穩(wěn)定性試驗(yàn)方案計(jì)劃

PAGE8StabilityStudyProtocolforExhibitBatchofChloroquinePhosphateTabletsUSP,250mg規(guī)格為250mg的USP磷酸氯喹片長(zhǎng)期、中期及加速穩(wěn)定性研究方案ProjectNo.項(xiàng)目號(hào)DP-ST-001-2008PreparedBy:Date:起草者：日期：ReviewedByQA:Date:審核者：日期：ApprovedBy:Date:批準(zhǔn)者：日期：StartingDate:CompletedDate:開始日期：結(jié)束日期：Contents目錄TOC\o"1-3"\p""\h\z\u1. Purpose目的…………………………12. Scope范圍…………………………..13. References參考資料…………………..14. GeneralInformation基本信息………………………..1 StabilitySamples穩(wěn)定性研究樣品…………1 ProductOutline樣品概述………………..……1 Formulation處方………………1 Container-ClosureSystems包裝……………1 Labeling標(biāo)簽…………………..1 SamplesandPackage樣品與包裝………….15. StabilityTesting穩(wěn)定性測(cè)試…………1 SampleReceiptandStorage樣品接收與儲(chǔ)存……………1 StorageConditionsandTestingTimePoints儲(chǔ)存條件與檢測(cè)時(shí)間點(diǎn)……1 Sampling取樣…………………1 TestingMatrix穩(wěn)定性測(cè)試項(xiàng)目表……………1 ParametersandAcceptanceCriteria檢測(cè)項(xiàng)目及質(zhì)量標(biāo)準(zhǔn)………………1 Degradationproducts降解產(chǎn)物……………16. DataPresentation數(shù)據(jù)匯總…………17. Reporting報(bào)告………………………1 IntermediateReports中期報(bào)告………………1 SummaryReport總結(jié)報(bào)告…………………1 StabilityDocuments穩(wěn)定性文件夾…………18. Appendix附件…………………………1

Purpose目的ThepurposeofstabilitytestingistoprovideevidenceofhowtheQuality,Strength,DegradationProductsandPurityoftheChloroquinePhosphateTabletsUSP,250mgwillchangewithtimeundertheinfluenceofenvironmentalroomtemperatureandrelativehumidityconditions.Datacollectedfromthestabilitystudywillenablerecommendedstorageconditionsandprovidejustificationforestablishingandsubmittingthedatatoregulatoryauthoritiesforapprovingtheshelflifeformarketingpurposes.Inaddition,3monthsofthestabilitydatawillbesubmittedtoUSFDAasrequiredforsubmissionpurposesoftheANDAapplication.此穩(wěn)定性研究的目的是為了考察磷酸氯喹片在環(huán)境因素的影響下(例如：溫度和濕度)其性質(zhì)、規(guī)格、降解產(chǎn)物和含量等隨時(shí)間而變化的規(guī)律，依據(jù)穩(wěn)定性研究的數(shù)據(jù)確定該產(chǎn)品的儲(chǔ)藏條件和有效期。Scope范圍ThisprocedureisapplicabletoFinishedProductStabilityLabatHisunPharmaceutical(Hangzhou)Co.Ltd.Fuyang,Hangzhou.適用于浙江臺(tái)州海正藥業(yè)成品藥穩(wěn)定性實(shí)驗(yàn)室。References參考資料ICHHarmonizedTripartiesGuidelineforStabilityTestingofNewDrugSubstancesandDrugProduct06,2003.[ICHQ1A(R2)]新原料藥和新制劑的穩(wěn)定性測(cè)試指南06,2003.[ICHQ1A(R2)]ASSAYMETHODVALIDATIONREPORTFORCHLOROQUINEPHOSPHATE,USP,APIANDCHLOROQUINEPHOSPHATE,USPTABLETS,250mgAND500mg.(ARD-VDR-FPTM025A)磷酸氯喹原料藥、250mg和500mg片的含量測(cè)定方法驗(yàn)證報(bào)告。RELATEDSUBSTANCESMETHODVALIDATIONREPORTFORCHLOROQUINEPHOSPHATE,USP,APIANDCHLOROQUINEPHOSPHATE,USPTABLETS,250mgAND500mg.(ARD-VDR-FPTM025B)磷酸氯喹原料藥、250mg和500mg片有關(guān)物質(zhì)方法驗(yàn)證報(bào)告。DISSOLUTIONMETHODVALIDATIONREPORTFORCHLOROQUINEPHOSPHATE,USPTABLETS,250mgAND500mg.(ARD-VDR-FPTM025C)磷酸氯喹250mg和500mg片溶出度方法驗(yàn)證報(bào)告。GeneralInformation基本信息StabilitySamples穩(wěn)定性樣品4.1.1OneExhibitBatchfor250mgstrengthwillbeincludedinthestabilitystudy.規(guī)格為250mg的磷酸氯喹片各一批。4.1.2Onebatchof250mgreferenceproductwillalsobeplacedonstabilitystudy.規(guī)格為250mg和的磷酸氯喹對(duì)照制劑各一批。

ProductOutline樣品信息BatchNo.批號(hào)Strength規(guī)格(mg)PackageSize包裝規(guī)格BatchSize批量(Tablets)Mfg.Date生產(chǎn)日期Pkg.Date包裝日期Manufacturer生產(chǎn)商25050Tablets/Bottle360,,000Hisun海正100Tablets/Bottle500Tablets/Bottle61924A25050Tablets/BottleNANANAWest-wardFormulation處方TheformulationofChloroquinePhosphateUSPTablets,250mg,isasfollows:規(guī)格為250mg的USP磷酸氯喹片處方如下：Table1.FormulaandbatchsizeBatchsize:360,000tablets(172.8Kg)成分Ingredientsmg/片mg/tabletKg/批Kg/batchManufacturer原料藥API*25090IPCA微晶纖維素(102)MCC(Type102)154JRS二水磷酸氫鈣DibasicCalciumPhosphateDihydrate40JRS滑石粉Talc24Merck膠體二氧化硅ColloidalSiliconDioxide(Aerosil200)Degussa硬脂酸鎂MagnesiumStearatePeterGreven總量Total480不適用

4Container-ClosureSystems包裝PackingMaterial包材BatchNo.批號(hào)PackingMaterialDescription包材描述Manufacturer供應(yīng)商60ccHDPEbottle60ccHDPE瓶WE070601Bottle:60ccopaquewhiteHDPEroundbottle瓶：60cc白色不透明HDPE圓瓶Cap:φ32mmopaquewhite蓋：φ32mm白色不透明TriveniPolymersPvt.Ltd(Bottle)VBCInc.(CRCCap)Tekniplex(Liner)上海海昌120ccHDPEbottle120ccHDPE瓶KQ080101Bottle:120ccopaquewhiteHDPEroundbottle瓶：120cc白色不透明HDPE圓瓶Cap:φ36mmopaquewhite蓋：φ36mm白色不透明TriveniPolymersPvt.Ltd(Bottle)VBCInc.(CRCCap)Tekniplex(Liner)上海海昌450ccHDPEbottle450ccHDPE瓶WA080101Bottle:450ccopaquewhiteHDPEroundbottle瓶：450cc白色不透明HDPE圓瓶Cap:φ58mmopaquewhiteCT蓋：φ58mm白色不透明CT圓蓋，帶內(nèi)封TriveniPolymersPvt.Ltd(BottleandCap)Tekniplex(Liner)上海海昌Labeling標(biāo)簽TheProductName,BatchNumber,Strength,StorageCondition,PackageType,No.andStoredby/StoreDatewillbeincludedonthelabel.標(biāo)簽應(yīng)包括品名、批號(hào)、規(guī)格、儲(chǔ)存條件、包裝類型、編號(hào)及儲(chǔ)存人/日期。FPStabilityLab成品藥穩(wěn)定性實(shí)驗(yàn)室ProductName品名：BatchNo./Strength批號(hào)/規(guī)格：StorageCondition儲(chǔ)存條件：Packagetype包裝類型：No.編號(hào)：StoredBy/Date儲(chǔ)存人/日期：

SamplesandPackage樣品與包裝Thedrugproductforstabilitytestingwillbepackagedinthesameconfigurationasthatforthemarketingpurposes.穩(wěn)定性研究樣品與上市的包裝要一致，同時(shí)藥品的大包裝也進(jìn)行穩(wěn)定性實(shí)驗(yàn)。StabilityTesting穩(wěn)定性試驗(yàn)SampleReceiptandStorage樣品接收與儲(chǔ)存AssoonasreceivedfromQAorFormulationDevelopmentDepartment,eachbatchofsampleswillbelabeledandplacedinstoragechambersundertherequiredconditions.從QA部門或者制劑研發(fā)部門接收到樣品，按規(guī)定條件貼好標(biāo)簽并儲(chǔ)存。BatchNo.批號(hào)Strength規(guī)格PackageSize包裝規(guī)格StorageCondition儲(chǔ)存條件SampleSize樣品數(shù)量250mg50Tablets/Bottle100Tablets/Bottle500Tablets/Bottle25℃±2℃/60%RH±5%RH23Bottles/Packagesize30℃±2℃/65%RH±5%RH15Bottles/Packagesize40℃±2℃/75%RH±5%RH12Bottles/Packagesize7011671250mg50Tablets/Bottle25℃±2℃/60%RH±5%RH2Bottles40℃±2℃/75%RH±5%RH1BottleNote注RLDrecommendedstorageconditionasStoreat20-25℃(68-77F)(ControlledRoomTemperature)andProtectfromlightandmoisture.室溫參照倉(cāng)庫(kù)溫度要求，室溫通常不超過(guò)30℃。Thereferenceproduct(RLD)willalsobelabeledandplacedinstoragechambersundertherequiredconditionsatthesametime.同時(shí)也將對(duì)照制劑（RLD）按規(guī)定條件貼好標(biāo)簽并儲(chǔ)存。StorageConditionsandTestingTimePoints儲(chǔ)存條件和檢測(cè)點(diǎn)StudyType穩(wěn)定性類型StorageCondition儲(chǔ)存條件Period周期TimePoints（months）2時(shí)間點(diǎn)（月）LongTerm長(zhǎng)期25℃±2℃/60%RH±5%RH24Months0,3,6,9,12,18,24Intermediate1中期30℃±2℃/65%RH±5%RH12Months0,3,6,9,12Accelerated加速40℃±2℃/75%RH±5%RH3Months0,1,2,3Note注Intermediatestabilitysampleswillbepulledandanalyzedonlyiftheambient(longterm)stabilityresultsfallsoutsideofthesetspecifications.當(dāng)完成加速穩(wěn)定性研究且無(wú)重大變化時(shí)，停止中期穩(wěn)定性研究。ReferencesampleswillbepulledoutandanalysedaccordingtoSOPARD-ST009.對(duì)照樣品依據(jù)SOPARD-ST009取樣檢測(cè)。Sampling取樣Strength規(guī)格PackageSize包裝規(guī)格StorageCondition儲(chǔ)存條件SamplingSize取樣量250mg50Tablets/Bottle100Tablets/Bottle*500Tablets/Bottle25℃±2℃/60%RH±5%RH1Bottle30℃±2℃/65%RH±5%RH40℃±2℃/75%RH±5%RHTheadditionalsamplespackedinbottleswillbedestroyedaccordingtorelatedSOPsbysupervisorofstabilityLabortheappointedpersonaftercompletingeachtimepointtest.Andthesamplespackedinpailwillbesealedagainandstoredinwarehouse.瓶裝樣品在每個(gè)檢測(cè)點(diǎn)檢驗(yàn)完畢后，樣品如果有剩余，應(yīng)交回給穩(wěn)定性實(shí)驗(yàn)室主管或指定人員做銷毀處理。桶裝樣品封好繼續(xù)在倉(cāng)庫(kù)中儲(chǔ)存。Note注*Usuallythesesamplesarenotusedfortesting,unlessresultsonotherconditionsarenotsatisfactoryorfailthespecifications.正常情況下不取樣檢測(cè)，除非客戶有特殊要求。

TestingMatrix穩(wěn)定性測(cè)試項(xiàng)目表TestingMatrix測(cè)試項(xiàng)目表Long-termConditions長(zhǎng)期穩(wěn)定性IntermediateConditions中期穩(wěn)定性AcceleratedCondition加速穩(wěn)定性250mg50Tablets/BottleTTT100Tablets/Bottle500Tablets/BottleTTTParametersandAcceptanceCriteria(toberevisedasperspecifications)檢測(cè)項(xiàng)目及質(zhì)量標(biāo)準(zhǔn)addMicrotestingattime0andendoflifeItems檢測(cè)項(xiàng)目Method方法Specification質(zhì)量標(biāo)準(zhǔn)Appearance性狀ESS-GM026250mgWhiteuncoatedtablets,roundbiconvexdebossedASCover109ononeside,bisectedononeside.白色非包衣片，圓形兩面凸的，片一面刻字“ASC109”，另一面中間帶有刻痕。Watercontent*水分ESS-GM036.待定。Dissolution溶出度ESS-STM-011CNotlessthan75%(Q)ofthelabeledamountin45minutes.45分鐘內(nèi)溶出度不少于75%（Q）。Assay含量ESS-STM-011AChloroquinePhosphateTabletscontainnotlessthanpercentandnotmorethanpercentofthelabeledamountofC18H26ClN3·2H3PO4.應(yīng)為標(biāo)示量的%%。Relatedsubstances/degradationproducts有關(guān)物質(zhì)/降解產(chǎn)物ESS-STM-011BIndividualunspecifiedimpurityisNMT%.單個(gè)未知雜質(zhì)不得過(guò)%。TotalimpurityisNMT%.總雜質(zhì)不得過(guò)%。*ItisonlyapplicabletoChloroquinePhosphateTablets,500mg.僅適用于500mg磷酸氯喹片。

Relatedsubstances/Degradationproducts有關(guān)物質(zhì)/降解產(chǎn)物Maximumdailydose最大日劑量Reportingthreshold報(bào)告限Identificationthreshold鑒定限Qualificationthreshold界定限1,000mgLOQ%%DataPresentation數(shù)據(jù)匯總ThestabilitydatawillbepresentedintheStabilitySummaryReport(seeexamplesinAppendixB).StabilitySummaryReportwillbecompletedforeachstorageconditionofdrugproductplacedonstability.穩(wěn)定性研究數(shù)據(jù)填寫在穩(wěn)定性研究匯總報(bào)告中（見附件B），按產(chǎn)品的儲(chǔ)存條件分別填寫附件B。Reporting報(bào)告IntermediateReports中期報(bào)告ThestabilitylaboratorywillissueintermediatereportsaccordingtoAppendixBwithin30daysateachtestingtimepoints.Thewrittenexplanationshouldbeprovidediftestresultisnotreportedwithinrequiredtime.在檢測(cè)點(diǎn)30天內(nèi)對(duì)該檢測(cè)點(diǎn)數(shù)據(jù)按附件B進(jìn)行中期報(bào)告，如果沒有按規(guī)定時(shí)間進(jìn)行報(bào)告，必須有書面說(shuō)明。SummaryReport總結(jié)報(bào)告Oncompletionofthestudy,thestabilitylaboratorywillissueareportsummarywithsignatureanddateaccordingtoappendixB.在完成穩(wěn)定性研究后，按照附件B進(jìn)行總結(jié)報(bào)告。StabilityDocuments穩(wěn)定性文件夾Thestabilitydocumentsshouldincludethefollowing,butnotlimitedto:穩(wěn)定性文件夾應(yīng)該包括但不局限于以下內(nèi)容：●Nameanddescriptionofdrugproduct品名及產(chǎn)品描述●Manufacturer,batchNo.,batchsize(s),m