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.