欧盟CGMP清洁验证方案1.doc

XXXX片（10mg规格）清洁验证方案Cleaning Validation Protocol of XXXX Tablets(10mg)方案起草Prepared by部门/岗位Dept./Position签名Signature起草日期DateQA年(Y) 月(M) 日(D)方案审核Reviewed by部门/岗位Dept./Position签名Signature审核日期DateQC主管QC Supervisor年(Y) 月(M) 日(D)QA主管QA Supervisor年(Y) 月(M) 日(D)方案批准Approved by部门/岗位Dept./Position签名Signature批准日期Date质量保证部经理QA Manager 年(Y) 月(M) 日(D)颁发部门Issued byQA生效日期：Effective Date分发部门Distributed to 制造部（1份）、QC（1份）Production Dept.(1 copy), QC (1 copy)制作备份：2份Copies prepared:2 pcs.目 录 Table of Contents1.清洁验证小组人员名单/Team Member List32.概述/General Introduction42.1本产品生产中使用的设备/Equipments used in the manufacturing42.2本产品生产中使用的容器具52.2Utensils used in the manufacturing52.3本产品生产中使用的设备主要材质52.3Construction materials contacting with drug product53.清洁验证目的/Purpose of cleaning validation54.职责/Responsibility64.1制造部/Production Dept.64.2质量保证部/QA Dept.64.3设备动力部/Engineering Dept.75.方案的执行/Execution of protocol85.1记录填写要求/Filling of Raw Data85.2偏差、OOS/OOT的调/Deviation, OOS/OOT investigation85.3方案改变的控制程序/Change Control86.清洁验证内容Content of cleaning validation96.1清洁验证的准备工作Preparation before cleaning validation96.2XXXX残留限度标准的设定/Criteria of residual limit136.3取样程序及取样方法/Sampling procedure and method146.4清洁验证过程/The process of cleaning validation206.5完成此清洁验证方案的所有人员身份资质的确认226.5 Identification of Personnel Executing this Protocol227.附件及索引Attachments and index238. 培训记录/Training Records24附件一 制造部及QC本次清洁确认过程中所有使用的设备、仪器、仪表、计量器具等确认或校验情况总结表26Attachment 1: list of verification for production equipments & QC instruments26附件二：取样位置示意图28Attachment 2 Schematic diagram for sampling locations28附件三：QC化学检测取样记录表41Attachment 3 Sampling record form for QC chemical testing41附件四：QC化学检测结果汇总表47Attachment 4 Summary table for QC chemical testing results47附件五：QC微生物检测取样记录表53Attachment 5 Sampling record form for QC Microbial testing53附件六：QC微生物检测结果汇总表62Attachment 6 Summary table for QC microbial testing results621.清洁验证小组人员名单/Team Member List组 长 Team Leader部门 Dept.岗位 Position姓名 Name制造部 Production Dept.业务经理 Supervisor小组成员 Team Member部门 Dept.岗位 Position姓名 Name设备动力部 Engineering Dept.业务经理 Supervisor制造部 Production Dept.工艺质量员 Technician制造部 Production Dept.生产协调员 Production Coordinator制造部 Production Dept.工艺质量员Production Coordinator制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员 Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员 Technician制造部 Production Dept.工段长 Team leader制造部 Production Dept.技术员TechnicianQCQC主管 QC SupervisorQC理化1组组长Leader of physicochemical team 1QC微生物组组长Leader of Microbial teamQC微生物检验员AnalyzerQAQA检查员 QA inspectorQAQA检查员 QA inspectorQAQA检查员 QA inspectorQA验证管理员Validation administrator2.概述/General Introduction根据GMP的要求，在口服固体制剂生产结束后，要对生产设备及操作间进行彻底清洁，以避免造成不同批号或不同品种产品之间的污染和交叉污染。根据各生产设备的操作、清洁及维护保养标准操作规程，将清洁方法分为水溶性及非水溶性两组，XXX属于水溶性组。为了验证清洁方法的稳定性与可靠性，在进行该产品10mg规格工艺验证的同时进行三次清洁验证。10mg规格每批生产结束后，对所有在生产中使用的生产设备及容器具进行清洁，清洁后取样检测化学残留及微生物残留，要求残留量低于设定的残留限度要求。因配料阶段原料不进行筛分，称重后放入塑料袋内再放入中转筒中储存，所以配料阶段清洁后只对接触原料的料铲进行化学及微生物取样，其它部位只进行微生物取样。According to requirements of GMP, the manufacturing equipments and rooms must be completely cleaned to avoid contamination of different batches of same products or cross-contamination of different products after manufacturing of oral solid dosage. There are two types of cleaning method based on SOPs of Operation/ Cleaning and maintenance for individual equipments: Water-cleaning method and non-water-cleaning method. The cleaning method for XXX belongs to the former. Three consecutive cleaning validation will be conducted synchronously during process validation of 10mg strength Tablets to validate the stability and reliability of cleaning method on the basis of finishing cleaning verification of trial batch. All equipments and utensils used in manufacturing must be completely cleaned once every batch of 10mg XXXX Tablets is finished, then sample to test chemical residual and microbial residual, the requirement is the level of residual is less than the limit of residual. Because API is not sieved during dispensing phase and directly put into a bag within a transferring container, only spoon contacting with API will be tested for chemical and microbial items, while other parts are only tested for microbial items.2.1本产品生产中使用的设备/Equipments used in the manufacturing列出本产品生产中所使用的所有设备List all equipments used in this product.2.2本产品生产中使用的容器具Utensils used in the manufacturing料仓、中转桶、料铲Bin, Transferring container and spoon.2.3本产品生产中使用的设备主要材质Construction materials contacting with drug product与药品接触的部位材质为304或316L不锈钢；铸铁；玻璃等。 Construction materials contacting with drug product is 304 or 316L stainless steel, cast iron or glass, etc.3.清洁验证目的/Purpose of cleaning validation验证制定的清洁程序可以使XXX的残留量及微生物残留量符合制定的残留限度的要求，清洁后的设备及容器具可以再次投入使用。The pre-determined cleaning methods will be validated that these methods can effectively remove residual and satisfy the limit for chemical residual and microbial residual. The equipments and utensils which are cleaned by this method can be reused again.4.职责/Responsibility4.1制造部/Production Dept.组织清洁验证方案及报告的起草；Prepare the cleaning validation protocol/report确定设备表面积、清洁方法、取样部位；Determine the surface area of equipments, cleaning method and sampling locations制定清洁操作规程；Establish cleaning procedure按清洁操作规程清洁设备和容器具；Clean equipments and utensils according to cleaning procedure确保清洁记录填写完整；Make sure the completeness of cleaning records将完成的清洁验证文件提交给QA审查；Submit the finalized cleaning documentation to QA review4.2质量保证部/QA Dept. QC审核清洁验证方案/报告；Review the cleaning validation protocol/report 制定清洁验证取样方法和检测方法； Establish sampling method and analytical method of cleaning validation对清洁后设备、容器具进行取样和检测，报告检验结果；Sample and test cleaned equipments and utensils, then report the testing results.使用在校验有效期内的仪器设备进行检测。 Use those instruments within calibration expired dateQA制定清洁验证计划及验证编号；Establish cleaning validation plan and No.负责组织审核清洁验证的方案/报告；Organize the review the cleaning validation protocol/report组织清洁验证相关部门进行清洁验证方案的培训并记录；Organize the training and record for cleaning validation protocol 负责验证实施过程的协调，保证验证项目实施进度；Coordinate the activities of cleaning validation to ensure the performance.验证实施中的监控检查；Supervise the validation activities.保证经验证的参数符合预期的标准；Make sure validated parameters meet pre-determined criteria负责组织验证方案中改变控制、偏差处理的调查；Organize the investigation for the change control and deviation handling.负责将完成的清洁验证文件归档。Archive the completed cleaning validation documentation质量保证部经理：QA Manager批准清洁验证方案、验证报告。Approve the cleaning validation protocol and report4.3设备动力部/Engineering Dept.保证清洁验证过程中，所用到的仪器仪表在校验有效期内；Ensure the instruments and meters involved in the cleaning validation have been calibrated and within calibration due date.保证验证过程中空调、纯化水、压缩空气、热水等的供应，确保清洁验证的实施。Ensure the normal working order and operation of HVAC, purified water system, compressed air, hot water for the cleaning validation.5.方案的执行/Execution of protocol5.1记录填写要求/Filling of Raw Data 所有清洁验证取样记录、检验结果应记录在批准过的方案的相应记录表格内；All sampling records and testing results related cleaning validation should be filled in the corresponding tables within approved validation protocol.记录、数据的填写、计算应审核并签字；Entry and calculation of raw data should be reviewed and signedQA应检查清洁验证数据记录是否完整、是否符合规定。QA should check the completeness of data records and make sure whether they are satisfied related requirements.5.2偏差、OOS/OOT的调/Deviation, OOS/OOT investigation当检测结果异常时，按照检验结果超标情况的处理文件编号XXX的操作规程执行。When the testing results are abnormal, follow the SOP the handling of out of specifications (Doc. No.:XXX) to investigate.当出现操作不符合SOP要求时，执行部门应通知QA，执行偏差调查。清楚地描述该偏差的情况、记录文件、对于偏差的影响的评估并经过批准、解决偏差所需采取的行动措施。偏差的调查应按照SOP偏差的处理文件编号XXX执行。When the operations dont meet the requirements specified in SOPs, the associated dept. should notify QA to make deviation investigation. It is required to describe the deviation occurance clearly and make reords. The evaluation focusing on the potential influence from the deviations should be done and the corrective actions must be approved. The deviation investigation should follow the SOP the handling of deviation (Doc. No.:XXX).5.3方案改变的控制程序/Change Control 当方案在执行的过程中，出现既定的内容或要求与实际执行情况或清洁验证的目的不一致，需要对原批准方案进行改变，执行部门应按照改变控制文件编号SOP-XXX的操作规程执行。 During implementing the protocol, when there happens some variance between the procedures specified in the protocol and actual situation or the purpose of validation and the approved protocol is in need of change, follow the SOP change control(Doc. No.: SOP-XXX).6.清洁验证内容Content of cleaning validation6.1清洁验证的准备工作Preparation before cleaning validation6.1.1进行生产设备清洁验证前，所有与清洁验证有关的仪器、设备应进行过校验或确认。仪表、计量器具等应校验合格，仪器、设备等应建立相应的操作、维护保养规程，对清洁验证的样品应建立相应的检验操作规程。本次清洁验证中制造部生产过程中所使用设备的确认情况及QC检验过程中所使用的仪器、设备、仪表、计量器具等确认或校验情况见附件一。 Before implementing the cleaning validation protocol, all instruments and equipments related to cleaning validation should be calibrated or verified. Instruments and gauges should be calibrated and within the calibration due date, instruments and equipments should have been established corresponding operation and maintenance procedure, and sample for cleaning validation have been established testing procedure. Attachment 1 is list of verification for equipments used in the manufacturing and instruments, equipments and gauges used in QC Lab.6.1.2清洁验证所需的试验条件/Testing condition needed for cleaning validationA.纯化水、培养基。Purified water, Culture MediaB.试剂、试液、对照品等。Reagents, solutions and reference standardsC.仪器、器具等。Instruments, utensilsD.其它条件。Etc.6.1.3清洁SOP名称及编号/SOPs name and number regarding to cleaning清洁SOP名称SOPs name regarding to cleaning SOP编号SOPs No.6.1.4清洁介质、用品及设备/Media, articles and equipments for cleaningA.清洁介质：饮用水、纯化水、压缩空气、75乙醇。 Cleaning media: drinking water, purified water, compressed air and 75% ethanolB.清洁用品：清洁布；一次性清洁布。 Articles for cleaning: cleaning cloth, single-service cleaning clothC.清洁设备：UC-3000P型超声波清洗机、全自动洗衣机。 Equipments for cleaning: UC-3000P-ultrasonic washing unit, automatic washer6.1.5清洁原则/Cleaning principle各工序严格按照自己工序使用的设备标准操作规程，在完成XXXX片10mg规格生产后，对本工序使用的设备及容器具进行清洁，清洁结束后通知QC人员取样检测，要求微生物及化学检测结果均符合规定的残留限度要求。Production staff should strictly follow the operating SOP for individual process and clean equipments and utensils used in the manufacturing after 10mg strength XXXX Tablets are finished, then inform QC analyst to sample. The object of clean is to make sure chemical residual and microbial residual meet pre-determined criteria. 6.1.6设备表面积/Surface area of individual equipments设备名称Equipment Name表面积（m2）Surface area合计 Total注：计算允许残留限度时，总面积按照2904dm2计算。Notes: Permitted residual level is calculated based on 2904dm2 of total surface area.6.1.7取样位置汇总表/Sampling locations取样点编号Sampling No.取样位置（材质）Sampling locations(construction materials)T001T002T003T004T005T006T007T008T009T010T011T012T013T014T015T016T017T018T019T020T021T022T023T024T025T026T027T028T029T030T031T032T033T034T035T036T037T038T039T040T041T042T043T044T045T046T047T048T049注：取样点示意图见附件二Note: Schematic diagram is shown as attachment 2 6.2XXXX残留限度标准的设定/Criteria of residual limitXXXX的最大残留限度应设定为25g/dm2。Maximum permitted residual limit of XXXX is 25g/dm2微生物残留不得超过20cfu/25cm2。Microbial residual must not exceed 20cfu/25cm26.3取样程序及取样方法/Sampling procedure and method6.3.1取样程序：生产人员清洁结束后，通知QC人员取样。取样应在清洁完成2小时内取样。取样时，取样人员首先对生产设备进行目检，可接受标准为：目视无可见残留。目检合格方可取样。取样时先进行微生物取样，再进行化测取样。 Sampling procedure: QC staff will be informed to sample after production staff finish cleaning. Sampling should be performed within 2 hours once cleaning is finished. When sampling, these equipments should be visual inspected the firstly, the acceptable criteria: No visual residual. Sampling will not be conducted if visual inspection doesnt meet the requirement. Microbiological sample should be sampled fisrtly, and then chemistry sample can be sampled secondly.6.3.2取样方法/Sampling methodA.用于药物活性成分残留测定样品的取样/Sampling for API residuall 选择适宜的PVC取样模板/Choose a suitable PVC sampling template若取样点表面形状规则，选择面积为100cm2的PVC模板；If the surface of sampling location is regular, choose a 100cm2 of PVC template.若取样点表面形状不规则,使用不同规格PVC模板,必须保证被取样面积为100cm2。If the surface of sampling location is irregular and PVC sampling template can be used with different shapes, then sampling area must be not less than 100cm2.l 取一烧杯，倒入适量色谱甲醇，将取样用棉签用色谱甲醇浸湿，在杯壁上挤掉棉签上多余的溶剂；将棉签头按在取样点表面上，用力使棉签杆稍弯曲，以使棉签一面与取样点表面完全接触，平稳而缓慢地按图一所示方向各均匀擦拭一遍，然后，翻转棉签，用另一面按图二所示方向进行第二次擦拭。擦拭完毕，将棉签头置具塞试管中。对每个取样点，用两根棉签重复取样两次，并将两个棉签头置同一具塞试管中。擦拭过程应覆盖整个PVC模板内所有表面。取样完毕，用一次性清洁布沾75%的乙醇擦拭被取样点表面。Add appropriate amount of methanol into a beaker, presoak a swab used for sampling with methanol. Expel the excess methanol from swab by pressing it against the beaker wall. Put the top of swab on the surface of sampling location, bend the handle of swab slightly to make a face of the swab completely contact the surface of sampling location, then swab this sampling location as the direction shown in schematic diagram 1.Turn this swab over, swab the same sampling location with another face of swab as the direction shown in schematic diagram 2. Then put the top of swab into a scintillation vial with stopper. There will be two swabs used to clean each sampling location, total two swabs will be collected into one scintillation vial. The whole face within the PVC template should be covered during swabbing. After sampling, clean the surface of sampling location with single-service cleaning cloth soaked with 75% ethanol.图一 图二Schematic diagram 1 Schematic diagram 1B.微生物检测样品取样/Sampling for microbial testingl 接触法/Contact plate若取样点位置光滑平整，面积大于25cm2，使用表面积为25cm2的接触碟以接触法取样，取样方法为：在靠近取样点的位置打开接触碟上盖，轻压接触碟使其与取样表面完全接触后，移开接触碟，立即盖上平皿并作好标识。取样完毕，用一次性清洁布蘸75的乙醇擦拭被取样点表面。If the surface of sampling location is smooth and area is more than 25cm2m 25cm2 of contact plate can be used for sampling. Sampling method is shown as following: open the cap of contact plate near sampling location, slightly press plate to make it completely contact the surface of sampling location, then remove the plate, immediately cap and label it. After sampling, clean the surface of sampling location with a single-service cleaning cloth soaked with 75% ethanol.l 擦拭法/Swabbing method若取样点位置凸凹不平或面积小于25cm2，可选择适宜大小的PVC模板确定取样面积。取一支3M快速取样棉签，将其红色按阀弯折45角，至听到按阀折断。挤压球腹使肉汤流入试管底端。抽出棉签，将棉签头按在取样表面上，使棉签与取样表面成30角，并用力使其稍弯曲，平稳而缓慢地按图一所示方向均匀擦拭一遍，然后，翻转棉签，用另一面按图二所示方向进行第二次擦拭。擦拭过程应覆盖整个PVC模板内所有表面。擦拭完毕，将棉签置试管中插紧并作好标识，取样完毕，用一次性清洁布蘸75的乙醇擦拭被取样点表面。If the surface of sampling location is not smooth or the area is less than 25cm2, choose an appropriate PVC template to determine sampling area. Take a 3M rapid sampling swab, bend the red valve to 45angle until valve is fracted. Expel the abdomen of ball to make broth flow into the bottom of tube, then draw out swab and press the top of swab on the surface of sampling location to make the angle between swab and sampling surface be 30and bend emphatically it, swab this sampling location as the direction shown in schematic diagram 1.Turn this swab over, swab the same sampling location with another face of swab as the direction shown in schematic diagram 2. The whole face within the PVC template should be covered during swabbing. After sampling, put swab in tube, seal and label, then clean the surface of sampling location with single-service cleaning cloth soaked with 75% ethanol.6.3.3化学检测方法及可接受标准 Chemical analytical method and acceptable criteriaA. 标准品溶液的配制： Standard solution: 标准品溶液浓度计算公式：Calculation formula of concentration for standard solutionB. 供试品的配制： Test solution: C.色谱条件: Chromatographic conditionsD.系统适用性试验/System suitability testE.计算/Calculationl 按外标法计算设备表面残留量。Calculate the residual on the surface of equipment according external reference methodF.可接受标准/Acceptable Criteria所有取样点药物活性成分残留量均不得超过25g/100cm2。对于计算修约后的为0g/100cm2的检测结果，报告为1g/100cm2；对于未检测出的检测结果，报告为ND。Residual of API on all sampling locations must not exceed 25g/100cm2. If testing results is 0g/100cm2 after rounded off, report it as 1g/100cm2; if testing results are “not detectable” , report it as ND.6.3.4微生物检测方法及可接受标准 Microbial analytical method and acceptable criteriaA. 培养/Incubationl 以cfu/25cm2形式报告Report the result in cfu/25cm2l 直接以培养结束后的菌落数报告。无菌落生长以1 cfu/25cm2报告。Report the number of cfu after incubation is finished, if there is no growth of microorganism, report is as 1 cfu/25cm2.l 可接受标准：所有取样点微生物残留不得超过20cfu/25cm2。Acceptable criteria: microbial residual on all smapling locations must be NMT 20cfu/25cm2.6.4清洁验证过程/The process of cleaning validation6.4.1XXXX片10mg规格生产结束后，制造部按各设备相应SOP的规定，对生产设备及容器具进行清洁。 Production staff will cle