XXXX片（10mg規(guī)格）清潔驗證方案Cleaning Validation Protocol of XXXX Tablets(10mg)方案起草Prepared by部門/崗位Dept./Position簽名Signature起草日期DateQA年(Y) 月(M) 日(D)方案審核Reviewed by部門/崗位Dept./Position簽名Signature審核日期DateQC主管QC Supervisor年(Y) 月(M) 日(D)QA主管QA Supervisor年(Y) 月(M) 日(D)方案批準Approved by部門/崗位Dept./Position簽名Signature批準日期Date質(zhì)量保證部經(jīng)理QA Manager 年(Y) 月(M) 日(D)頒發(fā)部門Issued byQA生效日期：Effective Date分發(fā)部門Distributed to 制造部（1份）、QC（1份）Production Dept.(1 copy), QC (1 copy)制作備份：2份Copies prepared:2 pcs.目 錄 Table of Contents1.清潔驗證小組人員名單/Team Member List32.概述/General Introduction42.1本產(chǎn)品生產(chǎn)中使用的設備/Equipments used in the manufacturing42.2本產(chǎn)品生產(chǎn)中使用的容器具52.2Utensils used in the manufacturing52.3本產(chǎn)品生產(chǎn)中使用的設備主要材質(zhì)52.3Construction materials contacting with drug product53.清潔驗證目的/Purpose of cleaning validation54.職責/Responsibility64.1制造部/Production Dept.64.2質(zhì)量保證部/QA Dept.64.3設備動力部/Engineering Dept.75.方案的執(zhí)行/Execution of protocol85.1記錄填寫要求/Filling of Raw Data85.2偏差、OOS/OOT的調(diào)/Deviation, OOS/OOT investigation85.3方案改變的控制程序/Change Control86.清潔驗證內(nèi)容Content of cleaning validation96.1清潔驗證的準備工作Preparation before cleaning validation96.2XXXX殘留限度標準的設定/Criteria of residual limit136.3取樣程序及取樣方法/Sampling procedure and method146.4清潔驗證過程/The process of cleaning validation206.5完成此清潔驗證方案的所有人員身份資質(zhì)的確認226.5 Identification of Personnel Executing this Protocol227.附件及索引Attachments and index238. 培訓記錄/Training Records24附件一 制造部及QC本次清潔確認過程中所有使用的設備、儀器、儀表、計量器具等確認或校驗情況總結(jié)表26Attachment 1: list of verification for production equipments & QC instruments26附件二：取樣位置示意圖28Attachment 2 Schematic diagram for sampling locations28附件三：QC化學檢測取樣記錄表41Attachment 3 Sampling record form for QC chemical testing41附件四：QC化學檢測結(jié)果匯總表47Attachment 4 Summary table for QC chemical testing results47附件五：QC微生物檢測取樣記錄表53Attachment 5 Sampling record form for QC Microbial testing53附件六：QC微生物檢測結(jié)果匯總表62Attachment 6 Summary table for QC microbial testing results621.清潔驗證小組人員名單/Team Member List組 長 Team Leader部門 Dept.崗位 Position姓名 Name制造部 Production Dept.業(yè)務經(jīng)理 Supervisor小組成員 Team Member部門 Dept.崗位 Position姓名 Name設備動力部 Engineering Dept.業(yè)務經(jīng)理 Supervisor制造部 Production Dept.工藝質(zhì)量員 Technician制造部 Production Dept.生產(chǎn)協(xié)調(diào)員 Production Coordinator制造部 Production Dept.工藝質(zhì)量員Production Coordinator制造部 Production Dept.工段長 Team leader制造部 Production Dept.技術(shù)員 Technician制造部 Production Dept.工段長 Team leader制造部 Production Dept.技術(shù)員Technician制造部 Production Dept.工段長 Team leader制造部 Production Dept.技術(shù)員Technician制造部 Production Dept.工段長 Team leader制造部 Production Dept.技術(shù)員 Technician制造部 Production Dept.工段長 Team leader制造部 Production Dept.技術(shù)員TechnicianQCQC主管 QC SupervisorQC理化1組組長Leader of physicochemical team 1QC微生物組組長Leader of Microbial teamQC微生物檢驗員AnalyzerQAQA檢查員 QA inspectorQAQA檢查員 QA inspectorQAQA檢查員 QA inspectorQA驗證管理員Validation administrator2.概述/General Introduction根據(jù)GMP的要求，在口服固體制劑生產(chǎn)結(jié)束后，要對生產(chǎn)設備及操作間進行徹底清潔，以避免造成不同批號或不同品種產(chǎn)品之間的污染和交叉污染。根據(jù)各生產(chǎn)設備的操作、清潔及維護保養(yǎng)標準操作規(guī)程，將清潔方法分為水溶性及非水溶性兩組，XXX屬于水溶性組。為了驗證清潔方法的穩(wěn)定性與可靠性，在進行該產(chǎn)品10mg規(guī)格工藝驗證的同時進行三次清潔驗證。10mg規(guī)格每批生產(chǎn)結(jié)束后，對所有在生產(chǎn)中使用的生產(chǎn)設備及容器具進行清潔，清潔后取樣檢測化學殘留及微生物殘留，要求殘留量低于設定的殘留限度要求。因配料階段原料不進行篩分，稱重后放入塑料袋內(nèi)再放入中轉(zhuǎn)筒中儲存，所以配料階段清潔后只對接觸原料的料鏟進行化學及微生物取樣，其它部位只進行微生物取樣。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本產(chǎn)品生產(chǎn)中使用的設備/Equipments used in the manufacturing列出本產(chǎn)品生產(chǎn)中所使用的所有設備List all equipments used in this product.2.2本產(chǎn)品生產(chǎn)中使用的容器具Utensils used in the manufacturing料倉、中轉(zhuǎn)桶、料鏟Bin, Transferring container and spoon.2.3本產(chǎn)品生產(chǎn)中使用的設備主要材質(zhì)Construction materials contacting with drug product與藥品接觸的部位材質(zhì)為304或316L不銹鋼；鑄鐵；玻璃等。 Construction materials contacting with drug product is 304 or 316L stainless steel, cast iron or glass, etc.3.清潔驗證目的/Purpose of cleaning validation驗證制定的清潔程序可以使XXX的殘留量及微生物殘留量符合制定的殘留限度的要求，清潔后的設備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.職責/Responsibility4.1制造部/Production Dept.組織清潔驗證方案及報告的起草；Prepare the cleaning validation protocol/report確定設備表面積、清潔方法、取樣部位；Determine the surface area of equipments, cleaning method and sampling locations制定清潔操作規(guī)程；Establish cleaning procedure按清潔操作規(guī)程清潔設備和容器具；Clean equipments and utensils according to cleaning procedure確保清潔記錄填寫完整；Make sure the completeness of cleaning records將完成的清潔驗證文件提交給QA審查；Submit the finalized cleaning documentation to QA review4.2質(zhì)量保證部/QA Dept. QC審核清潔驗證方案/報告；Review the cleaning validation protocol/report 制定清潔驗證取樣方法和檢測方法； Establish sampling method and analytical method of cleaning validation對清潔后設備、容器具進行取樣和檢測，報告檢驗結(jié)果；Sample and test cleaned equipments and utensils, then report the testing results.使用在校驗有效期內(nèi)的儀器設備進行檢測。 Use those instruments within calibration expired dateQA制定清潔驗證計劃及驗證編號；Establish cleaning validation plan and No.負責組織審核清潔驗證的方案/報告；Organize the review the cleaning validation protocol/report組織清潔驗證相關(guān)部門進行清潔驗證方案的培訓并記錄；Organize the training and record for cleaning validation protocol 負責驗證實施過程的協(xié)調(diào)，保證驗證項目實施進度；Coordinate the activities of cleaning validation to ensure the performance.驗證實施中的監(jiān)控檢查；Supervise the validation activities.保證經(jīng)驗證的參數(shù)符合預期的標準；Make sure validated parameters meet pre-determined criteria負責組織驗證方案中改變控制、偏差處理的調(diào)查；Organize the investigation for the change control and deviation handling.負責將完成的清潔驗證文件歸檔。Archive the completed cleaning validation documentation質(zhì)量保證部經(jīng)理：QA Manager批準清潔驗證方案、驗證報告。Approve the cleaning validation protocol and report4.3設備動力部/Engineering Dept.保證清潔驗證過程中，所用到的儀器儀表在校驗有效期內(nèi)；Ensure the instruments and meters involved in the cleaning validation have been calibrated and within calibration due date.保證驗證過程中空調(diào)、純化水、壓縮空氣、熱水等的供應，確保清潔驗證的實施。Ensure the normal working order and operation of HVAC, purified water system, compressed air, hot water for the cleaning validation.5.方案的執(zhí)行/Execution of protocol5.1記錄填寫要求/Filling of Raw Data 所有清潔驗證取樣記錄、檢驗結(jié)果應記錄在批準過的方案的相應記錄表格內(nèi)；All sampling records and testing results related cleaning validation should be filled in the corresponding tables within approved validation protocol.記錄、數(shù)據(jù)的填寫、計算應審核并簽字；Entry and calculation of raw data should be reviewed and signedQA應檢查清潔驗證數(shù)據(jù)記錄是否完整、是否符合規(guī)定。QA should check the completeness of data records and make sure whether they are satisfied related requirements.5.2偏差、OOS/OOT的調(diào)/Deviation, OOS/OOT investigation當檢測結(jié)果異常時，按照檢驗結(jié)果超標情況的處理文件編號XXX的操作規(guī)程執(zhí)行。When the testing results are abnormal, follow the SOP the handling of out of specifications (Doc. No.:XXX) to investigate.當出現(xiàn)操作不符合SOP要求時，執(zhí)行部門應通知QA，執(zhí)行偏差調(diào)查。清楚地描述該偏差的情況、記錄文件、對于偏差的影響的評估并經(jīng)過批準、解決偏差所需采取的行動措施。偏差的調(diào)查應按照SOP偏差的處理文件編號XXX執(zhí)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方案改變的控制程序/Change Control 當方案在執(zhí)行的過程中，出現(xiàn)既定的內(nèi)容或要求與實際執(zhí)行情況或清潔驗證的目的不一致，需要對原批準方案進行改變，執(zhí)行部門應按照改變控制文件編號SOP-XXX的操作規(guī)程執(zhí)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.清潔驗證內(nèi)容Content of cleaning validation6.1清潔驗證的準備工作Preparation before cleaning validation6.1.1進行生產(chǎn)設備清潔驗證前，所有與清潔驗證有關(guān)的儀器、設備應進行過校驗或確認。儀表、計量器具等應校驗合格，儀器、設備等應建立相應的操作、維護保養(yǎng)規(guī)程，對清潔驗證的樣品應建立相應的檢驗操作規(guī)程。本次清潔驗證中制造部生產(chǎn)過程中所使用設備的確認情況及QC檢驗過程中所使用的儀器、設備、儀表、計量器具等確認或校驗情況見附件一。 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清潔驗證所需的試驗條件/Testing condition needed for cleaning validationA.純化水、培養(yǎng)基。Purified water, Culture MediaB.試劑、試液、對照品等。Reagents, solutions and reference standardsC.儀器、器具等。Instruments, utensilsD.其它條件。Etc.6.1.3清潔SOP名稱及編號/SOPs name and number regarding to cleaning清潔SOP名稱SOPs name regarding to cleaning SOP編號SOPs No.6.1.4清潔介質(zhì)、用品及設備/Media, articles and equipments for cleaningA.清潔介質(zhì)：飲用水、純化水、壓縮空氣、75乙醇。 Cleaning media: drinking water, purified water, compressed air and 75% ethanolB.清潔用品：清潔布；一次性清潔布。 Articles for cleaning: cleaning cloth, single-service cleaning clothC.清潔設備：UC-3000P型超聲波清洗機、全自動洗衣機。 Equipments for cleaning: UC-3000P-ultrasonic washing unit, automatic washer6.1.5清潔原則/Cleaning principle各工序嚴格按照自己工序使用的設備標準操作規(guī)程，在完成XXXX片10mg規(guī)格生產(chǎn)后，對本工序使用的設備及容器具進行清潔，清潔結(jié)束后通知QC人員取樣檢測，要求微生物及化學檢測結(jié)果均符合規(guī)定的殘留限度要求。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設備表面積/Surface area of individual equipments設備名稱Equipment Name表面積（m2）Surface area合計 Total注：計算允許殘留限度時，總面積按照2904dm2計算。Notes: Permitted residual level is calculated based on 2904dm2 of total surface area.6.1.7取樣位置匯總表/Sampling locations取樣點編號Sampling No.取樣位置（材質(zhì)）Sampling locations(construction materials)T001T002T003T004T005T006T007T008T009T010T011T012T013T014T015T016T017T018T019T020T021T022T023T024T025T026T027T028T029T030T031T032T033T034T035T036T037T038T039T040T041T042T043T044T045T046T047T048T049注：取樣點示意圖見附件二Note: Schematic diagram is shown as attachment 2 6.2XXXX殘留限度標準的設定/Criteria of residual limitXXXX的最大殘留限度應設定為25g/dm2。Maximum permitted residual limit of XXXX is 25g/dm2微生物殘留不得超過20cfu/25cm2。Microbial residual must not exceed 20cfu/25cm26.3取樣程序及取樣方法/Sampling procedure and method6.3.1取樣程序：生產(chǎn)人員清潔結(jié)束后，通知QC人員取樣。取樣應在清潔完成2小時內(nèi)取樣。取樣時，取樣人員首先對生產(chǎn)設備進行目檢，可接受標準為：目視無可見殘留。目檢合格方可取樣。取樣時先進行微生物取樣，再進行化測取樣。 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取樣方法/Sampling methodA.用于藥物活性成分殘留測定樣品的取樣/Sampling for API residuall 選擇適宜的PVC取樣模板/Choose a suitable PVC sampling template若取樣點表面形狀規(guī)則，選擇面積為100cm2的PVC模板；If the surface of sampling location is regular, choose a 100cm2 of PVC template.若取樣點表面形狀不規(guī)則,使用不同規(guī)格PVC模板,必須保證被取樣面積為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 取一燒杯，倒入適量色譜甲醇，將取樣用棉簽用色譜甲醇浸濕，在杯壁上擠掉棉簽上多余的溶劑；將棉簽頭按在取樣點表面上，用力使棉簽桿稍彎曲，以使棉簽一面與取樣點表面完全接觸，平穩(wěn)而緩慢地按圖一所示方向各均勻擦拭一遍，然后，翻轉(zhuǎn)棉簽，用另一面按圖二所示方向進行第二次擦拭。擦拭完畢，將棉簽頭置具塞試管中。對每個取樣點，用兩根棉簽重復取樣兩次，并將兩個棉簽頭置同一具塞試管中。擦拭過程應覆蓋整個PVC模板內(nèi)所有表面。取樣完畢，用一次性清潔布沾75%的乙醇擦拭被取樣點表面。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.圖一 圖二Schematic diagram 1 Schematic diagram 1B.微生物檢測樣品取樣/Sampling for microbial testingl 接觸法/Contact plate若取樣點位置光滑平整，面積大于25cm2，使用表面積為25cm2的接觸碟以接觸法取樣，取樣方法為：在靠近取樣點的位置打開接觸碟上蓋，輕壓接觸碟使其與取樣表面完全接觸后，移開接觸碟，立即蓋上平皿并作好標識。取樣完畢，用一次性清潔布蘸75的乙醇擦拭被取樣點表面。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若取樣點位置凸凹不平或面積小于25cm2，可選擇適宜大小的PVC模板確定取樣面積。取一支3M快速取樣棉簽，將其紅色按閥彎折45角，至聽到按閥折斷。擠壓球腹使肉湯流入試管底端。抽出棉簽，將棉簽頭按在取樣表面上，使棉簽與取樣表面成30角，并用力使其稍彎曲，平穩(wěn)而緩慢地按圖一所示方向均勻擦拭一遍，然后，翻轉(zhuǎn)棉簽，用另一面按圖二所示方向進行第二次擦拭。擦拭過程應覆蓋整個PVC模板內(nèi)所有表面。擦拭完畢，將棉簽置試管中插緊并作好標識，取樣完畢，用一次性清潔布蘸75的乙醇擦拭被取樣點表面。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化學檢測方法及可接受標準 Chemical analytical method and acceptable criteriaA. 標準品溶液的配制： Standard solution: 標準品溶液濃度計算公式：Calculation formula of concentration for standard solutionB. 供試品的配制： Test solution: C.色譜條件: Chromatographic conditionsD.系統(tǒng)適用性試驗/System suitability testE.計算/Calculationl 按外標法計算設備表面殘留量。Calculate the residual on the surface of equipment according external reference methodF.可接受標準/Acceptable Criteria所有取樣點藥物活性成分殘留量均不得超過25g/100cm2。對于計算修約后的為0g/100cm2的檢測結(jié)果，報告為1g/100cm2；對于未檢測出的檢測結(jié)果，報告為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微生物檢測方法及可接受標準 Microbial analytical method and acceptable criteriaA. 培養(yǎng)/Incubationl 以cfu/25cm2形式報告Report the result in cfu/25cm2l 直接以培養(yǎng)結(jié)束后的菌落數(shù)報告。無菌落生長以1 cfu/25cm2報告。Report the number of cfu after incubation is finished, if there is no growth of microorganism, report is as 1 cfu/25cm2.l 可接受標準：所有取樣點微生物殘留不得超過20cfu/25cm2。Acceptable criteria: microbial residual on all smapling locations must be NMT 20cfu/25cm2.6.4清潔驗證過程/The process of cleaning validation6.4.1XXXX片10mg規(guī)格生產(chǎn)結(jié)束后，制造部按各設備相應SOP的規(guī)定，對生產(chǎn)設備及容器具進行清潔。 Production staff will cle