺能够有效并重复地生产出符合所有事先确定的质量标准与品质的中间产品，并且如果适用的话，确认在制造完成后至包装开始前的预先设定的中间品保留时间能够始终一致地保证中间产品的质量特性。

?

提出一个工艺验证方案。该方案确定在实际操作条件下需要监控的关键工艺参数和变量，概括对中间品样品的取样与检测的要求，并规定工艺监控及产品检测的接受标准。

更具体而言，本次工艺再验证工作的目的是用书面证据来证明当运行操作正确时，A100mg口服片剂的生产工艺过程能够始终一致地生产出符合已确定的接受标准的产品。 1.4 范围Scope

本验证草案适用于甲苯咪唑100mg片的制造工艺再验证，依据本次验证的目的，在本次验证中将要研究的工艺步骤如下：

No 工艺步骤 Process step 简述 Description 将物料微晶纤维素101、微粉硅胶、甲苯咪唑和羧甲淀粉钠按顺序过筛粉 Sieving 筛并收集于一步制粒机容器中。 Pass ingredients （Microcrystalline Cellulose 101, Colloidal Anhydrous Silica, Mebendazole and Carboxymethylstarch Sodium） through Sweco 800L into the container of WSG-UD-200 验证范围 Scope 适用Applicable 不适用Not Applicable 1 2 制备粘合液 Binder solution 将糖精钠、日落黄、十二烷基硫酸钠（进口）加入中制成色液，同时制成淀粉浆，将色液加入淀粉浆中搅拌均匀 过筛后的物料在1/B/R01 混合均匀。关键参数包括阀控制压力、工作适用Applicable 不适用Not Applicable 适用Applicable 不适用Not Applicable 3 干混 Dry mixing 压力、排风阀位臵、进风温度和混合时间 Mix the materials from sieving to homogeneous with 1B/R01. critical parameters include Control pressure of valves, Operating pressure, Exhaust-air flap, Inlet-air temp. and Premixing time 利用喷液泵向混合后物料中喷入淀粉浆后再喷入已溶于2335ml异丙醇的桔子香精和500ml的异丙醇。关键参数包括喷液压力、进风温度、适用Applicable 不适用Not Applicable 4 喷液 Spraying 排风阀位臵、喷嘴口径、喷嘴数目和泵速 Spray the solution into mixed material with spray pump. Then spray the Flavour solution and isopropanal onto granules. critical parameters include Spraying pressure, Inlet-air temp., Exhaust-air flap, Nozzle diameter, Number of nozzles and Pump speed 5 颗粒干燥 Drying 关键参数包括进风温度和产品温度 critical parameters include Inlet-air temp. and Product temp. 用整粒机将1/2亚批的物料整粒 适用Applicable 不适用Not Applicable 适用Applicable 不适用Not Applicable 7 整粒 Breaking Pass the 1/2 subbatch through 1/B/S02 & collect in the 1/B/R02-V2 用整粒机将物料微晶纤维素101、滑石粉与2/2亚批的物料整粒Check and pass the materials （Microcrystalline cellulose 101 and Talc）& 2/2 subbatch through 1/B/S02 & collect in 1/B/R02-V2。 加硬脂酸镁前混合将收集到混合机的两个亚批物料进行混合。关键参数包括混合时间和转速 Mixing the two subtach materials from breaking step. Critical parameters include mxing time and speed. 使用20目不锈钢筛对硬脂酸镁进行手工过筛，然后加入到混合机中混适用Applicable 不适用Not Applicable 8 Blending without Magnesium stearate 适用Applicable 不适用Not Applicable 9 终混Final bleanding 合均匀。关键参数包括混合时间和转速 Sieving the Magnesium stearate with S.S Sieve 20mesh and then add

No 工艺步骤 Process step 简述 Description it into mixing machine 1/B/R02-V2. Critical parameters include mxing time and speed. 验证范围 Scope 10 11 装桶 In drums 中间体贮存 Granula holding 装桶储存 Filling in drums 在半成品库存放至压片工序开始 Storage in HFP warehourse till compression 在压片机上用双凹冲将物料压成片子，直接装入带盖100L不锈钢桶中 适用Applicable 不适用Not Applicable 适用Applicable 不适用Not Applicable 适用Applicable 不适用Not Applicable 12 压片 Tableting The mixture is pressed to circular tablets by the tablet press machine (1/C/K01, 1/C/K02) using biconcave punches. Transfer the tablets into s.s. buckets with a cover. 13 半成品贮存 Tablet holding 在半成品库存放至包装工序开始 Storage in HFP warehourse till packaging 适用Applicable 不适用Not Applicable 甲苯咪唑片100mg的制造工艺参见生产批记录BPR2340 05，其中筛粉、制粒和整粒等工艺步骤为两个亚批分别进行生产，在混合阶段合为一个整批。

2. 责任RESPONSIBILITY

部门 Department 姓名 职责 Name Responsibility 验证协调人Validation corrdinator ? 起草验证草案Draft protocol 负责验证数据的收集及数据分析Collect and analysis the validation results 负责对相关人员进行培训，确保验证工作按草案进行Train related person 协调进行验证中可能出现的偏差的调查、完成变更的书面记录、完成验证报告Coordinate the deviation and change handling during validation, draft validation report 新产品与技术支持 NPI&TS ? ? ? 车间协调人Corrdinator in workshop ? 负责安排具有资格的操作人员及IPC人员开展验证工作Responsible for arranging qualified operator and IPC tester 负责设备的清洁、安装、生产等工作并提供原始记录Responsible for equipment cleaning, installing, manufacturing and data recording 负责向验证管理小组及时报告验证中出现的问题Report timely discrepency observed during validation to Validation Team 协助验证协调人完成验证报告Assist to finish validation report 固体制造 Solid ? ? ? ? 车间操作人员负责按照草案设计的要求执行验证，验证中观察到的实际工艺参数和变量记录在批记录中完成。The process validation are exectued by the operators strictly based on the approved protocol. The process parameters and variables should be recored in Batch Production Record by operators. IPC检查由IPC检验人员完成，同时将检验结果填写在批记录或本草案设计的附件记录表中，在检验过程中产生的任何打印记录须附在相应的记录表中。The IPC test should be performed by IPC operators. The results will be recorded in the Batch Production Record or annexed forms designed in this protocol, together with any print-out during test. QC负责完成验证中规定的检验项，同时将检验过程和结果记录在相应的检验记录和本草案设计的附件记录表中，在检验过程中目产生的任何打印记录须附在相应的记录表中。The predefined test items for QC will be performed in QC laboratories. The results will be recorded in the related Test Record or annexed forms designed in this protocol, together with any print-out during test. QA负责验证现场执行的监控QA is responsible for site supervision of validation implementation ? ? ? ? 固体制造Solid 新产品与技术支持 NPI&TS 质量控制 QC 质量保证 QA 验证处 V&Q 验证管理小组Validation management team ? ? 负责验证草案及报告的审核及批准Review and approval of the project documents concerning contents, correctness, completeness 负责对验证中出现的问题提出指导意见、执行偏差调查、批准变更等Coach the investigation for observations and approve the change during validtaion ? 质量认证部Q&C ? 负责验证草案及报告的批准Approval of the project documents concerning contents, correctness, completeness 负责对验证中出现的问题提出指导意见、执行偏差调查、批准变更等Coach the investigation for observations and approve the change during validtaion 3. 方法APPROACH

3.1 工艺验证与验证批释放Process validation and release of the validation batch 此次验证为同步验证。采用供应商提供3批共计300kg的甲苯咪唑进行生产。本次验证中变更的物料及使用的入库序号参见下表。

参考文件 Reference Document 原辅料名称 Raw Material Name 物料编号 Material Number 入库序号Lot number 第一批 第二批 第三批 For first batch For second batch For third batch 各物料的生产商和供应商参见4.1.2节the information about manufacturer and vendor see section 4.1.2 本次工艺验证应该进行3个连续而且成功的批次。验证批为正常生产批量300kg/批。

验证批产品必须经过验证测试结果分析，符合释放要求，且验证报告被批准后，才可以释放。

由于本次验证为同步验证，没有对处方、工艺步骤、工艺参数、生产设备等进行变更，因此对于每个验证批的产品可以在测试结果合格、经过分析符合释放要求的前提下，形成中间报告支持释放。

3.2 Comparison to biobatch

由于本产品已经上市多年(始于1990年)，所以不涉及。

3.3 稳定性研究Stability study to this process validation

依据稳定性考察程序制订稳定性考察方案，结果仅用于公司内部质量控制。由于本次验证没有进行任何影响产品生产和质量的变更，同时每年均对首批生产的该产品进行稳定性考察，因此本次验证不涉及验证批的稳定性研究。

3.4 与工艺验证相关的清洁验证Cleaning validation related to this process validation 参见4.3节“生产设备与设施”项。

See section 4.3, Manufacturing Equipment and Facility.

3.5 分析方法与IPC/释放标准Analytical method overview including IPC /release

specifications

方法/标准列表List of test method and specification

程序号 对象 方法类别 标准类别 Procedure code Objects Type of Test Method Type of specification 方法验证列表List of test method validation

文件编号Document Code 验证方法名称Validation Name 验证时间Year 3.6 结果记录与评估的方法Methods for recording & evalusting results

草案设计的记录单、批记录和检验记录的填写主要涉及内容为工艺参数和变量的记录、IPC检验记录以及QC检验记录，所有这些记录的填写必须符合XJP质量记录管理程序SMP-DCP003的要求。

验证协调人负责收集整理批记录、IPC检验结果和QC检验结果。将结果进行汇总、统计和科学分析，并与上一次验证结果进行比较后完成验证结果评估，总结验证结论。

4. 工艺介绍PROCESS

4.1 产品处方Product Formulation 4.1.1 处方Formulation 下表列出在甲苯咪唑片100mg生产时产品的处方。

Table below presents the product formulation used for the manufacture of Mebendazole tablet 100mg.

参考文件 Reference Document: 物料编号 Material Number 010193 Master Formula No. (QA Authoritation number) F84 原辅料名称 Raw Material Name 批量 Batch Size: 每批的数量 Quantity per Batch 亚批次 Sub.batch 备注COMMENTS: NA

4.1.2 原材料合格供户清单Qualified suppliers List of raw materials 下表列出了在工艺验证批次中将要使用的所有物料合格供户。

Table below lists the qualified suppliers of all the materials to be used in the process validation batches.

参考文件 Reference Document 原辅料名称 Raw Material Name 进口合格供户Xian Janssen Import Qualified Suppliers List (2005.11.15) 国内合格供户Xian Janssen Local Qualified Suppliers List (2005.11.15) 物料编号 Material Number 生产商 Manufacturer 供应商 Vendor 如果对于某个给定的原辅料所列的制造商或供应商多于一个时，请注明在执行该验证时所使用的该物料的制造商或供应商。 If more than one manufacturer or supplier is listed for a given raw material, please indicate which manufacturer or supplier’s material will be used in the execution of this PQ. 依据RATIONALE: （如果对于给定的物料，其生产商或供应商多于一个）。(If more than one manufacturer or supplier is listed for a given raw material ) NA 备注COMMENTS: NA 4.2 接触容器Immediate containers

阶段Phase 接触容器Immediate containers 制造阶段与产品直接接触的设备Contact 筛粉机、一步制粒机、整粒机、混合机和压片机与产品接触部分：304不锈钢 equipments in the manufacturing Contact parts of Sieving machine, Fluid bed granulator, Breaking machine, process Mixing machine and Compression machine: 304 stainless steel 颗粒、片子贮存的容器Containers for granula and tablets 内包装材料（国内销售）Primary packaging material (Local) 内包装材料（国外销售）Pramery packaging material (Export) 不锈钢桶SS bucket PVC硬片、铝箔Foil PVC and Alu. Foil 黑色塑料袋 Black plastic bag 4.3 生产设备和设施Manufacturing Equipment and Facility

根据制造甲苯咪唑片100mg的现行版批记录BF2340 05在检查表1中列出了在工艺验证批次中将使用的所有生产设备。

用于A100mg片制造的主要生产设备必须完成设备验证、处于校验有效期内；相应的清洁程序的验证状态须进行回顾或评估。具体的检查结果参见检查表1。

与甲苯咪唑片100mg制造相关的设施与公用系统均得到验证，可用于生产。

4.4 工艺流程图Process Flow Diagram

4.5 关键工艺参数与变量Critical Process Parameters and Variables

下表列出所有关键工艺参数和关键工艺变量。关键工艺参数必须设定在特定的设定点或范围内，而关键工艺变量则必须控制和维持在特定的目标或范围内。

工艺阶段 Process Stage 关键的工艺参数与变量 Critical Process Parameters and Variable 批记录步骤编 参数设定值/目标值（范围） BPR Step Parameter Number Set point / Variable Target (Range) 流化床制粒Granulation with Fluid bed granulator 阀控制压力Control pressure of valves 工作压力Operating pressure 干混 排风阀位臵Exhaust-air flap Pre-Mixing 进风温度Inlet-air temp. 混合时间Premixing time 喷液压力Spraying pressure 进风温度Inlet-air temp 排风阀位臵Exhaust-air flap 制粒Granulation 喷嘴口径Nozzle diameter 喷嘴数目Number of nozzles 泵速Pump speed 颗粒干燥 Drying 进风温度 Inlet-air temp. 4 4 4 5 3mm 6 155-175rpm 75-85℃ 3 3 3 3 3 4 4 4 1.45bar 6bar 38-48% 50-60℃ 2-4min 3.5bar 55- 60℃ 38-48% 混合Blending 不加硬脂酸镁的混合 混合时间Mixing time Mixing without Magnesium stearate 转速Speed 加硬脂酸镁的混合 混合时间Mixing time Mixing with Magnesium stearate 转速Speed 7a 7a 7c 7c 20min. 1 10min. 1 压片Tableting 压片机速度Speed 9 9 9 冲头标记Inscription 9 120,000 ~ 150,000 tablets / hr. 300±7.5 mg 10.0mm 片重Weight 冲头直径Punch diameter 压片Tableting 上冲 upper punch 100 下冲 lower punch Me

5 工艺验证过程PROCESS VALIDATION

5.1 粘合液制备Prepare binding solution

工艺步骤 主要设备 Process step Critical Equipment 200L配液罐 制备粘合液 变速搅拌器 Prepare binding solution 批记录对应步骤 Reference Step 2 in BF2340 05 5.1.1 目的和关键参数Objective and critical parameters 证明使用糖精钠、日落黄、十二烷基硫酸钠（进口）和淀粉搅拌能够持续及重复地制备出符合要求的粘合液。 To demonstrate that the manufacturing process for using Saccharin Sodium, Sunset yellow, Sodium lauryl sulfate and starch to produce consistently and reproducibly binder solution 观察粘合液并进行粘度测试。粘合液无泡沫和可见团块，粘度仅作为参考。 Observe the paste and check the viscosity. The paste should be foamless and no lumps should be visible. The viscosity of paste is for information only. 关键参数 Critical parameters: a. 搅拌速度mixing speed b. 搅拌时间mixing time c. 在线匀化时间homogenizing time by in-line mixer 5.1.2 取样计划Sampling plan 取样时间：喷液前 Time of sampling: before spraying 取样位臵：容器的上下部的中央位臵 Place of sampling: the middle of top and bottom in the container. 取样量：每个样品50ml Sampling size: about 50 ml each. 5.1.3 测试计划Test plan 喷液前取样臵于透明容器中目测 Visual aspect immediately before spraying (in a clear transparent recipient) 喷液前取样50ml臵于容器中进行温度测试 Perform a temperature measurement before spraying (about 50ml in recipient) 进行粘度测试 Perform a viscosity measurement. Refer to Tylenol binding solution test method 5.1.4 可接受标准Acceptance citeria 无团块、不溶性颗粒和泡沫 No lumps and insoluble particles should be visible and the solution should be foamless. 温度结果留存供参考 The temperature of the paste is for information only.

工艺步骤 主要设备 Process step Critical Equipment 200L配液罐 制备粘合液 变速搅拌器 Prepare binding solution 粘度结果留存供参考 The viscosity of the paste is for information only. 批记录对应步骤 Reference Step 2 in BF2340 05 5.1.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果、建议和测试结果记录在结果附件Script1中 Monitor and record the pre-defined manufacturing process parameters and variables, then record process observation results, the comments of process obrvation and test resluts are recorded in Script1

5.2 干混工序Dry-mixing (Pre-mixing)

工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 干混工序 一步制粒机 Dry-mixing (Pre-mixing) Granulation machine, 1/B/R01 Step 3 in BF2340 05 5.2.1 目的和关键参数Objective and critical parameters 证明按规定的加料次序将API等物料加入一步制粒机，经一步制粒机一步完成预混，能够持续稳定的制备出符合所有相关产品质量标准的颗粒。 To demonstrate that under the stated material feeding process (including API), the manufacturing process for using granulator that could complete pre-mix process step and could consistently and reproducibly produce a granule that compiles with all relevant product specifications. 在完成预混工序后由容器中部取样进行粒度。测试结果仅供参考。 To determine the particle size distribution of the sample taken from the middle of the vessel with a sampling thief after pre-mixing. Test is performed only for information. 关键参数 Critical parameters: a. 阀控制压力Control pressure of valves b. 工作压力Operating pressure b. 排风阀位臵Exhaust-air flap c. 进风温度Inlet-air temp. d. 混合时间Premixing time 5.2.2 取样计划Sampling plan 5.2.2.1 粒度分布Particle size distribution 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：>100 g Sampling size: >100 g 5.2.3 测试计划Test plan 5.2.3.1 粒度分布Particle size distribution 仪器Apparatus: Fritsch analysette 3 (1/F/L 03) with sieve-size: 1000um, 850um, 500um, 250um, 150um, 75um and bottom 方法Method: Vibration time: 5 minutes, vibration height: 1.5 mm 5.2.4 可接受标准Acceptance citeria 5.2.4.1 粒度分布Particle size distribution 信息留存供参考 For information only 5.2.5 结果记录Results recording 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 干混工序 一步制粒机 Dry-mixing (Pre-mixing) Granulation machine, 1/B/R01 Step 3 in BF2340 05 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script2.1中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 2.1

5.3 湿法制粒和干燥工序Wet Granulation and Drying

工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 湿法制粒和干燥工序 一步制粒机 Wet Granulation and Drying Granulation machine, 1/B/R01 Step 4/5 in BF2340 05 5.3.1 目的和关键参数Objective and critical parameters 证明按规定的加料次序将物料加入一步制粒机，经一步制粒机一步完成混合、制粒、干燥的工序能够持续稳定的制备出符合所有相关产品质量标准的颗粒。 To demonstrate that under the stated material feeding process, the manufacturing process for using granulator that could complete pre-mix, granulation & granule dry process steps and could consistently and reproducibly produce a granule that compiles with all relevant product specifications. 在完成干燥工序后由容器中部取样进行粒度和干燥失重测试，同时进行含量均匀性分析。测试结果仅供参考。 To determine the particle size distribution, and LOD of the sample taken from the middle of the vessel and content uniformity with a sampling thief after drying. Test is performed only for information. 关键参数 Critical parameters: a. 喷液速率spray rate b. 喷嘴口径Nozzle diameter b. 喷液时间spraying time c. 产品温度product temperature d. 干燥时间drying time 5.3.2 取样计划Sampling plan 5.3.2.1 粒度分布Particle size distribution 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：>100 g Sampling size: >100 g 5.3.2.2 干燥失重Loss on drying 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：10 g Sampling size: 10 g 5.3.2.3 含量均匀性Content homogeinity 取样位臵：参见图5-1 Place of sampling: see figure 5 - 1. 取样量：每个样约150mg（1-3倍剂量），每个位臵取三份样 Sampling size: about 150mg (1~3 times unit dose) in triplicate for each location. (备注：因为当前的取样器对A中间体最多只能取样150~160mg，虽然取样量低于甲苯咪唑片的单剂量，但参考QC检验方法的使用量，可得出对该步验证目的无影响的结论。 Remarks: present unit dose only can sampling 150-160mg Mebendazole intermediate. Alough the sampling weight is less than the tablet unit, refers to QC testing method, we can draw the conclusion that 150-160mg sampling do no impact on validation validaty.) 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 湿法制粒和干燥工序 一步制粒机 Wet Granulation and Drying Granulation machine, 1/B/R01 Step 4/5 in BF2340 05 6 5 4 7 8 9 10 Front View 5.3.3 测试计划Test plan 取样方法：使用unit dose进行取样 45度插入取样，取样室开口朝上 到达位臵后，打开取样室 所取样品整体进行分析，不允许第二次取样 Sample method: The samples are taken with a unit dose sampling thief equipped with the appropriate die (0.2g or 0.4g die, depends on the test before take samples). Prior to use, the thief (including the die) is primed by coating it with a thin layer of the formulation. The closed thief is inserted at an angle of approx. 45 degrees, the sample chamber oriented upwards. The thief is then opened in order to allow flowing of the power into the die. The complete sample is analyzed (i.e. sub-sampling is not allowed). 图5-1 1 1 2 figure 5 - 1 3 1 2 3 7 10 4 5 2 8 3 9 8 7 10 9 6 4 5 6 Top View Three dimension 5.3.3.1 粒度分布Particle size distribution 仪器Apparatus: Fritsch analysette 3 (1/F/L 03) with sieve-size: 1000um, 850um, 500um, 250um, 150um, 75um and bottom 方法Method: Vibration time: 5 minutes, vibration height: 1.5 mm 5.3.3.2 干燥失重Loss on drying: 仪器Apparatus: SARTORIUS thermo control (1/F/ W02) 方法Method: see SOP – IPC 004, time: 15 minutes, temperature: 105 °C, programme 3 5.3.3.3 含量均匀性Content homogeinity 仪器Apparatus: UV-VIS spectrum meter 方法Method: Details see USP29 ＆ SOP-HPS005 00 5.3.4 可接受标准Acceptance citeria 5.3.4.1 粒度分布Particle size distribution 信息留存供参考 For information only 5.3.4.2 干燥失重Loss on drying: 信息留存供参考 For information only

工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 湿法制粒和干燥工序 一步制粒机 Wet Granulation and Drying Granulation machine, 1/B/R01 5.3.4.3 含量均匀性Content homogeinity Step 4/5 in BF2340 05 信息留存供参考The API content distribution of granule mixture is for information only. 该步骤甲苯咪唑理论含量为100mg/269.15mg Theoretical content of Mebendazole Polymorph C is 100mg/269.15mg 5.3.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script2.2和2.3中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 2.2 and 2.3

5.4 整粒工序Breaking

工艺步骤 主要设备 Process step Critical Equipment 整粒工序Breaking 整粒机Oscillatines Sieving MG800, 1/B/S02 混合机容器Container of mixing machine, 1/B/R02-V2 批记录对应步骤 Reference Step 6a/6b in BF2340 05 5.4.1 目的和关键参数Objective and critical parameters 证明湿法制粒的混合物通过1/B/S02整粒后能够持续及稳定地生产出颗粒均匀分布的中间产品，符合所有相关的产品质量标准。 To demonstrate that the manufacturing process for using granule mixture to produce consistently and reproducibly a particle mixture with consistent size that complies with all relevant product specifications. 在加入外相前由容器中部取样测试粒度，测试结果仅供参考。 To determine the particle size distribution of the sample taken from the middle of the vessel with a sampling tool before adding outside phase. Test is performed only for information. 5.4.2 取样计划Sampling plan 5.4.2.1 粒度分布Particle size distribution 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：>100 g Sampling size: >100 g 5.4.3 测试计划Test plan 5.4.3.1 粒度分布Particle size distribution 仪器Apparatus: Fritsch analysette 3 (1/F/L 03) 过滤尺寸sieve-size: 1000um, 850um, 500um, 250um, 150um, 75um，和底部 and bottom 1000um, 850um, 500um, 250um, 150um, 75um and bottom 方法Method: 振动5分钟，高度1.5mm Vibration time: 5 minutes, vibration height: 1.5 mm 5.4.4 可接受标准Acceptance citeria 5.4.4.1 粒度分布Particle size distribution 信息留存供参考 For information only 5.4.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script3中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 3 5.5 不加硬脂酸镁的混合Mixing without Magnesium stearate

工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 不加硬脂酸镁的混合Mixing without Magnesium stearate 证明2亚批未加硬脂酸镁的中间产品经过1/B/R02中混合均匀，能符合所有相关的产品质量标准 To demonstrate the active drug substance is homogeneously distributed in the compression mixture of two subbatches after final blending without magnesium stearate in the planetary mixture. 关键参数 Critical parameters: a. 混合速度blending speed b. 混合时间blending time 混合机Mixing Machine MPH1500, 1/B/R02 Step 7a in BF2340 05 5.5.1 目的和关键参数Objective and critical parameters 5.5.2 取样计划Sampling plan 5.5.2.1 含量均匀性Content uniformity 取样位臵：参见图5-2 Place of sampling: see figure 5 - 2. 取样量：每个样约150mg（1-3倍剂量），每个位臵取三份样 Sampling size: about 150mg (1~3 times unit dose) in triplicate for each location. (备注：因为当前的取样器对A中间体最多只能取样150~160mg，虽然取样量低于甲苯咪唑片的单剂量，但参考QC检验方法的使用量，可得出对该步验证目的无影响的结论。 Remarks: present unit dose only can sampling 150-160mg Mebendazole intermediate. Alough the sampling weight is less than the tablet unit, refers to QC testing method, we can draw the conclusion that 150-160mg sampling do no impact on validation validaty.) 取样方法： 终混20min的中间产品取样 使用unit dose进行取样 45度插入取样，取样室开口朝上 到达位臵后，打开取样室 所取样品整体进行分析，不允许第二次取样 Sample method: After 20min blending, Sample in the container The samples are taken with a unit dose sampling thief equipped with the appropriate die (0.2g or 0.4g die, depends on the test before take samples). Prior to use, the thief (including the die) is primed by coating it with a thin layer of the formulation. The closed tool is inserted at an angle of approx. 45 degrees, the sample chamber oriented upwards. The thief is then opened in order to allow flowing of the power into the die. The complete sample is analyzed (i.e. sub-sampling is not allowed). 图5-2 1 1 2 1 2 3 3 figure 5 - 2 4 7 5 8 10 6 9 7 4 10 5 2 8 3 8 10 9 6 4 5 7 9 6 Front View Top View Three dimension 5.5.3 测试计划Test plan 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 不加硬脂酸镁的混合Mixing without Magnesium stearate 混合机Mixing Machine MPH1500, 1/B/R02 Step 7a in BF2340 05 5.5.3.1 含量均匀性Content uniformity 仪器Apparatus: UV-VIS spectrum meter 方法Method: Details see USP 29 ＆ SOP-HPS005 00 5.5.4 可接受标准Acceptance citeria 5.5.4.1 含量均匀性Content uniformity 单值individual: 85.0%-115.0% 平均值 average: 90.0-110.0%(absolute) 相对标准偏差RSD%:〈 5% 5.5.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script4中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 4

5.6 加硬脂酸镁的混合Mixing with Magnesium stearate

工艺步骤 主要设备 Process step Critical Equipment 加硬脂酸镁的混合 混合机 Mixing with Magnesium stearate Mixing Machine MPH1500, 1/B/R02 批记录对应步骤 Reference Step 7c in BF2340 05 5.6.1 目的和关键参数Objective and critical parameters 证明加入硬制酸镁后终混工序能够持续及稳定地在1/B/R02中将颗粒混合物混合均匀，制备出符合所有相关的产品质量标准的中间产品。 To demonstrate that the final blending process by adding Magnesium stearate, in the planetary mixer, could produce consistently and reproducibly a homogenous compression mixture that complies with all relevant product specifications. Determine the angle of repose, the loose and tapped density, the particle size distribution of a sample taken from the middle of the vessel with a sampling thief, LOD of three samples from top, middle and bottom of the vessel, the content uniformity of the API in the vessel. 关键参数 Critical parameters: a. 混合速度blending speed b. 混合时间blending time 5.6.2 取样计划Sampling plan 5.6.2.1 粒度分布Particle size distribution 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：>100 g Sampling size: >100 g 5.6.2.2 休止角Angle of repose 取样位臵：容器中部 Place of sampling: in the middle of the container 取样量：100 g Sampling size: 100 g 5.6.2.3 松容积Loose and tapped bulk density 取样位臵：容器中部（可使用休止角样品） Place of sampling: in the middle of the container (use the sample of angle of repose) 取样量：100 g Sampling size: 100 g 5.6.2.4 干燥失重Loss on drying 取样位臵：于容器上中下部1/2处取样 Place of sampling: at ? position of the top, middle and bottom of the container 取样量：10 g Sampling size: 10 g each

工艺步骤 主要设备 Process step Critical Equipment 加硬脂酸镁的混合 混合机 Mixing with Magnesium stearate Mixing Machine MPH1500, 1/B/R02 批记录对应步骤 Reference Step 7c in BF2340 05 5.6.2.5 含量均匀性Blend uniformity 取样位臵：参见图5-3 Place of sampling: see figure 5 - 3. 取样量：每个样约150mg（1-3倍剂量），每个位臵取三份样 Sampling size: about 150mg (1~3 times unit dose) in triplicate for each location. (备注：因为当前的取样器对A中间体最多只能取样150~160mg，虽然取样量低于甲苯咪唑片的单剂量，但参考QC检验方法的使用量，可得出对该步验证目的无影响的结论。 Remarks: present unit dose only can sampling 150-160mg Mebendazole intermediate. Alough the sampling weight is less than the tablet unit, refers to QC testing method, we can draw the conclusion that 150-160mg sampling do no impact on validation validaty.) 取样方法：使用unit dose进行取样 45度插入取样，取样室开口朝上 到达位臵后，打开取样室 所取样品整体进行分析，不允许第二次取样 Sample method: The samples are taken with a unit dose sampling thief equipped with the appropriate die (0.2g or 0.4g die, depends on the test before take samples). Prior to use, the thief (including the die) is primed by coating it with a thin layer of the formulation. The closed thief is inserted at an angle of approx. 45 degrees, the sample chamber oriented upwards. The thief is then opened in order to allow flowing of the power into the die. The complete sample is analyzed (i.e. sub-sampling is not allowed). 图5-3 figure 5 - 3 1 1 2 1 2 3 3 9 7 6 10 6 4 5 5 2 5 6 4 4 7 8 9 7 8 8 9 3 10 10 Front View Top View Three dimension 5.6.2.6 微生物限度测试Microbiological purity test 取样位臵：容器的上中下部 Place of sampling: in the top, middle and bottom of the container 取样量：各30g Sampling size: 30 g for each point 5.6.3 测试计划Test plan 5.6.3.1 粒度分布Particle size distribution 工艺步骤 主要设备 Process step Critical Equipment 加硬脂酸镁的混合 混合机 Mixing with Magnesium stearate Mixing Machine MPH1500, 1/B/R02 批记录对应步骤 Reference Step 7c in BF2340 05 仪器Apparatus: Fritsch analysette 3 (1/F/L 03) 过滤尺寸sieve-size: 1000um, 850um, 500um, 250um, 150um, 75um，和底部 and bottom 1000um, 850um, 500um, 250um, 150um, 75um and bottom 方法Method: 振动5分钟，高度1.5mm Vibration time: 5 minutes, vibration height: 1.5 mm 5.6.3.2 休止角Angle of repose 仪器Apparatus: ERWEKA-CTB 方法Method: see SOP – IOP 081 5.6.3.3 松容积Loose and tapped bulk density 仪器Apparatus: Tapped Volumeter SVM 102 (1/F/L04) 方法Method: see SOP-IOP079 5.6.3.4 干燥失重Loss on drying 仪器Apparatus: SARTORIUS thermo control (1/F/ W02) 方法Method: 参见SOP – IPC 004 （温度105°C，15分钟，程序3） see SOP – IPC 004, time: 15 minutes, temperature: 105 °C, programme 3 5.6.3.5 含量均匀性Blend uniformity 仪器Apparatus: UV-VIS分光光度计UV-VIS spectrum meter 方法Method: 参见Details see USP29 ＆ SOP-HPS005 00 5.6.3.6 微生物限度测试Microbiological purity test 参见See SOP-MRB083 00 （不检混合样Do not form a composite.） 5.6.4 可接受标准Acceptance citeria 5.6.4.1 粒度分布Particle size distribution 信息留存供参考 For information only 5.6.4.2 休止角Angle of repose 信息留存供参考 For information only 5.6.4.3 松容积Loose and tapped bulk density 信息留存供参考 For information only 5.6.4.4 干燥失重Loss on drying 测试结果不超过2.5~3.5% The result should be within 2.5~3.5% 工艺步骤 主要设备 Process step Critical Equipment 加硬脂酸镁的混合 混合机 Mixing with Magnesium stearate Mixing Machine MPH1500, 1/B/R02 5.6.4.5 含量均匀性Blend uniformity 单值individual: 85.0-115.0% 平均值 average:90.0-110.0%(absolute) 相对标准偏差RSD%:< 5.0% 该步骤甲苯咪唑理论含量为100mg/300.15mg Theoretical content of Mebendazole Polymorph C is 100mg/300.15mg 5.6.4.6 微生物限度测试Microbiological purity test 总需氧菌Total aerobic bacteria：≤100CFU/g 总霉菌和酵母菌Total mould and yeast：≤100CFU/g 沙门菌：10g检品中不得检出Salmonella: Absence in 10g product 大肠埃希菌：1g检品不得检出E. coil: Absence in 1g product 批记录对应步骤 Reference Step 7c in BF2340 05 5.6.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script5.1和5.2中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 5.1 and 5.2

5.7 中间体桶料In drums

工艺步骤 Process step 主要设备 批记录对应步骤 Critical Equipment Reference 中间体桶料 不锈钢桶 Step 7d in BF2340 05 In drums SS. buckets 5.7.1 目的和关键参数Objective and critical parameters 证明分装到贮存和转运容器中的中间体活性成分是均匀分布的。 To demonstrate that the active drug substance of the final blending mixture filled into the small storage buckets are homogenous. 在桶里静臵5分钟后取样进行含量均匀性考察 To determine the API content uniformity of the sample taken from the middle of the vessel with a sampling thief after 5 min statics in drums. 5.7.2 取样计划Sampling plan 5.7.2.1 含量均匀性Content homogeinity 取样位臵：参见图5-4 Place of sampling: see figure 5 - 4. 取样量：每个样约150mg*（1-3倍剂量），第一、三、五、七桶的每个位臵取三份样 Sampling size: about 150mg (1~3 times unit dose) in triplicate for each location. *XJP当前的取样器对A中间体最多只能取样150~160mg，取样量低于甲苯咪唑片的单剂量，对该步验证目的无影响 XJP present unit dose only can sampling 150-160mg Mebendazole intermediate. Because the sampling weight is less than the tablet unit, no impact on validation validaty could be gotten. 取样方法： 终混20min的中间产品取样 使用unit dose进行取样 45度插入取样，取样室开口朝上 到达位臵后，打开取样室 所取样品整体进行分析，不允许第二次取样 Sample method: After 20min blending, Sample in the container The samples are taken with a unit dose sampling thief equipped with the appropriate die (0.2g or 0.4g die, depends on the test before take samples). Prior to use, the thief (including the die) is primed by coating it with a thin layer of the formulation. The closed thief is inserted at an angle of approx. 45 degrees, the sample chamber oriented upwards. The thief is then opened in order to allow flowing of the power into the die. The complete sample is analyzed (i.e. sub-sampling is not allowed). 图5-4 figure 5 – 4 Top middle bottom 工艺步骤 Process step 主要设备 批记录对应步骤 Critical Equipment Reference 中间体桶料 不锈钢桶 Step 7d in BF2340 05 In drums SS. buckets 5.7.3 测试计划Test plan 5.7.3.1 含量均匀性Content homogeinity 仪器Apparatus: UV-VIS分光光度计 UV-VIS spectrum meter 方法Method: 参见Details see USP29 & SOP-HPS005 00 5.7.4 可接受标准Acceptance citeria 5.7.4.1 含量均匀性Content homogeinity 单值individual: 85.0-105.0% 平均值 average: 90.0-110.0%(absolute) 相对标准偏差RSD%: < 5.0% 5.7.5 结果记录Results recording 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script6中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 6

5.8 压片工序The tableting process

工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 5.8.1 目的和关键参数Objective and critical parameters 证明能够持续及稳定地在1/C/K01,02压片机上以120,000~180,000 tablets/hr的速度生产出符合所有相关的产品质量标准的半成品。 To demonstrate that the tablets should be maken consistently and reproducibly by using a rotary tableting machine, Courtoy R 100/36 at speed 100,000~200,000 tablets/hr and they always meet the relevant product specification 关键参数：压片机转速度 Critical parameters: machine speed. 测试项目包括 The tablet properties to be investigate: 外观Appearance 片重差异Weight variation 片厚Thickness 硬度Hardness 崩解时限Disintegration time 脆碎度Friability 含量均匀性Content uniformity 含量Assay 有机溶剂残留Residue 微生物Microbiological purity 设备先以120,000/hr运行0.5小时、再以180,000/hr运行0.5小时，最后以常速150,000/hr运行至生产结束。 Compression with low speed 120,000t/hr for running half an hour, high speed 180,000t/hr for running half an hour and normal speed 150,000t/hr till end. 5.8.2 取样和测试计划Sampling and testing plan 在完成片重等调机后进行取样 After adjustment for tablet weight and tablet characteristics. 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 项目 Item 外观 Appearance 片重差异 Weight variation 硬度 Hardness 片厚 Thickness 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 取样量Sample size 40片 40 tablets 40片 40 tablets 10片 10 tablets 10片 10 tablets 取样频率 Frequency 每30分钟 every 30 min 每30分钟 every 30 min 每30分钟 every 30 min 每30分钟 every 30 min 测试方法 Test 目检 Visual SOP-IPC004 12 使用梅特勒分析天平 Mettler SOP-IPC004 12 硬度仪 1/F/L01, ERWEKA TBH28 TBH28 SOP-IPC004 12 片厚仪 1/F/L06, AKKURAT J15 SOP-IPC004 12 崩解仪 1/F/L02, ERWEKA SOP-HPS005 02 测试者Tester 固体车间Solids 固体车间Solids 固体车间Solids 固体车间Solids 崩解时限Disintegration 脆碎度 Friability 含量均匀性Content uniformity Beginning End Beginning 135,000t/hr End Beginning 150,000t/hr End 每个取样点20Beginning 120,000t/hr 片 End 20 tablets each Beginning 135,000t/hr End Beginning 150,000t/hr End 每个取样点7片120,000t/hr Beginning （至少20个取Middle 样点） End 7 tablets each 150,000t/hr Beginning (totally at least Middle 20 sampling End locatioins) 135,000t/hr Beginning 每个取样点6片 120,000t/hr 6 tablets each At least 12 times sampling (the same interval) QC 脆碎度仪 1/F/L05, ERWEKA TADR SOP-IPC004 12 固体车间Solids 仪器Apparatus: UV-VIS 方法Method: Details see SOP-HPS005 00 QC End 含量 Assay 有机溶剂残留 Residue 微生物限度检查 Microbiological purity 每个取样点30片 30 tablets each 每个取样点30片 30 tablets each 共取样60片 Total 60 tablets 120,000t/hr 135,000t/hr 150,000t/hr Beginning Middle End At the beginning, middle and end of the compression process 仪器Apparatus: HPLC 方法Method: Details see USP29 & SOP-HPS005 02 仪器Apparatus: GC 方法Method: Details see SOP-HPS005 02 See SOP-MRB083 00 QC QC QC 5.8.3 可接受标准Acceptance criteria 5.8.3.1 外观Appearance 桔色、圆形、直径为10.0mm，无粘冲，无裂片 Light orange, flat round tablet, diameter with 10.0mm, no capping or sticking tablets 上冲字样in upper punch： 下冲字样in lower punch： 5.8.3.2 片重差异Tablet weight variation 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.3.7 5.8.3.8 5.8.3.9 平均值为：292.5-307.5mg Average tablet weight should be within 292.5-307.5mg 单值为：285-315mg Individual tablet weight: all values to be within 285-315mg 极差Range: 17.5mg 硬度Hardness 平均值为：60-140N All average values to be within 60-140N 厚度Thickness 3.2mm±0.2mm 脆碎度Friability 单值为：<= 0.5% Each value should be <= 0.5% 崩解时限Disintegration time All values should be ≤15 minutes. 含量均一性Content uniformity 单值individual: 85.0-115.0% 平均值 average: 95.0 -105.0% 相对标准偏差RSD%: ≤6.0% The relative standard deviation should be less than or equal to 6.0%. 含量Assay 5片混合样的含量测定值在95.0％-105.0％之间 The assay of a composite sample 5 tablets should be between 95.0% ~ 105.0% of the stated amount. 残留Residue Peak area of sample is less than the reference 样品峰面积小于对照品峰面积 5.8.3.10 微生物检测Microbiological testing 总需氧菌Total aerobic bacteria：≤100CFU/g 总霉菌和酵母菌Total mould and yeast：≤100CFU/g 沙门菌：10g检品中不得检出Salmonella: Absence in 10g product 大肠埃希菌：1g检品不得检出E. coil: Absence in 1g product 5.8.4 结果记录Results recording 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 监控事先确定的制造工艺参数及变量并将观察结果记录在批记录BF2340 05中、对观察到工艺的建议和测试结果记录在结果附件Script7中 Monitor and record the pre-defined manufacturing process parameters and variables in Batch Record BF2340 05, then process observation results, the comments of process obrvation and test resluts are recorded in Script 7

5.9 贮存时间Holding time study

工艺步骤 主要设备 Process step Critical Equipment 贮存时间验证 100L不锈钢桶 Holding time study 批记录对应步骤 Reference After Step7d/9 in BF2340 05 5.9.1 目的和关键参数Objective and critical parameters 证明颗粒中间体和压得的片子在半成品库的存放时间。 To demonstrate the holding time of the granula and tablets in the Half-finished product warehourse. 颗粒中间体装于100L带盖不锈钢桶中，在半成品库贮存30天，分别于第0天、第15天和第30天取样测试。 The granula is filled in 100L SS. Bucket with cover and storaged in Half-finished product warehourse for 30 days. The samples taken from day0, day 15, day 30 will be tested according to SOP-INS005 06. 片子半成品装于100L带盖不锈钢桶中，在半成品库贮存90天，分别于第0天、第30天、第60天和第90天取样测试。 The tablets is filled in 100L SS. Bucket with cover and stroaged in Half-finished product warehourse for 90 days. The samples taken from day0, day30, day60 and day90 will be tested according to SOP-HPS005 02. 完成包装后，成品进行3个月加速稳定性试验。 3 months accelerated stability study will be executed for the finished products used for the holding time study. 验证执行顺序Executing plan： 固体中间体在半成品库中存放30天 intermediate holding 30 days in HFP Warehouse 依据中间体取样周期定期取样检测 sampling according to sampling plan 符合可接受标准SOP-INS005 meet the specifications of SOP-INS005 固体中间体加工成为半成品 manufacture for HFP 固体半成品在半成品库中存放90天 HFP holding 90 days in HFP Warehouse 依据半成品取样周期定期取样检测 sampling according to sampling plan period 符合可接受标准SOP-HPS005 meet the specifications of SOP-HPS005 meet the specifications of SOP-INS005 固体半成品加工成为成品 manufacture for FP 符合成品可接受标准SOP-FPS005 meet the specifications of SOP-FPS005

工艺步骤 主要设备 Process step Critical Equipment 贮存时间验证 100L不锈钢桶 Holding time study 批记录对应步骤 Reference After Step7d/9 in BF2340 05 进行3个月加速稳定性监测 Accelareted stability test of 3 months 符合稳定性可接受标准SOP-STS004 meet the specifications of SOP-STS004 留样产品可以释放 release the retained product 5.9.2 取样和测试计划Sampling and testing plan 中间体 Intermediate 取样时间 Sampling time 取样位臵Sampling position 取样量 化学Chem. 测试方法即可接受标准Test method / Acceptance criteria 加速稳定性 半成品 Accelareted stability Half finsihed product test 第0天、第15天、第30天分第0天、第30天、第60天、第0天、第1月、第2月、第别取样sampling on the 0, 15, 第90天分别取样sampling on 3月分别取样sampling on the 30 days the 0, 30,60,90 days 0, 1, 2, 3 months SMP-QMP014 微生物Micro. 物料上表面取 on the surface SMP-QMP051 盛装容器内物料中心位臵in the inner center 化学Chem. 微生物Micro. 微生物100g，每次均应取各自的备份样 Micro: 100mg, backup sample is needed 化学200g，每次均应取各自的备份样 Chem: 200 mg, backup sample is needed SOP-INS005 SOP-HPS005 QF0016 SOP-STS004 测试项目 Test Items 形状、含量测定、微生物限度性状、鉴别（甲苯咪唑、日落性状、崩解时限、有关物质、检查appearance, assay, 黄）、重量差异、崩解时限、含量测定、微生物限度检查micro. apperance, disintegration, 脆碎度、有关物质、含量测定、有机溶剂残留量、微生物impurity test, assay, micro. test 限度检查apperance,identification( Mebendazole,Sunset yellow), tablet weight variation, disintegration, friability, impurity test, assay, residual solvents, micro. test

6 验证中偏差/变更处理DEVIATION AND CHANGE HANDLING

验证过程中如果出现偏差和变更，应立即通知验证小组并对偏差和变更进行详细记录（QF1039验证偏差处理单，QF1040验证变更处理单），分析偏差产生的根本原因、进行影响分析并提出解决方法。所有偏差和变更得到有效处理后，并且已被质量认证部代表批准和关闭，验证方可进入下一步骤。原始的偏差处理单和变更处理单经过批准后必须附在最终的验证报告中。

If any deviation and change is issued during validation, it must be immediately informed to validation team and recored in the deviation handling form and/or change handling form (QF1039 and QF1040). The root cause, impact assement and CAPA should be givend after full investigation. The validation could be continued only after effective handling with approving by Q&C representative. The handling form should be attached to the final validation report.

7 培训TRAINING

验证草案起草人有责任在验证草案批准后对本次验证相关人员进行培训，该培训记录连同在验证中完成的其他相关培训记录一起附在最终的验证报告中。

The validation author is responsible for train the related person after receiving the approved protocol. All of he training records should be attached to the final validation report.

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