5.8 压片工序The tableting process
工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 5.8.1 目的和关键参数Objective and critical parameters 证明能够持续及稳定地在1/C/K01,02压片机上以120,000~180,000 tablets/hr的速度生产出符合所有相关的产品质量标准的半成品。 To demonstrate that the tablets should be maken consistently and reproducibly by using a rotary tableting machine, Courtoy R 100/36 at speed 100,000~200,000 tablets/hr and they always meet the relevant product specification 关键参数：压片机转速度 Critical parameters: machine speed. 测试项目包括 The tablet properties to be investigate: 外观Appearance 片重差异Weight variation 片厚Thickness 硬度Hardness 崩解时限Disintegration time 脆碎度Friability 含量均匀性Content uniformity 含量Assay 有机溶剂残留Residue 微生物Microbiological purity 设备先以120,000/hr运行0.5小时、再以180,000/hr运行0.5小时，最后以常速150,000/hr运行至生产结束。 Compression with low speed 120,000t/hr for running half an hour, high speed 180,000t/hr for running half an hour and normal speed 150,000t/hr till end. 5.8.2 取样和测试计划Sampling and testing plan 在完成片重等调机后进行取样 After adjustment for tablet weight and tablet characteristics. 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 项目 Item 外观 Appearance 片重差异 Weight variation 硬度 Hardness 片厚 Thickness 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 取样量Sample size 40片 40 tablets 40片 40 tablets 10片 10 tablets 10片 10 tablets 取样频率 Frequency 每30分钟 every 30 min 每30分钟 every 30 min 每30分钟 every 30 min 每30分钟 every 30 min 测试方法 Test 目检 Visual SOP-IPC004 12 使用梅特勒分析天平 Mettler SOP-IPC004 12 硬度仪 1/F/L01, ERWEKA TBH28 TBH28 SOP-IPC004 12 片厚仪 1/F/L06, AKKURAT J15 SOP-IPC004 12 崩解仪 1/F/L02, ERWEKA SOP-HPS005 02 测试者Tester 固体车间Solids 固体车间Solids 固体车间Solids 固体车间Solids 崩解时限Disintegration 脆碎度 Friability 含量均匀性Content uniformity Beginning End Beginning 135,000t/hr End Beginning 150,000t/hr End 每个取样点20Beginning 120,000t/hr 片 End 20 tablets each Beginning 135,000t/hr End Beginning 150,000t/hr End 每个取样点7片120,000t/hr Beginning （至少20个取Middle 样点） End 7 tablets each 150,000t/hr Beginning (totally at least Middle 20 sampling End locatioins) 135,000t/hr Beginning 每个取样点6片 120,000t/hr 6 tablets each At least 12 times sampling (the same interval) QC 脆碎度仪 1/F/L05, ERWEKA TADR SOP-IPC004 12 固体车间Solids 仪器Apparatus: UV-VIS 方法Method: Details see SOP-HPS005 00 QC End 含量 Assay 有机溶剂残留 Residue 微生物限度检查 Microbiological purity 每个取样点30片 30 tablets each 每个取样点30片 30 tablets each 共取样60片 Total 60 tablets 120,000t/hr 135,000t/hr 150,000t/hr Beginning Middle End At the beginning, middle and end of the compression process 仪器Apparatus: HPLC 方法Method: Details see USP29 & SOP-HPS005 02 仪器Apparatus: GC 方法Method: Details see SOP-HPS005 02 See SOP-MRB083 00 QC QC QC 5.8.3 可接受标准Acceptance criteria 5.8.3.1 外观Appearance 桔色、圆形、直径为10.0mm，无粘冲，无裂片 Light orange, flat round tablet, diameter with 10.0mm, no capping or sticking tablets 上冲字样in upper punch： 下冲字样in lower punch： 5.8.3.2 片重差异Tablet weight variation 工艺步骤 主要设备 批记录对应步骤 Process step Critical Equipment Reference 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.3.7 5.8.3.8 5.8.3.9 平均值为：292.5-307.5mg Average tablet weight should be within 292.5-307.5mg 单值为：285-315mg Individual tablet weight: all values to be within 285-315mg 极差Range: 17.5mg 硬度Hardness 平均值为：60-140N All average values to be within 60-140N 厚度Thickness 3.2mm±0.2mm 脆碎度Friability 单值为：<= 0.5% Each value should be <= 0.5% 崩解时限Disintegration time All values should be ≤15 minutes. 含量均一性Content uniformity 单值individual: 85.0-115.0% 平均值 average: 95.0 -105.0% 相对标准偏差RSD%: ≤6.0% The relative standard deviation should be less than or equal to 6.0%. 含量Assay 5片混合样的含量测定值在95.0％-105.0％之间 The assay of a composite sample 5 tablets should be between 95.0% ~ 105.0% of the stated amount. 残留Residue Peak area of sample is less than the reference 样品峰面积小于对照品峰面积 5.8.3.10 微生物检测Microbiological testing 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 5.8.4 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 压片Compression 压片机 Step 9 in BF2340 05 Tableting Machine COUNTER R100/36, 1/C/K01,02 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Script7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 7
5.9 贮存时间Holding time study
工艺步骤 主要设备 Process step Critical Equipment 贮存时间验证 100L不锈钢桶 Holding time study 批记录对应步骤 Reference After Step7d/9 in BF2340 05 5.9.1 目的和关键参数Objective and critical parameters 证明颗粒中间体和压得的片子在半成品库的存放时间。 To demonstrate the holding time of the granula and tablets in the Half-finished product warehourse. 颗粒中间体装于100L带盖不锈钢桶中，在半成品库贮存30天，分别于第0天、第15天和第30天取样测试。 The granula is filled in 100L SS. Bucket with cover and storaged in Half-finished product warehourse for 30 days. The samples taken from day0, day 15, day 30 will be tested according to SOP-INS005 06. 片子半成品装于100L带盖不锈钢桶中，在半成品库贮存90天，分别于第0天、第30天、第60天和第90天取样测试。 The tablets is filled in 100L SS. Bucket with cover and stroaged in Half-finished product warehourse for 90 days. The samples taken from day0, day30, day60 and day90 will be tested according to SOP-HPS005 02. 完成包装后，成品进行3个月加速稳定性试验。 3 months accelerated stability study will be executed for the finished products used for the holding time study. 验证执行顺序Executing plan： 固体中间体在半成品库中存放30天 intermediate holding 30 days in HFP Warehouse 依据中间体取样周期定期取样检测 sampling according to sampling plan 符合可接受标准SOP-INS005 meet the specifications of SOP-INS005 固体中间体加工成为半成品 manufacture for HFP 固体半成品在半成品库中存放90天 HFP holding 90 days in HFP Warehouse 依据半成品取样周期定期取样检测 sampling according to sampling plan period 符合可接受标准SOP-HPS005 meet the specifications of SOP-HPS005 meet the specifications of SOP-INS005 固体半成品加工成为成品 manufacture for FP 符合成品可接受标准SOP-FPS005 meet the specifications of SOP-FPS005