欧盟清洁验证方案.doc

Subject/主题Lovastatin Tablets 20mg Cleaning Validation Protocol鲨鱼软骨片清洁验证方案文件编号：Table of contents目录1. Responsibility职责2. Purpose 目的3. Frequency 周期4. Relevant SOPs 相关的 SOPs5. Equipment 设备6. Test Method 测试方法7. Acceptance Criteria 接受限度8. Risk Analysis 风险分析9. Sampling Plan 抽样计划10. Action taken when out-of-limit result found对不符合接受限度的测试结果所采取的措施12. Revalidation 再验证13. Cleaning Validation Executive Record清洁验证过程记录14. Conclusion结论Attachments附件 Written by: 制订者：Date: 日期：Reviewed by: 复核者：Date: 日期：Approved by: 批准者：Date: 日期：Approved by: 批准者：Date: 日期：1. Responsibility 职责l QA is responsible for plan the cleaning validation. QA负责整个清洁验证的安排l QC is responsible for sampling and analysis.QC 负责抽样及测试l Production Department is responsible for performing cleaning production equipment.生产部负责设备的清洁.2. Purpose目的The purpose of this cleaning validation protocol is to demonstrate that the cleaning procedure used to clean JHZ-250B high shear mixer / granulator, threedimensional mixer，CT-C-2 Hot Air Circulating Drier， JZF-400 granulators & mill Korsch PH300-36 Tablet Press，BGD-150D high-efficiency coating machine and DPP-250B blister packaging machine can effectively remove residues of the products manufactured in ZS-650 Vortex Oscillator/Compact Sieve，JHZ-250B high shear mixer / granulator, threedimensional mixer，CT-C-2 Hot Air Circulating Drier， JZF-400 granulators & mill Korsch PH300-36 Tablet Press，BGD-150D high-efficiency coating machine and DPP-250B blister packaging machine to a predetermined level that does not raise any safety concerns.清洗验证方案的目的是证明JHZ-250B高效湿法制粒机、 HLD-1000B型料斗式混合机清洁操作规程、CT-T-II型热风循环烘箱、JZF-400型整粒、粉碎机、Korsch PH-300-36旋转式压片机、BGD-150D型高效包衣机和DPP-250B型多功能自动铝塑包装所使用的清洗程序能够有效地除去产品残留，达到预先确定的限度，从而达到对下批产品无影响。 3. Frequency周期The cleaning validation study is performed after three consecutive major cleanings of ZS-650 Vortex Oscillator/Compact Sieve，JHZ-250B high shear mixer / granulator, threedimensional mixer，CT-C-2 Hot Air Circulating Drier， JZF-400 granulators & mill Korsch PH300-36 Tablet Press，BGD-150D high-efficiency coating machine and DPP-250B blister packaging machine after the manufacture of Lovastatin Tablets.连续三批生产后，进行清洗验证研究。4. Relevant SOPs相关的 SOPsSOP-PD-304-00Cleaning procedure forHLSG-300High Speed Mixer/GranulatorHLSG-300型高效湿法混合制粒机清洁操作规程SOP-PD-304-00Cleaning procedure forLF120E-B airpillow-dry GranulatorLF120E-B型沸腾干燥制粒机清洁操作规程SOP-PD-310-00Cleaning procedure for ZP43 High Speed rotary tablet press高效ZP43旋转式压片机清洁操作规程SOP-PD-307-00Cleaning procedure for HLD-1000B Hopper type of blenderHLD-1000B型料斗式混合机清洁操作规程SOP-PD-306-00Cleaning procedure for YK-160 granulators YK-160整粒机清洁操作规程SOP-PD-311-00Cleaning procedure for BG-300E high-efficiency coating machineBG-300E型高效包衣机清洁操作规程SOP-PD-313-00Cleaning procedure forDPH-130、 DPP-250B blister packaging machine DPH-130、DPP-250型铝塑袍罩包装机清洁操作规程ESS-VD007Validation guideline cleaning验证指南清洁验证ESS-VD011Surface sampling for cleaning validation清洗验证设备表面取样ESS-VD014Selection of the worst case in cleaning validation清洁验证中最坏情况的选择SOP-QC-1075检验操作规程ESS-GM066Microbe Test 微生物限度检测法5. Equipments设备No.序号Equipment No.设备编号Equipment Name设备名称Product Contact Surface Area与产品接触面积(m2)1HLSG-300 high speed mixer / granulatorHLSG-300高效湿法混合制粒机2.81LF120E-B airpillow-dry GranulatorLF120E-B沸腾干燥制粒机器5.903ZP43Tablet PressZP43旋转式压片机64METAL DETECTOR金属探测仪0.35HLD-1000BHLD-1000B Hopper type of blenderHLD-1000B型料斗式混合机5.256YK-160granulators YK-160型整粒机0.377DPH-130DPP-250blister packaging machineDPH-130、DPP-250型多功能自动铝塑包装机1.08BG-300Ehigh-efficiency coating machineBG-300E型高效包衣机8.43Total Product Contact Surface Area (m2)与产品接触面积总和(m2)99.625.1 List of Equipment设备清单The list of Equipment used in the manufacture of Lovastatin Tablets:有关鲨鱼软骨片生产线的所有机器列出如下：1HLSG-300 high speed mixer / granulator HLSG-300高效湿法混合制粒机 2. LF120E-B airpillow-dry Granulator LF120E-B沸腾干燥制粒机器 3. ZP43Tablet Press ZP43 Tablet Press ZP43旋转式压片机 4. METAL DETECTOR 金属探测仪 5. HLD-1000BHLD-1000B Hopper type of blender HLD-1000B 型料斗式混合机 6. YK-160granulators YK-160 型整粒机7. DPH-130DPP-250blister packaging machine DPH-130、DPP-250型多功能自动铝塑包装机8. BG-300Ehigh-efficiency coating machine BG-300E型高效包衣机Table 1表1:5.2 Validation Scope验证范围 l HLSG-300 high shear mixer / granulator HLSG-300高效湿法制粒机l LF120E-B airpillow-dry Granulator LF120E-B沸腾干燥制粒机器l ZP43Tablet Press ZP43旋转式压片机l METAL DETECTOR 金属探测仪l HLD-1000B granule mixer HLD-1000B型料斗式混合机l YK-160 granulators YK-160型整粒机l DPH-130、DPP-250 blister packaging machine DPH-130、DPP-250型多功能 自动铝塑包装机l BG-300Ehigh-efficiency coating machine BG-300E型高效包衣机6. Test Method测试方法The cleaning validation studies are based on the swabbing technique and rinsing sampling. The selected swabs should be characterized for their suitability and a recovery test should be performed prior to the validation studies. The validation studies include swabbing of the main surface area as well as the hard-to-clean locations. Swabbing and ringing is carried out for the active ingredient.清洁验证研究用擦拭取样法和最终淋洗水取样。验证研究之前，选择的棉签的特性应适合并进行回收率研究。验证研究包括主要表面积和难清洁部位的擦拭。对活性成分擦拭取样和淋洗水取样。l Sampling Method抽样方法Swab Sampling擦拭法Ringing sampling最终淋洗水取样法7. Acceptance Criteria 接受限度l Visual Inspection目测检查- Acceptance Criteria接受限度There is no visible residue in equipment surface after cleaning.设备在清洁后，无可见的物质残留在设备表面l Acceptance Criteria of microbe微生物测试接受限度- For swab samples 对擦拭样品：Microbes微生物含量: 2 CFU/cm2 ，即 50 CFU / 25 cm2- For rinsing samples / 对冲淋样品：Microbes微生物含量: 100 CFU/mll Acceptance Criteria of assay化学测试接受限度 Active Ingredient (see Attachment 26)活性成分 (见附件26)MC (mg/swab) = _0.0843_ (Active) For rinsing samples 对冲淋样品：MC (mg/L) = _0.084_ (Active)l Test frequency检测次数The cleaning validation studies are conducted after three consecutive major cleanings of Nourkrin Tablets.三批鲨鱼软骨片生产结束后进行清洗验证。8. Risk Analysis风险分析 The residues of the products are not distributed uniformity, so the risk analysis should be done before cleaning validation sampling. The Critical location will be determined at risk analysis. Risk analyses are summarized in Attachment 1and Attachment 18.由于上一产品生产对下一产品的污染并不是均匀分布在整个设备的接触面上，因此清洁验证的活性成分抽样计划的确定必须先进行风险分析，且在风险分析中确定清洁验证的关键部位。风险分析见附件1到附件18：风险分析表9. Sampling Plan抽样计划 For active ingredient活性成分9.1 Swab sampling擦拭法The following location will be sampled as risk analysis: 根据风险分析，在下列抽样部位取样：9.1.1HLSG-300high shear mixer/granulator HLSG-300高效湿法混合制粒机Total are 7 samples:总共7个取样点:Table 3表3:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积Pan制粒锅Side侧面HLSG-300-1200Underside底面HLSG-300-2200出料口Inner surface内表面HLSG-3003200腔盖Rim area under the seal 盖的边缘 HLSG-300-4200内表面HLSG-300-5200切粒切刀桨片HLSG-300-6全部搅拌切刀下表面HLSG-300-72009.1.3 ZP43Tablet Press ZP43旋转式压片机Total are 8 samples:总共8个取样点:Table 5表5:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积下料斗内表面PG16、ZP43-1200饲料靴表面PG16、ZP43-2200孔PG16、ZP43-3200出片器内表面PG16、ZP43-4200除粉器内表面PG16、ZP43-5200转盘侧面PG16、ZP43-6200底面PG16、ZP43-7200模孔内表面PG16、ZP43-82009.1.4 HLD-1000BHLD-1000B Hopper type of blender HLD-1000料斗式混合机Total are 3 samples:总共3个取样点:Table 6表6:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料口内表面JSH-600-1200边缘JSH-600-2200出料口内表面JSH-600-32009.1.6 JZF-400 granulators & millJZF-400型整粒、粉碎机Total are 6 samples:总共6个取样点:Table 8表8:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积盖子内表面JZF-400-1200内表面JZF-400-2200容器内侧面JZF-400-3200内底部JZF-400-4200出料口表面JZF-400-5200表面JZF-400-62009.1.7 DPP-250B blister packaging machineDPP-250B型多功能自动铝塑包装机Total are 4 samples:总共4个取样点:Table 9表9:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料斗侧面DPP-250B-1200底部DPP-250B-2200分料刷表面DPP-250B-3200滚刷表面DPP-250B-42009.1.8 METAL DETECTOR金属探测仪Total are 4 samples:总共4个取样点:Table 10表10:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料斗上侧面M-1200下侧面M-2200出料斗内表面M-3200废片出口内表面M-42009.1.9 BGD-150D high-efficiency coating machine包衣机Total are 8 samples:总共8个取样点:Table 11表11:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积配料锅顶部BGD-150D-1200侧面BGD-150D-2200底部BGD-150D-3200包衣锅侧面BGD-150D-4200底部BGD-150D-5200顶部BGD-150D-6200接缝处BGD-150D-7200边缘BGD-150D-82009.2 Ringing sampling淋洗水取样BGD-150D high-efficiency coating machine包衣机Sampling location取样部位：硅胶管、喷枪Threedimensional mixer HLD-1000B型料斗式混合机清洁操作规程Sampling location取样部位：腔体For Microbes微生物取样点9.3.1 JHZ-250B high shear mixer/granulator JHZ-250B高效湿法制粒机Total are 7 samples:总共7个取样点:Table 12表12:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积Pan制粒锅Side侧面JHZ-250B-A25Underside底面JHZ-250B-B25出料口Inner surface内表面JHZ-250B-C25腔盖Rim area under the seal 盖的边缘 JHZ-250B-D25内表面JHZ-250B-E25切粒切刀桨片JHZ-250B-F25搅拌切刀下表面JHZ-250B-G259.3.2 ZS-650 Vortex Oscillator/Compact Sieve ZS-650漩涡振荡筛Total are 5 samples:总共5个取样点:Table 13表13:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积上盖内表面ZS-650-A25筛网上表面ZS-650-B25出料口内表面ZS-650-C25密封圈内表面ZS-650-D25容器内表面ZS-650-E259.3.3 Korsch PH300-36 Tablet Press KORSCH PH-300-36旋转式压片机Total are 8 samples:总共8个取样点:Table 14表14:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积下料斗内表面PH-300-36-A25饲料靴表面PH-300-36-B25孔PH-300-36-C25出片器内表面PH-300-36-D25除粉器内表面PH-300-36-E25转盘侧面PH-300-36-F25底面PH-300-36-G25模孔内表面PH-300-36-H259.3.4 Threedimensional mixerHLD-1000B型料斗式混合机清洁操作规程Total are 3 samples:总共3个取样点:Table 15表15:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料口内表面JSH-600-A25边缘JSH-600-B25出料口内表面JSH-600-C259.3.5 CT-C-2 Hot Air Circulating DrierCT-C-2型热风循环烘箱Total are 10 samples:总共10个取样点:Table 16表16:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积烘盘表面CT-C-2-A25内侧面CT-C-2-B25箱体左侧CT-C-2-C25右侧CT-C-2-D25顶部CT-C-2-E25接缝处CT-C-2-F25台车托架CT-C-2-G25边缘CT-C-2-H25箱门内表面CT-C-2-I25密封条CT-C-2-J259.3.6 JZF-400 granulators & millJZF-400型整粒、粉碎机Total are 6 samples:总共6个取样点:Table 17表17:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积盖子内表面JZF-400-A25内表面JZF-400-B25容器内侧面JZF-400-C25内底部JZF-400-D25出料口表面JZF-400-E25表面JZF-400-F259.3.7 DPP-250B blister packaging machineDPP-250B型多功能自动铝塑包装机Total are 4 samples:总共4个取样点:Table 18表18:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料斗侧面DPP-250B-125底部DPP-250B-225分料刷表面DPP-250B-325滚刷表面DPP-250B-4259.3.8 METAL DETECTOR金属探测仪Total are 4 samples:总共4个取样点:Table 19表19:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积加料斗上侧面M-A25下侧面M-B25出料斗内表面M-C25废片出口内表面M-D259.3.9 BGD-150D high-efficiency coating machine包衣机Total are 8 samples:总共8个取样点:Table 20表20:Part Name部件名称Sampling Location取样位置Sampling No.取样点Swab Area Ss (cm2)取样面积配料锅顶部BGD-150D-A25侧面BGD-150D-B25底部BGD-150D-C25包衣锅侧面BGD-150D-D25底部BGD-150D-E25顶部BGD-150D-F25接缝处BGD-150D-G25边缘BGD-150D-H259.4 Ringing sampling淋洗水取样BGD-150D high-efficiency coating machine包衣机Sampling location取样部位：硅胶管、喷枪Threedimensional mixer HLD-1000B型料斗式混合机清洁操作规程Sampling location取样部位：腔体10. Action taken when out-of-limit result found对不符合接受限度的测试结果所采取的措施 Inspect the process of operation检查测试过程1. Inspect the equipment of assay检查分析所用的仪器 2. Inspect the step of operation检查实验步骤3. Inspect the process of sampling检查抽样过程 QA，QC and the production department calculate with the results of inspect.QA，QC及生产部对检查结果进行讨论 Modify the validation plan; revalidate the items, which are not applicable before.修改验证计划，对不符合的项目进行重验证。11. Revalidation再验证Revalidation should be considered under the following circumstances:在下列情况发生时，必须考虑是否要进行重验证：- Cleaning method changed/清洁程序变化时- Cleaning detergents changed/清洁剂变化时- Product changed/产品变化时12. Cleaning Validation Executive Record清洁验证过程记录 附件1-18Risk Analysis Table风险分析表附件19Visual Inspection and Sampling for Active Ingredient目检和取样附件20Visual Inspection and Sampling for Microbes目检和取样附件21Analytical Results for Active Ingredient分析结果附件22Analytical Results for Microbes分析结果附件23 Sampling Recovery Test取样回收率试验附件24 Swab Chacterization for Cleaning Validation清洗验证棉签特性研究附件25 Swab Sampling for Cleaning Validation清洗验证棉签取样附件26 Calculation for Acceptance Criteria接受限度的计算 14. CONCLUSION结论The results obtained should not exceed the calculated contamination limit. The cleaning procedure for all pieces of production equipment effectively removes residues of Lovastatin Tablets manufactured in this equipment and is therefore deemed validated. Microbes limit comply with the requirement.测试结果不得大于计算出的检测限.设备的清洁程序可以有效清除产品残留，认为验证有效。 微生物限度符合要求。65 / 65Attachment附件1: Risk Analysis Table for active ingredient风险分析表:FormatA+B Equipment Name 设备名称: JHZ-250B High Shear Mixer / Granulator Date日期: JHZ-250B高效湿法制粒机12341.11.2*2.1Critical关键3.1Risk for Process Step风险 3.2Eval.of risk风险评估3.3Follow-upof risk是否确认为有风险4.1Possible cause可能的原因4.2Validation measur验证措施4.3Validation plan验证计划4.4Date日期4.5Responsible person负责人No.序号ComponentName部件名称Sam. No.取样部位Contact Area药品接触表面Yes是No否Yes是No否12345制粒锅出料口腔盖切粒切刀搅拌切刀Inner surface内表面内表面内表面表面表面XXXXPossibility of contamination with previous product与前批产品交叉污染的可能性Ditto同上Ditto同上 Ditto同上MMMHHXxxxXCleaning procedure of SOP is not efficient清洁方法不足够有效Ditto同上Ditto同上Ditto同上 Check cleaning result at defined location在规定部位检查清洁结果Ditto同上Ditto同上Ditto同上 See validation protocol 见清洁验证方案 1.2* Sample No. see the seven sampling points on Table3. 取样部位： 共7个取样点 见表3.Attachment附件2 : Risk Analysis Table for active ingredient风险分析表:FormatA+B Equipment Name设备名称: ZS-650 Vortex Oscillator/Compact Sieve Date日期: ZS-650漩涡振荡筛12341.11.22.1Critical关键3.1Risk for Process Step风险 3.2Eval.of risk风险评估3.3Follow-upof risk是否确认为有风险4.1Possible cause可能的原因4.2Validation measure验证措施4.3Validation plan验证计划4.4Date日期4.5Responsible person负责人No序号 ComponentName部件名称*Sam.No.取样部位ContactArea药品接触表面 Yes 是No否Yes是No否12345上盖筛网出料口密封圈容器Inner surface内表面Surface表面Surface内表面内表面内表面xxxxxPossibility of contamination with previous product与前批产品交叉污染的可能性Ditto同上Ditto同上Ditto同上Ditto同上LHH MMxxxxXCleaning procedure of SOP is not efficient清洁方法不足够有效 Ditto同上Ditto同上Ditto同上Ditto同上Check cleaning result at defined location在规定部位检查清洁结果Ditto同上Ditto同上Ditto同上Ditto同上See validation protocol 见清洁验证方案1.2 * Sample No. see five sampling points on Table 4. 取样部位：共5个取样点见表4.Attachment附件3: Risk Analysis Table for active ingredient风险分析表:FormatA+B Equipment Name