欧盟清洁验证方案

1、Subject/ 主题Lovastat in Tablets 20mg Clea ning Validati on Protocol鲨鱼软骨片清洁验证方案文件编号：Table of contents目录1. Resp on sibility 职责2. Purpose目的3. Freque ncy 周期4. Releva nt SOP' s相关的SOP s5. Equipme nt设备6. Test Method测试方法7. Accepta nee Criteria 接受限度8. Risk An alysis风险分析9. Sampli ng Pla n抽样计划10. Action tak

2、e n whe n 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. Clea ning Validati on Executive Record 清洁验证过程记录14. Con clusi on结论Attachme nts 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. Respo nsibility职责QA is resp on sible for pla

3、 n the clea ning validati on.QA负责整个清洁验证的安排QC is resp on sible for sampli ng and an alysis.QC负责抽样及测试Product ion Departme nt is resp on sible for perform ing clea ning product ion equipme nt.生产部负责设备的清洁.2. Purpose 目的The purpose of this clea ning validatio n protocol is to dem on strate that the clea ni

4、ng procedure used to clean JHZ-250B high shear mixer / granulator, three dimensional mixer , CT-C-2 Hot Air Circulating Drier, JZF-400 granulators & mill Korsch PH300-36 TabletPress , BGD-150D high-efficie ncy coati ng mach ine andDPP-250B blister packag ing machi necan effectively remove residu

5、es of the products manu factured in ZS-650 Vortex Oscillator/Compact Sieve , JHZ-250B high shear mixer / granulator, three dimensionalmixer , CT-C-2 Hot Air Circulating Drier, JZF-400 granulators & mill Korsch PH300-36Tablet Press , BGD-150D high-efficie ncy coati ng machi ne andDPP-250B blister

6、 packagi ngmach ine to a predeterm ined 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 clea ning va

7、lidati on study is performed after three con secutive major clea nings ofZS-650 Vortex Oscillator/Compact Sieve , JHZ-250B high shear mixer / granulator, threedimensional mixer , CT-C-2 Hot Air CirculatingDrier , JZF-400 granulators & mill KorschPH300-36 Tablet Press , BGD-150D high-efficie ncy

8、coati ng machi ne andDPP-250B blisterpackagi ng mach ine after the manufacture of Lovastati n Tablets.连续三批生产后，进行清洗验证研究。4. Releva nt SOP ' s 相关的 SOP sSOP-PD-304-00Clea ning procedure forHLSG-300High Speed Mixer/Gra nu latorHLSG-300型高效湿法混合制粒机清洁操作规程SOP-PD-304-00Clea ning procedure forLF120E-B airpi

9、llow-dry Gran ulatorLF120E-B型沸腾干燥制粒机清洁操作规程SOP-PD-310-00Clea ning 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-307-00Clea ning procedure forHLD-1000B Hopper type of ble nderHLD-1000B型料斗式混合机清洁操作规程SOP-PD-306-00Clea ning procedure for YK-160gra nu latorsYK-160整粒机清洁操作规程SOP-PD

10、-311-00Clea ning procedure for BG-300E high-efficie ncy coat ing mach ineBG-300E型高效包衣机清洁操作规程SOP-PD-313-00Clea ning procedure forDPH-130、DPP-250B blister packag ingmach ineDPH-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 sampli ng for clea ning validati on

11、清洗验证设备表面取样ESS-VD014Select ion of the worst case in clea ning validatio n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Equipme nt Name设备名称Product Con tact SurfaceArea与产品接触面积（m ）1HLSG-300 high speed mixer / granulatorHLSG-300高效湿法混合制粒机2.81LF120E-B airp

12、illow-dry Gra nulatorLF120E-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-160gra nulatorsYK-160型整粒机0.377DPH-130DPP-250blisterpackag ingmachi neDPH-130 DPP-250型多功能自动铝塑包装机1.08BG-300Ehigh-efficie ncy coat ing machi neBG

13、-300E型高效包衣机8.432Total Product Con tact Surface Area （m）与产品接触面积总和（m）99.625.1 List of Equipme nt设备清单The list of Equipme nt used in the manufacture of Lovastati n Tablets:有关鲨鱼软骨片生产线的所有机器列出如下：1. HLSG-300 high speed mixer / granulator HLSG-300高效湿法混合制粒机2. LF120E-B airpillow-dry Gran ulatorLF120E-B 沸腾干燥制粒机

14、器3. ZP43Tablet Press ZP43 Tablet PressZP43 旋转式压片机4.METAL DETECTORS 属探测仪5. HLD-1000BHLD-1000B Hopper type of ble nder HLD-1000B型料斗式混合机6. YK-160gra nulators YK-160型整粒机7. DPH-130DPP-250blister packaging machinedph-130 dpp-250型多功能自动8. BG-300Ehigh-efficiency coating machineBG-300E型高效包衣机Table 1 表 1:5.2 Va

15、lidation Scope 验证围HLSG-300 high shear mixer / granulatorHLSG-300 高效湿法制粒机LF120E-B airpillow-dry Granulator机器ZP43Tablet Press ZP43METAL DETECTORHLD-1000B granule mixer HLD-1000BYK-160 granulators YK-160LF120E-B沸腾干燥制粒旋转式压片机金属探测仪型料斗式混合机型整粒机DPH-130、DPP-250 blister packaging machine 台匕能BG-300Ehigh-efficie

16、ncy coating machine6. Test Method 测试方法DPH-130、DPP-250 型多功自动铝塑包装机BG-300E型高效包衣机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 stud

17、ies. 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。Sampling Method 抽样方法Swab Sampling 擦拭

18、法Ringing sampling 最终淋洗水取样法7. Acceptanee Criteria接受限度Visual In spect ion目测检查Accepta nee Criteria接受限度There is no visible residue in equipme nt surface after clea ning.设备在清洁后，无可见的物质残留在设备表面Accepta nee 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/cm 2，即 50 CFU / 25 cm 2- For

19、rinsing samples /对冲淋样品：Microbes 微生物含量：100 CFU/mlAccepta nee Criteria of assay化学测试接受限度Active In gredie nt (see Attachme nt 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)Test freque ncy检测次数The clea ning validati on studies are con ducted after three con secutiv

20、e major clea nings of Nourkri n 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 analysisshouldbe done before cleaning validation sampling. The Criticallocationwill be determinedat risk analysis. Risk analyses are summarized in A

21、ttachment land 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 in gredie nt活性成分9.1 Swab sampli ng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：9.1.1 HLSG-300high shear m

22、ixer/gra nulator 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Sampli ng Locati on取样位置Sampli ng 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 表面HLSG-3003200腔盖Rim area un der the seal盖的边缘HLSG-300-4200表面HLSG-300-5200切粒切刀桨片HLSG-3

23、00-6全部搅拌切刀下表面HLSG-300-72009.1.3 ZP43Tablet PressZP43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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积下料斗表面PG16 ZP431200饲料靴表面PG16 ZP432200孔PG16 ZP433200出片器表面PG16 ZP434200除粉器表面PG16 ZP435200转盘侧面PG16 ZP43-6200底面PG16 ZP437 :200模孔表面PG

24、16 ZP4382009.1.4 HLD-1000BHLD-1000B Hopper type of ble nderHLD-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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积加料口表面JSH-600-1200边缘JSH-600-2200出料口表面JSH-600-32009.1.6 JZF-400 granu lators & mill JZF-400型整粒、粉碎机Total are 6

25、samples:总共6个取样点：Table 8 表 8:Part Name部件名称Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积盖子表面JZF-400-1200表面JZF-400-2200容器侧面JZF-400-3200底部JZF-400-4200出料口表面JZF-400-5200表面JZF-400-62009.1.7 DPP-250B blister packagi ng machi neDPP-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

26、Name部件名称Sampli ng Locati on取样位置Sampli ng 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 NameSampli ng Locati onSampli ng No.Swab Area Ss (cm2) 取样面积部件名称取样位置取样点加料斗上侧面M-1200下侧面M-22

27、00出料斗表面M-3200废片出口表面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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积配料锅顶部BGD-150D1200侧面BGD-150D2200底部BGD-150D3200包衣锅侧面BGD-150D4200底部BGD-150D5200顶部BGD-150D6200接缝处BGD-150D7200边缘B

28、GD-150D82009.2 Ri ngi ng sampli ng 淋洗水取样BGD-150D high-efficie ncy coati ng mach ine包衣机Sampling location取样部位：硅胶管、喷枪Three dimensional mixerHLD-1000B型料斗式混合机清洁操作规程Sampli ng location取样部位：腔体For Microbes微生物取样点9.3.1 JHZ -250B high shear mixer/granulatorJHZ-250B高效湿法制粒机Total are 7 samples:总共7个取样点：Table 12 表 1

29、2:Part Name部件名称Sampli ng Locati on取样位置Sampli ng 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 表面JHZ-250B-C25腔盖Rim area un der the seal盖的边缘JHZ-250B-D25表面JHZ-250B-E25切粒切刀桨片JHZ-250B-F25搅拌切刀下表面JHZ-250B-G25ZS-650漩涡振荡筛Total are 5 samples:总共5个取样点：Table 13 表 1

30、3:Part Name部件名称Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积上盖表面ZS-650-A25筛网上表面ZS-650-B25出料口表面ZS-650-C25密封圈表面ZS-650-D25容器表面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Sampli ng Locati on取样位置Sampli ng No.取

31、样点Swab Area Ss (cm2) 取样面积下料斗表面PH-300-36-A25饲料靴表面PH-300-36-B25孔PH-300-36-C25出片器表面PH-300-36-D:25除粉器表面PH-300-36-E25转盘侧面PH-300-36-F25底面PH-300-36-G25模孔表面PH-300-36-H259.3.4 Three dime nsional 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Sampli ng Locati on取样位置Sampli ng

32、 No.取样点Swab Area Ss (cm2) 取样面积加料口表面JSH-600-A25边缘JSH-600-B25出料口表面JSH-600-C259.3.5 CT-C-2 Hot Air Circulati ng 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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积烘盘表面CT-C-2-A 25侧面CT-C-2-B25箱体左侧CT-C-2-C25右侧CT-C-2-D25顶

33、部CT-C-2-E25接缝处CT-C-2-F:25台车托架CT-C-2-G25边缘CT-C-2-H25箱门表面CT-C-2-I25密封条CT-C-2-J259.3.6 JZF-400 granu lators & mill JZF-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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积盖子表面JZF-400-A25表面JZF-400-B25容器侧面JZF-400-C25底部JZF-400-

34、D25出料口表面JZF-400-E25表面JZF-400-F259.3.7 DPP-250B blister packagi ng machi neDPP-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Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积加料斗侧面DPP-250B-125底部DPP-250B-2:25分料刷表面DPP-250B-325滚刷表面DPP-250B-4259.3.8 METAL DETECTOR金属探测仪

35、Total are 4 samples:总共4个取样点：Table 19 表 19:Part Name部件名称Sampli ng Locati on取样位置Sampli ng No.取样点Swab Area Ss (cm2) 取样面积加料斗上侧面M-A25下侧面M-B:25出料斗表面M-C25废片出口表面M-D259.3.9 BGD-150D high-efficie ncy coat ing machi ne 包衣机Total are 8 samples:总共8个取样点：Table 20 表 20:Part Name部件名称Sampli ng Locati on取样位置Sampli ng N

36、o.取样点Swab Area Ss (cm2) 取样面积配料锅顶部BGD-150DA25侧面BGD-150DB25底部BGD-150DC25包衣锅侧面BGD-150DD25底部BGD-150DE25顶部BGD-150DF25接缝处BGD-150DG25边缘BGD-150DH259.4 Ri ngi ng sampli ng 淋洗水取样BGD-150D high-efficie ncy coati ng mach ine包衣机Sampling location取样部位：硅胶管、喷枪Three dimensional mixer HLD-1000B型料斗式混合机清洁操作规程 Sampli ng l

37、ocation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? In spect the process of operati on检查测试过程1.In spect the equipme nt of assay检查分析所用的仪器2.In spect the step of operati on检查实验步骤3.In spect the process of sampli ng检查抽样过程QAQC and the product ion departme nt calculate with the

38、 results of in spect.QAQC 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.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

39、时 Product changed/ 产品变化时附件 1-18附件 19 和取样 附件 2012. Cleaning Validation Executive Record 清洁验证过程记录Risk Analysis Table风险分析表Active Ingredient目检Microbes 目检和取样清洗验证棉签取样接受限度的计算Visual Inspection and Sampling forActive Ingredient 分析结果Microbes 分析结果 取样回收率试验Visual Inspection and Sampling for附件 21Analytical Result

40、s for附件 22Analytical Results for附件 23Sampling Recovery Test附件 24附件 25附件 26Swab Chacterization for Cleaning Validation 清洗验证棉签特性研究Swab Sampling for Cleaning Validation Calculation for Acceptance Criteria14. CONCLUSION结论The results obtained should not exceed the calculated contamination limit. The clea

41、ning 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。1.1No.序号nt NameFormatA+BComp one

42、nt Name 部件名称制粒锅出料口腔盖切粒切刀搅拌切刀设备名称:JHZ-250B High Shear Mixer / GranulatorJHZ-250B高效湿法制粒机Date日期:1.2*Sam.No.取样部位Con tactArea药品接触表面Inner surface 表面表面表面表面表面22.1Critica l关 键Yes是No 否3.1Risk forProcess Step风险Possibility of con tam in ati on 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1.2* Sample

43、 No. see the seven sampling points on Table3.3.2Eval. of risk 风险 评估3.3Follow-upof risk是否确认为有风险Yes是No 否4.1Possible cause 可能的原因Clea ning procedure of SOP is not efficie nt 清洁方法不足 够有效Ditto 同上Ditto同上Ditto同上取样部位：共7个取样点 见表3.4.2Validati onmeasur验证措施Check clea ning result at defi ned locati on 在规定部位检 查清洁结果D

44、itto同上Ditto同上Ditto同上4.3 Validati on pla n 验证计划See validati on protocol 见清洁验证4.4Date日期4.5Resp on sib le pers on负责人FormatA+BEquipme nt Name设备名称：ZS-650 Vortex Oscillator/Compact Sieve Date ZS-650漩涡振荡筛日期:12341.11.22.13.13.23.34.14.24.34.44.5*Eval.Follow-upPossibleValidati onValidati onDateResp on sibleN

45、oComp onentSam.Con tactCriticalRisk for Processofof riskcausemeasurepla n日期pers on序Name No.Area关键Steprisk是否确认为可能的原因验证措施验证计划负责人号部件名称取样药品接触表风险风险有风险部位面评估NoYesNoYes否是否是in gredie nt 风险分析表：设备名称：Korsch PH300-36 Tablet Press DateKORSCH PH-300-36旋转式压片机日期:12345上盖筛网出料口密封圈容器Inn er surface 表面Surface 表面Surface表面表

46、面表面xxxxxPossibility of con tam in ati on 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LHHMMxxxxXClea ning procedure of SOP is not efficie nt 清洁方法不足 够有效Ditto 同上Ditto 同上Ditto 同上Ditto 同上Check clea ning result at defi ned locati on 在规定部位检 查清洁结果Ditto 同上Ditto 同上Ditto 同上Ditto 同上See va

47、lidati on 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 activent NameFormat1231.11.2*2.13.13.23.3Sam.Con tactCriticaRisk forEval.Follow-upNoComp onentNo.ArealProcess Stepof riskof riskName取样药品接触表关风险风险是否确认为序部件名称部位面键评

48、估有风险号YesNoYesNo是否是否4.1Possible cause 可能的原因4.2Validati on measur 验证措施4.3Validati onpla n验证计划4.4Date日期A+B12345Hopper下料斗饲料靴出片器除粉器 压片室隔板Inn er surface 表面表面及孔表面表面表面XXXXXPossibility of con tam in ati on with previous product 与前批产品交叉污 染的可能性Ditto 同上DittoMHMMLxxxXXClea ning procedure of SOP is not efficie nt 清洁方法不足 够有效Ditto 同上Ditto 同上Check clea ning result at defi ned locati on 在规定部位检 查清洁结果Ditto 同上DittoSee validati on protocol 见清洁验