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