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:
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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。
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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