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