穩(wěn)定性試驗(yàn)方案

1、Stability Study Protocol穩(wěn)定性方案Chloroquine Phosphate Tablets Protocol No.: PRO-ST-001-2008(1.2)磷酸氯喹片 方案編號(hào)：PRO-ST-001-2008(1.2)Stability Study Protocol for Exhibit Batch of Chloroquine Phosphate Tablets USP, 250mg 規(guī)格為250 mg的USP磷酸氯喹片長(zhǎng)期、中期及加速穩(wěn)定性研究方案Project No.項(xiàng)目號(hào)DP-ST-001-2008Prepared By: Date:起草者： 日期： R

2、eviewed By QA: Date:審核者： 日期： Approved By: Date:批準(zhǔn)者： 日期： Starting Date: Completed Date:開(kāi)始日期： 結(jié)束日期： Stability Lab Page 8/ 9穩(wěn)定性實(shí)驗(yàn)室Contents目 錄1.Purpose目的12.Scope范圍.13.References參考資料.14.General Information基本信息.14.1Stability Samples穩(wěn)定性研究樣品14.2Product Outline樣品概述.14.3Formulation處方14.4Container-Closure Syst

3、ems包裝14.5Labeling標(biāo)簽.14.6Samples and Package樣品與包裝.15.Stability Testing穩(wěn)定性測(cè)試15.1Sample Receipt and Storage樣品接收與儲(chǔ)存15.2Storage Conditions and Testing Time Points儲(chǔ)存條件與檢測(cè)時(shí)間點(diǎn)15.3Sampling取樣15.4Testing Matrix穩(wěn)定性測(cè)試項(xiàng)目表15.5Parameters and Acceptance Criteria檢測(cè)項(xiàng)目及質(zhì)量標(biāo)準(zhǔn)15.6Degradation products降解產(chǎn)物16.Data Presentati

4、on數(shù)據(jù)匯總17.Reporting報(bào)告17.1Intermediate Reports中期報(bào)告17.2Summary Report總結(jié)報(bào)告17.3Stability Documents穩(wěn)定性文件夾18.Appendix附件11. Purpose目的The purpose of stability testing is to provide evidence of how the Quality, Strength, Degradation Products and Purity of the Chloroquine Phosphate Tablets USP, 250mg will chan

5、ge with time under the influence of environmental room temperature and relative humidity conditions. Data collected from the stability study will enable recommended storage conditions and provide justification for establishing and submitting the data to regulatory authorities for approving the shelf

6、 life for marketing purposes. In addition, 3 months of the stability data will be submitted to US FDA as required for submission purposes of the ANDA application. 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。2. Scope范圍This procedure is applicable to Finishe

7、d Product Stability Lab at Hisun Pharmaceutical (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。3. References參考資料3.1 ICH Harmonized Triparties Guideline for Stability Testing of New Drug Substances and Drug Product 06, 2003. ICH Q1A (R2)新原料藥和新制劑的穩(wěn)定性測(cè)試指南06, 2003. ICH Q1A(R2)3.2 ASSAY METHOD

8、 VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP, API AND CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 500 mg. (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。3.3 RELATED SUBSTANCES METHOD VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP, API AND CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 5

9、00 mg. (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。3.4 DISSOLUTION METHOD VALIDATION REPORT FOR CHLOROQUINE PHOSPHATE, USP TABLETS, 250 mg AND 500 mg. (ARD-VDR-FPTM025C)磷酸氯喹250mg和500mg片溶出度方法驗(yàn)證報(bào)告。4. General Information基本信息4.1 Stability Samples穩(wěn)定性樣品4.1.1 One Exhibit Batch for 250mg strength will

10、be included in the stability study.規(guī)格為250mg的磷酸氯喹片各一批。4.1.2 One batch of 250mg reference product will also be placed on stability study.規(guī)格為250mg和的磷酸氯喹對(duì)照制劑各一批。4.2 Product Outline樣品信息Batch No.批號(hào)Strength規(guī)格(mg)Package Size包裝規(guī)格Batch Size批量(Tablets)Mfg. Date生產(chǎn)日期Pkg. Date包裝日期Manufacturer生產(chǎn)商25050 Tablets/ Bo

11、ttle360,000Hisun海正100 Tablets/ Bottle500 Tablets/ Bottle61924A25050 Tablets/ BottleNANANAWest-ward4.3 Formulation處方4.3.1 The formulation of Chloroquine Phosphate USP Tablets, 250 mg, is as follows:規(guī)格為250mg的USP磷酸氯喹片處方如下：Table 1. Formula and batch size Batch size: 360,000 tablets ( 172.8 Kg )成分Ingredi

12、entsmg / 片 mg / tabletKg / 批 Kg / batchManufacturer 原料藥API*25090IPCA微晶纖維素(102)MCC (Type 102)15455.44JRS二水磷酸氫鈣Dibasic Calcium Phosphate Dihydrate 4014.4JRS滑石粉Talc248.64Merck膠體二氧化硅Colloidal Silicon Dioxide (Aerosil 200)4.81.728Degussa硬脂酸鎂Magnesium Stearate7.22.592Peter Greven總量Total480172.84.4 不適用4Con

13、tainer-Closure Systems包裝Packing Material包材Batch No.批號(hào)Packing Material Description包材描述Manufacturer供應(yīng)商60 cc HDPE bottle60 cc HDPE瓶WE070601Bottle: 60 cc opaque white HDPE round bottle瓶：60cc白色不透明HDPE圓瓶Cap: 32 mm opaque white CRC cap, with induction sealing 蓋：32mm白色不透明CRC圓蓋，帶內(nèi)封Triveni Polymers Pvt. Ltd (

14、Bottle) VBC Inc. (CRC Cap)Tekniplex (Liner) 上海海昌120 cc HDPE bottle120 cc HDPE瓶KQ080101Bottle: 120 cc opaque white HDPE round bottle瓶：120cc白色不透明HDPE圓瓶Cap: 36 mm opaque white CRC cap, with induction sealing 蓋：36mm白色不透明CRC圓蓋，帶內(nèi)封Triveni Polymers Pvt. Ltd (Bottle) VBC Inc. (CRC Cap)Tekniplex (Liner) 上海海昌

15、450 cc HDPE bottle450 cc HDPE瓶WA080101Bottle: 450 cc opaque white HDPE round bottle瓶：450cc白色不透明HDPE圓瓶Cap: 58 mm opaque white CT cap, with induction sealing 蓋：58mm白色不透明CT圓蓋，帶內(nèi)封Triveni Polymers Pvt. Ltd (Bottle and Cap) Tekniplex (Liner) 上海海昌4.5 Labeling標(biāo)簽The Product Name, Batch Number, Strength, Stor

16、age Condition, Package Type, No. and Stored by/ Store Date will be included on the label.標(biāo)簽應(yīng)包括品名、批號(hào)、規(guī)格、儲(chǔ)存條件、包裝類(lèi)型、編號(hào)及儲(chǔ)存人/日期。FP Stability Lab成品藥穩(wěn)定性實(shí)驗(yàn)室Product Name品名： Batch No./ Strength批號(hào)/規(guī)格：Storage Condition儲(chǔ)存條件：Package type包裝類(lèi)型：No.編號(hào)：Stored By/ Date儲(chǔ)存人/日期：4.6 Samples and Package樣品與包裝The drug product

17、 for stability testing will be packaged in the same configuration as that for the marketing purposes.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)。5. Stability Testing穩(wěn)定性試驗(yàn)5.1 Sample Receipt and Storage樣品接收與儲(chǔ)存As soon as received from QA or Formulation Development Department, each batch of samples will be labele

18、d and placed in storage chambers under the required conditions.從QA部門(mén)或者制劑研發(fā)部門(mén)接收到樣品，按規(guī)定條件貼好標(biāo)簽并儲(chǔ)存。Batch No.批號(hào)Strength規(guī)格Package Size包裝規(guī)格Storage Condition儲(chǔ)存條件Sample Size樣品數(shù)量250 mg50 Tablets/ Bottle100 Tablets/ Bottle500 Tablets/ Bottle25 ± 2/ 60% RH ± 5% RH23 Bottles/ Package size30 ± 2/ 6

19、5% RH ± 5% RH15 Bottles/ Package size40 ± 2/ 75% RH ± 5% RH12 Bottles/ Package size7011671250 mg50 Tablets/ Bottle25 ± 2/ 60% RH ± 5% RH2 Bottles40 ± 2/ 75% RH ± 5% RH1 BottleNote注1. RLD recommended storage condition as Store at 20-25 ( 68-77F) (Controlled Room Tem

20、perature) and Protect from light and moisture.室溫參照倉(cāng)庫(kù)溫度要求，室溫通常不超過(guò)30。The reference product (RLD) will also be labeled and placed in storage chambers under the required conditions at the same time.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。5.2 Storage Conditions and Testing Time Points儲(chǔ)存條件和檢測(cè)點(diǎn)Study Type穩(wěn)定性類(lèi)型Storage Con

21、dition儲(chǔ)存條件Period周期Time Points（months）2時(shí)間點(diǎn)（月）Long Term長(zhǎng)期25 ± 2/ 60% RH ± 5% RH24 Months0, 3, 6, 9, 12, 18, 24Intermediate1中期30 ± 2/ 65% RH ± 5% RH12 Months0, 3, 6, 9, 12Accelerated加速40 ± 2/ 75% RH ± 5% RH3 Months0, 1, 2, 3Note注1. Intermediate stability samples will be pu

22、lled and analyzed only if the ambient (long term) stability results falls outside of the set specifications.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。2. Reference samples will be pulled out and analysed according to SOP ARD-ST009.對(duì)照樣品依據(jù)SOP ARD-ST009取樣檢測(cè)。5.3 Sampling取樣Strength規(guī)格Package Size包裝規(guī)格Storage Condition儲(chǔ)存條

23、件Sampling Size取樣量250 mg50 Tablets/ Bottle100 Tablets/ Bottle*500 Tablets/ Bottle25 ± 2/ 60% RH ± 5% RH1 Bottle30 ± 2/ 65% RH ± 5% RH40 ± 2/ 75% RH ± 5% RHThe additional samples packed in bottles will be destroyed according to related SOPs by supervisor of stability Lab

24、or the appointed person after completing each time point test. And the samples packed in pail will be sealed again and stored in warehouse.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(xiāo)毀處理。桶裝樣品封好繼續(xù)在倉(cāng)庫(kù)中儲(chǔ)存。Note注* Usually these samples are not used for testing, unless results on other conditions are not s

25、atisfactory or fail the specifications. 正常情況下不取樣檢測(cè)，除非客戶(hù)有特殊要求。5.4 Testing Matrix穩(wěn)定性測(cè)試項(xiàng)目表Testing Matrix測(cè)試項(xiàng)目表Long-term Conditions長(zhǎng)期穩(wěn)定性Intermediate Conditions中期穩(wěn)定性Accelerated Condition加速穩(wěn)定性250 mg50 Tablets/ BottleTTT100 Tablets/ Bottle500 Tablets/ BottleTTT5.5 Parameters and Acceptance Criteria (to be r

26、evised as per specifications) 檢測(cè)項(xiàng)目及質(zhì)量標(biāo)準(zhǔn) add Micro testing at time 0 and end of lifeItems檢測(cè)項(xiàng)目Method 方法Specification 質(zhì)量標(biāo)準(zhǔn)Appearance性狀ESS-GM026250 mgWhite uncoated tablets, round biconvex debossed ASC over 109 on one side, bisected on one side.白色非包衣片，圓形兩面凸的，片一面刻字“ASC 109”，另一面中間帶有刻痕。Water content*水分ESS-

27、GM036.待定。Dissolution溶出度ESS-STM-011CNot less than 75%(Q) of the labeled amount in 45 minutes.45分鐘內(nèi)溶出度不少于75%（Q）。Assay含量ESS-STM-011AChloroquine Phosphate Tablets contain not less than 93.0 percent and not more than 107.0 percent of the labeled amount of C18H26ClN3·2H3PO4.應(yīng)為標(biāo)示量的93.0%-107.0%。Related

28、 substances/ degradation products有關(guān)物質(zhì)/降解產(chǎn)物ESS-STM-011BIndividual unspecified impurity is NMT 0.10%.單個(gè)未知雜質(zhì)不得過(guò)0.10%。Total impurity is NMT 1.0%.總雜質(zhì)不得過(guò)1.0%。* It is only applicable to Chloroquine Phosphate Tablets, 500 mg. 僅適用于500mg磷酸氯喹片。5.6 Related substances/ Degradation products有關(guān)物質(zhì)/降解產(chǎn)物Maximum daily

29、dose最大日劑量Reporting threshold報(bào)告限Identification threshold鑒定限Qualification threshold界定限1,000 mgLOQ0.2%0.2%6. Data Presentation數(shù)據(jù)匯總The stability data will be presented in the Stability Summary Report (see examples in Appendix B). Stability Summary Report will be completed for each storage condition of d

30、rug product placed on stability.穩(wěn)定性研究數(shù)據(jù)填寫(xiě)在穩(wěn)定性研究匯總報(bào)告中（見(jiàn)附件B），按產(chǎn)品的儲(chǔ)存條件分別填寫(xiě)附件B。7. Reporting報(bào)告7.1 Intermediate Reports中期報(bào)告The stability laboratory will issue intermediate reports according to Appendix B within 30 days at each testing time points. The written explanation should be provided if test result

31、is not reported within required time.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(méi)有按規(guī)定時(shí)間進(jìn)行報(bào)告，必須有書(shū)面說(shuō)明。7.2 Summary Report總結(jié)報(bào)告On completion of the study, the stability laboratory will issue a report summary with signature and date according to appendix B.在完成穩(wěn)定性研究后，按照附件B進(jìn)行總結(jié)報(bào)告。7.3 Stability Documents穩(wěn)定性文件夾The stability documents should include the following, but not limited to:穩(wěn)定性文件夾應(yīng)該包括但不局限于以下內(nèi)容： Name and description of drug product 品名及產(chǎn)品描述 Manufacturer, batch No., batch size(s), mfg. date, package type and package date 產(chǎn)品生產(chǎn)廠商、批號(hào)、批量、生產(chǎn)日期、包裝類(lèi)型和包裝日期 Drug product strength 產(chǎn)品規(guī)格 API ma