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