Q1aR2-200新原料藥及新制劑穩(wěn)定性研究中英文精編版

1、醫(yī)藥資料推薦1INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTSREGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH HARMONISEDTRIPARTITEGUIDELINESTABILITYTESTING OFNEWDRUGSUBSTANCES ANDPRODUCTSQ1A(R2)Current Step 4 versiondated 6 February 2003This Guideline has been developed by the appropria

2、te ICH Expert Working Group and has been subject toconsultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the finaldraft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.FOR醫(yī)藥資料推薦2ICH 指導(dǎo)原則新藥物與新產(chǎn)品穩(wěn)定性研究 Q1A (R2)2003

3、26現(xiàn)行第4版Q1A(R2) Document HistoryFirstCodificati onHistoryDateNewCodificati onNovember 2005Q1Approval by the Steering Committee under Step 2 and releasefor public con sultati on.16 September1992Q1Q1AApproval by the Steering Committee under Step 4 and recommendati on for adopti on to the three ICH regu

4、latory bodies.Q1 was ren amed Q1A.27 October1993Q1AQ1A(R)Approval by the Steeri ng Committee of thefirst revisio nun der Step 2 and release for public con sultati on.7 October1999Q1A(R1)Q1A(R)Approval by the Steeri ng Committee of thefirst revisio nunder Step 4 and recommendation for adoption to the

5、 three ICHregulatory bodies.8 November2000Q1A(R1)Current Step 4versionQ1A(R2)Approval by the Steering Committee of the second revisiondirectly under Step 4 without further public consultation, toinclude consequences of the adoption of Q1F (Stability DataPackage for Registration Applications in Clima

6、tic Zones III andIV), and recomme ndati on for adopti on to the three ICHregulatory bodies.6 February2003Q1A(R2)Cover Note for Revision of Q1A(R)Stability Testing of New Drug Substances and Products新藥物與新產(chǎn)品穩(wěn)定性研究 Q1A (R)修正說明醫(yī)藥資料推薦3The purpose of this note is to outline the changes made in Q1A(R) that

7、result from adoption of ICHQ1F “ Stability Data Package for Registration Applications in Climatic Zones III and IV Thesechanges are:本注釋的目的是概述 R1A (R)的變化，這些變化是因采納了ICH Q 仆，即 在氣候帶 III和 IV 地區(qū)注冊申請的穩(wěn)定性研究要求 ”這一指導(dǎo)原則而產(chǎn)生的，內(nèi)容包括：1.The intermediate storage condition has been changed from 3C0 2 C/60% RH 5% RHto 3

8、0C 2 C/65% RH 5% RH in the following sections: Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case Drug products packaged in semi-permeable containers3Glossary - “ Intermediate testing”下列章節(jié)中，中間放置環(huán)境由30C i2C/60%R 5%修正為 30C2E/65%R 5%2

9、.1.7.1 原料藥-放置條件-一般情況 制劑-放置條件-一般情況 半滲透容器包裝的制劑3 術(shù)語-中間試驗(yàn)”2.30C 2 C/65% RH 5% RH can be a suitable alternative long-term storage condition to25C 2 C/60% RH 5% in the following sections: Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - Gen

10、eral Case在下列章節(jié)中，30r TC/65%R 5%可作為長期試驗(yàn)放置條件 25r TC/60%R 5% 的合適替代條件： 原料藥放置條件一般情況 制劑放置條件一般情況3.30C 2C/35% RH 5% RH has been added as a suitable alternative long-term storagecondition to 25C 2C/40% RH 5% and the corresponding example for the ratio ofwater-loss rates has been included in the

11、following section: Drug products packaged in semi-permeable containers在下列章節(jié)中，30C2C/35%R 5%已作為長期放置條件 5C2C/40%R 5%的合適 替代條件，相應(yīng)的計算失水率比值的例子已包括其中： 半滲透容器包裝的制劑Mid-stream switch of the intermediate storage condition from 30C 2 C/60% RH5% RH to30C 2 C/65% RH 5% RH can be appropriate provided tha

12、t the respective storageconditions and the date of the switch are clearly documented and stated in the registrationapplication.醫(yī)藥資料推薦4中間放置條件可從 30C坐C/60%R 5%轉(zhuǎn)為 30CLZ /65%R 5%,但必須清楚記錄轉(zhuǎn)換 前后的放置條件和轉(zhuǎn)換日期并在注冊申請中闡明。It is recommended that registration applications contain data from complete studies at theinte

13、rmediate storage condition 30C 2 C/65% RH 5% RH, if applicable, by three years afterthe date of publication of this revised guideline in the respective ICH tripartite region. 本修正指南頒布三年內(nèi),建議向各 ICH 機(jī)關(guān)提交的注冊申請內(nèi)容包括中間放置條件 30C2C/65%RH 5%的全部試驗(yàn)數(shù)據(jù)。醫(yī)藥資料推薦5TABLE OF CONTENTS目 錄1.INTRODUCTION引言 .61.1. Objectives o

14、f the Guideline目的 .61.2. Scope of the Guideline 范圍 . 61.3. General Principles 通則 . 72.GUIDELINES 指導(dǎo)原則 . 72.1. Drug Substance 原料藥 . 72.1.1. General 通則 . 72.1.2. Stress Testing 影響因素試驗(yàn) . 72.1.3. Selection of Batches 批的選擇 . 82.1.4. Container Closure System 包裝容器 . 92.1.5. Specification 規(guī)范 . 92.1.6. Testi

15、ng Frequency 檢測頻率 . 92.1.7. Storage Conditions 放置條件 . 102.1.8. Stability Commitment 穩(wěn)定性承諾 . 142.1.9. Evaluation 樣品評價 . 152.1.10. Stateme nts/Labeli ng 說明 / 標(biāo)簽. 162.2. Drug Product 制劑（略） . 163.GLOSSARY 術(shù)語. 174.REFERENCES 參考文獻(xiàn)（略） . 20Stability Testing of New Drug Substances and Products新原料藥及新制劑穩(wěn)定性研究IN

16、TRODUCTION 引言醫(yī)藥資料推薦6Objectives of the Guideline 目的The following guideline is a revised version of the ICH Q1A guideline and defines the stability datapackage for a new drug substance or drug product that is sufficient for a registration application withinthe three regions of the EC, Japan, and the U

17、nited States. It does not seek necessarily to cover thetesting for registration in or export to other areas of the world.本指南為ICH Q1A修訂版， 界定了向歐盟、 日本、 美國三大機(jī)構(gòu)提交新原料藥和新制劑注冊申請 的穩(wěn)定性數(shù)據(jù)包，無意滿足向世界其他地區(qū)申報或出口藥物之需。The guideline seeks to exemplify the core stability data package for new drug substances andproducts,

18、 but leaves sufficient flexibility to encompass the variety of different practical situations thatmay be encountered due to specific scientific considerations and characteristics of the materials beingevaluated. Alternative approaches can be used when there are scientifically justifiable reasons.本指南

19、致力于解釋新原料藥和新制劑穩(wěn)定性數(shù)據(jù)包，鑒于所考察藥物的性質(zhì)和特定科研用途，針 對各種不同實(shí)際情況本指南留有充足的可變通之處， 只要有正當(dāng)?shù)目茖W(xué)依據(jù)就可以采用這些變通。Scope of the Guideline 范圍The guideline addresses the information to be submitted in registration applications for new molecularentities and associated drug products. This guideline does not currently seek to cover th

20、e informationto be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc.本指南介紹了用于新化合物及其相關(guān)制劑提交注冊申請的信息， 目前版本不包括簡化或刪節(jié)申請、 申請變更及臨床試驗(yàn)申請等所需提交的信息。Specific details of the sampling and testing for particular dosage forms in their proposed containerclosures are not co

21、vered in this guideline.已包裝制劑的取樣和檢測細(xì)節(jié)問題在本指南中沒有涉及到。Further guidance on new dosage forms and on biotechnological/biological products can be found inICH guidelines Q1C and Q5C, respectively.新劑型、生物技術(shù)產(chǎn)品及生物制品分別參見ICH Q1C和Q5C.General Principles 通則The purpose of stability testing is to provide evidence on ho

22、w the quality of a drug substance or drugproduct varies with time under the influence of a variety of environmental factors such as temperature,humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drugproduct and recommended storage conditions. 穩(wěn)定性研究的

23、目的是考察溫度、濕度和光對原料藥和制劑質(zhì)量的影響隨時間的變化， 建立原料藥復(fù)驗(yàn)期和制劑有效期，以供儲存條件作參考。The choice of test conditions defined in this guideline is based on an analysis of the effects of climaticconditions in the three regions of the EC, Japan and the United States. The mean kinetic temperaturein any part of the world can be deriv

24、ed from climatic data, and the world can be divided into four醫(yī)藥資料推薦7climatic zones, I-IV. This guideline addresses climatic zones I and II. The principle has beenestablished that stability information generated in any one of the three regions of the EC, Japan andthe United States would be mutually a

25、cceptable to the other two regions, provided the information isconsistent with this guideline and the labeling is in accord with national/regional requirements. 本指南中樣品儲存條件的選擇是在對歐盟、日本、美國氣候條件進(jìn)行分析的基礎(chǔ)上建 立的，世界各地的動態(tài)溫度可以從氣候數(shù)據(jù)中得到，全世界可以劃分為I-W四個氣候帶，本指南選擇氣候帶I和U。原則上，如果穩(wěn)定性數(shù)據(jù)與本指南一致，且標(biāo)記符 合當(dāng)?shù)匾螅跉W盟、日本和美國任一地區(qū)做的穩(wěn)定性數(shù)據(jù)

26、都可以在另兩個地區(qū)通用。GUIDELINES 指南Drug Substance 原料藥General 概論Information on the stability of the drug substance is an integral part of the systematic approach tostability evaluation.原料藥穩(wěn)定性信息是穩(wěn)定性系統(tǒng)評價的一個組成部分。Stress Testing 影 響因素試驗(yàn)Stress testing of the drug substance can help identify the likely degradation pr

27、oducts, which can in turnhelp establish the degradation pathways and the intrinsic stability of the molecule and validate thestability indicating power of the analytical procedures used. The nature of the stress testing will dependon the individual drug substance and the type of drug product involve

28、d.原料藥影響因素試驗(yàn)可以幫助確定可能降解產(chǎn)物， 反過來又可以幫助建立降解途徑以 及分子內(nèi)在穩(wěn)定性，驗(yàn)證所用分析方法的穩(wěn)定性指示能力，影響因素試驗(yàn)的種類取決 于所用原料藥以及制劑類型。Stress testing is likely to be carried out on a single batch of the drug substance.It should include theeffect of temperatures (in 10C increments(e.g., 50C, 60 C, etc.) above that for accelerated testing),hum

29、idity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance.The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a widerange of pH values when in solution or suspension. Photostability testing should be an integral part

30、 ofstress testing. The standard conditions for photostability testing are described in ICH Q1B.影響因素試驗(yàn)最好以原料藥單批樣品進(jìn)行，應(yīng)該包括溫度(比加速試驗(yàn)高10C(如50C,60C等)，需要時再加上濕度(如 75%RH 或更高)，氧氣和光照對原料藥 的影響。對于溶液或混懸液，檢驗(yàn)還應(yīng)包括在一個較寬 pH 范圍內(nèi)對原料藥水解可能 性的評價。光學(xué)穩(wěn)定性試驗(yàn)應(yīng)該是影響因素試驗(yàn)的一個組成部分 ,光學(xué)穩(wěn)定性試驗(yàn)標(biāo)準(zhǔn) 條件見 ICH Q1B 。Examining degradation products un

31、der stress conditions is useful in establishing degradationpathways and developing and validating suitable analytical procedures. However, it may not benecessary to examine specifically for certain degradation products if it has been demonstrated thatthey are not formed under accelerated or long ter

32、m storage conditions.醫(yī)藥資料推薦8影響因素試驗(yàn)中對樣品降解產(chǎn)物的研究有助于建立降解途徑， 建立和驗(yàn)證可行的分析 方法。然而，如果確定影響因素試驗(yàn)中的降解產(chǎn)物在加速試驗(yàn)和長期實(shí)驗(yàn)中不會產(chǎn)生， 則不必特定研究這些。Results from these studies will form an integral part of the information provided to regulatoryauthorities.以上研究的結(jié)果應(yīng)整理成文并報告給管理部門。2.1.3.Selection of Batches比的選擇Data from formal stability

33、 studies should be provided on at least three primary batches of the drugsubstance. The batches should be manufactured to a minimum of pilot scale by the same syntheticroute as, and using a method of manufacture and procedure that simulates the final process to be usedfor, production batches. The ov

34、erall quality of the batches of drug substance placed on formal stabilitystudies should be representative of the quality of the material to be made on a production scale. 正式的穩(wěn)定性研究數(shù)據(jù)應(yīng)由至少三批原料藥得出，這些批次應(yīng)達(dá)到中放最低量；所采 用的合成路線應(yīng)與大生產(chǎn)一致，制備工藝和操作流程模擬最終生產(chǎn)過程。用于正式穩(wěn) 定性研究的原料藥批次應(yīng)具有代表性，產(chǎn)品質(zhì)量可以代表最終產(chǎn)品。Other supporting data c

35、an be provided. 其他有用數(shù)據(jù)也可以提供。挀挀 戀戀挀挀 戀戀攀攀 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀攙戀攀愀挀攙戀攀 挀挀昀昀 攙昀攙昀 攙攙戀戀 戀戀挀攙挀攙愀愀攀攀 一甀洀戀攀爀攀攙開昀一甀洀戀攀爀攀攙開昀攙攙挀挀 愀愀 戀戀挀三百三十四萬二千三百八十五挀三百三十四萬二千三百八十五 1521愀愀昀昀攙攙 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀愀挀ontainer Closure System 包裝容器The stability studies should be conducted on the drug substance packaged in a contai

36、ner closuresystem that is the same as or simulates the packaging proposed for storage and distribution. 用于穩(wěn)定性研究的原料藥應(yīng)包裝于與藥物儲存及運(yùn)輸相同或相似包裝內(nèi)。挀挀 戀戀挀挀 戀戀攀攀 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀攙戀攀愀挀攙戀攀 挀挀昀昀 攙昀攙昀 攙攙戀戀 戀戀挀攙挀攙愀愀攀攀 一甀洀戀攀爀攀攙開昀一甀洀戀攀爀攀攙開昀攙攙挀挀 愀愀 戀戀挀三百三十四萬二千三百八十六挀三百三十四萬二千三百八十六 1521愀愀昀昀攙攙 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀愀挀peci

37、fication 規(guī)范Specification, which is a list of tests, reference to analytical procedures, and proposed acceptancecriteria, is addressed in ICH Q6A and Q6B. In addition, specification for degradation products in a drugsubstance is discussed in Q3A. 規(guī)格作為檢驗(yàn)、 分析方法參考、 預(yù)期驗(yàn)收標(biāo)準(zhǔn)的一系列要求， 在 ICH Q6A中有詳細(xì) 描述，關(guān)于藥物降解產(chǎn)

38、物規(guī)格的討論在 Q3A 中。Stability studies should include testing of those attributes of the drug substance that are susceptible tochange during storage and are likely to influence quality, safety, and/or efficacy. The testing shouldcover, as appropriate, the physical, chemical, biological, and microbiological

39、 attributes. Validatedstability-indicating analytical procedures should be applied. Whether and to what extent replicationshould be performed will depend on the results from validation studies. 穩(wěn)定性研究應(yīng)該包括對有可能造成改變藥物包裝的因素，以及可能影響藥物質(zhì)量、安 全性或藥效的因素的考察；檢驗(yàn)內(nèi)容應(yīng)該涵蓋醫(yī)藥資料推薦9物理、化學(xué)、生物及微生物方面；所采 用的分析方法應(yīng)該經(jīng)過穩(wěn)定性指示驗(yàn)證的。 試驗(yàn)是

40、否需要重復(fù)以及重復(fù)次數(shù)應(yīng)該取決 于驗(yàn)證性研究結(jié)果。挀挀 戀戀挀挀 戀戀攀攀 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀攙戀攀愀挀攙戀攀 挀挀昀昀 攙昀攙昀 攙攙戀戀 戀戀挀攙挀攙愀愀攀攀 一甀洀戀攀爀攀攙開昀一甀洀戀攀爀攀攙開昀攙攙挀挀 愀愀 戀戀挀三百三十四萬二千三百八十七挀三百三十四萬二千三百八十七 1521愀愀昀昀攙攙 一甀洀戀攀爀攀攙開一甀洀戀攀爀攀攙開愀挀愀挀esting Frequency!檢驗(yàn)頻率For long term studies, frequency of testing should be sufficient to establish the stability pr

41、ofile of thedrug substance. For drug substances with a proposed re-test period of at least 12 months, thefrequency of testing at the long term storage condition should normally be every 3 months over the firstyear, every 6 months over the second year, and annually thereafter through the proposed re-

42、testperiod. 長期穩(wěn)定性研究中檢驗(yàn)頻率以能夠建立原料藥穩(wěn)定性特征為宜， 對于預(yù)設(shè)復(fù)驗(yàn)期至少 12 個月的原料藥，長期穩(wěn)定性研究檢驗(yàn)頻率為：第 1 年每 3 個月一次，第二年每 6 個月一次，以后每年一次。At the accelerated storage condition, a minimum of three time points, including the initial and final timepoints (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expect

43、ation (basedon development experience) exists that results from accelerated studies are likely to approachsignificant change criteria, increased testing should be conducted either by adding samples at the finaltime point or by including a fourth time point in the study design.在加速試驗(yàn)放置條件為期 6 個月的研究中，至少

44、進(jìn)行包括初次和末次的 3 個時間點(diǎn)(如 0，3，6 月)。根據(jù)研發(fā)經(jīng)驗(yàn)，預(yù)計加速試驗(yàn)結(jié)果可能會接近顯著變化限度，則應(yīng)在 最后一個時間點(diǎn)增加樣本數(shù)或在研究設(shè)計中增加第 4 個時間點(diǎn)。When testing at the intermediate storage condition is called for as a result of significant change at theaccelerated storage condition, a minimum of four time points, including the initial and final time points

45、(e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.當(dāng)加速試驗(yàn)結(jié)果產(chǎn)生了顯著變化， 則應(yīng)進(jìn)行中間放置條件下的試驗(yàn)， 建議進(jìn)行為期 12 個月的研究，取樣時間點(diǎn)包括起始和結(jié)束在內(nèi)的四個時間點(diǎn)(如1，6， 9，12 月)。2.1.7 Storage Conditions 放置條件In general, a drug substance should be evaluated under storage conditions (with appropriatetolerances) that test its therma

46、l stability and, if applicable, its sensitivity to moisture. The storageconditions and the lengths of studies chosen should be sufficient to cover storage, shipment, andsubsequent use. 通常，藥物需要在儲存條件下評價，測試其熱穩(wěn)定性，必要時也檢驗(yàn)其對濕度的敏感性。放置條件及考察時間的選擇應(yīng)考慮到儲存、運(yùn)輸及應(yīng)用的整個過程。The long term testing should cover a minimum o

47、f 12 months duration on at least three primarybatches at the time of submission and should be continued for a period of time sufficient to cover theproposed re-test period. Additional data accumulated during the assessment period of the registration醫(yī)藥資料推薦10application should be submitted to the auth

48、orities if requested. Data from the accelerated storagecondition and, if appropriate, from the intermediate storage condition can be used to evaluate theeffect of short term excursions outside the label storage conditions (such as might occur duringshipping). 長期穩(wěn)定性試驗(yàn)應(yīng)屆時提交至少包括三批最初樣品 12 個月的數(shù)據(jù)，試驗(yàn)應(yīng)繼續(xù)進(jìn)行

49、以達(dá)到設(shè)定的復(fù)驗(yàn)期，如果需要，申報期間的實(shí)驗(yàn)數(shù)據(jù)也應(yīng)該提交審批機(jī)構(gòu)。如果可 以，中間條件下的加速實(shí)驗(yàn)數(shù)據(jù)可以用于評價儲存條件偏差對藥物的影響(如運(yùn)輸過 程中可能發(fā)生的情況)Long term, accelerated, and, where appropriate, in termediate storage con diti ons for drug substances are detailed in the secti ons below. The gen eral case applies if the drug substa nee is notspecifically covere

50、d by a subseque nt secti on. Alter native storage con diti ons can be used if justified.長期、加速或中間放置條件下藥物實(shí)驗(yàn)安排具體如以下部分，如果下面?zhèn)€部分中沒有 準(zhǔn)確包括適合該藥物的情況，可以采用通常條件。經(jīng)評價，試驗(yàn)條件可更改。2.171 General case 般情況StudyStorage con diti onMinimum time period covered bydata at submissi onLong term*25 C 2 C/60% RH 5% RHor0C 2 C/65% R

51、H 5% RH12 mon thsIn termediate*30 C 2 C/65% RH 5% RH6 mon thsAccelerated40 C 2 C/75% RH 5% RH6 mon ths研究內(nèi)容放置條件申報文件涵蓋的 最少時間周期長期實(shí)驗(yàn)*25C 2C/60%RH5%RH 或30C 2C/65%RH5%RH12 月中間條件*30C C/65%R5%RH6 月加速試驗(yàn)40C C/75%R5%RH6 月* It is up to the applicant to decide whether long term stability studies are performed at

52、 25 士 2 C/60%RH 士 5% RH or 30 C 2 C/65% RH 士 5% RH.取決于申報人所選擇的長期穩(wěn)定性試驗(yàn)是在25C/60%R 5%RH 還是30C TC/65%RH5%RH 條件下進(jìn)行的。* If 30 C 2 /65% RH 土 5% RH is the Ion g-term con ditio n, there is no in termediate con diti on.如果長期穩(wěn)定性試驗(yàn)是在 30C C/65%R5%RH 條件下進(jìn)行的，則無需中間條件 試驗(yàn)。醫(yī)藥資料推薦11If Ion g-term studies are con ducted at

53、25 C 2 C/60% RH 5% Rliigntfica ntcha nge ” occurs at any time duri ng 6 mon ths testi ng at the accelerated storage con ditioradditi onal test ing at the in termediate storage con diti on should be con ducted and evaluated aga instsig nifica nt cha nge criteria. Test ing at the in termediate storage

54、 con diti on should in clude all tests,uni ess otherwise justified. The in itial applicati on should in clude a mi nimum of 6 mon ths datafrom-an1b2th study at the in termediate storage con diti on.如果長期穩(wěn)定性試驗(yàn)是在 25 度，相對濕度 65%下進(jìn)行，加速試驗(yàn) 6 個月內(nèi)發(fā)生 顯著 變化”，則中間條件實(shí)驗(yàn)樣品需增加針對顯著變化”的檢測項(xiàng)目。若無修正，中間條件實(shí)驗(yàn)樣品的檢測應(yīng)包括所有項(xiàng)目，初步申報

55、應(yīng)包括中間條件下實(shí)驗(yàn)樣品12 個月數(shù)據(jù)中的至少 6 個月數(shù)據(jù)?！?Significant change” for a drug substanee is defined as failure to meet its specification.針對原料藥的 顯著變化”指的是可以造成樣品專屬性不符的變化。 Drug substances intended for storage in a refrigeratO 擬冷藏的藥物StudyStorage con diti onMinimum time period covered bydata at submissi onLong te

56、rm5C 3 C12 mon thsAccelerated25 C 2 C/60% RH 5% RH6 mon ths研究內(nèi)容放置條件申報文件涵蓋的最少時間周期長期實(shí)驗(yàn)5C C12 月加速試驗(yàn)25r 2C/60%R5%RH6 月Data from refrigerated storage should be assessed accord ing to the evaluati on secti on of this guideline, except where explicitly no ted below.若非下文明確指出，冷藏儲存樣品實(shí)驗(yàn)數(shù)據(jù)應(yīng)照本指導(dǎo)原則評價部分進(jìn)行評估。If sig

57、 ni fica nt cha nge occurs betwee n 3 and 6non ths testi ng at the accelerated storage condition,the proposed re-test period should be based on the real time data available at the long term storagecon diti on.如果加速試驗(yàn) 3-6 個月期間發(fā)生顯著變化，預(yù)設(shè)的再檢測應(yīng)基于長期實(shí)驗(yàn)實(shí)際時間所 得數(shù)據(jù)。If sig ni fica nt cha nge occurs withi n the f

58、irst 3 mon ths testi ng at the accelerated storage con diti on,a discussi on should be provided to address the effect of short term excursi ons outside the labelstorage con diti on, e.g., duri ng shipp ing or han dli ng. This discussi on can be supported, ifappropriate, by further testing on a singl

59、e batch of the drug substance for a period shorter tha n 3 mon醫(yī)藥資料推薦12ths but with more freque nt testi ng tha n usual. It is con sidered unn ecessary to con ti nue to test adrug substa nce through 6 mon ths whe n a sig nifica nt cha nge has occurred with in the first 3 months.如果加速試驗(yàn) 3 個月以內(nèi)發(fā)生顯著性變化，應(yīng)

60、討論短時儲存條件偏差（如運(yùn)輸或處理）對藥物的影響。如果條件允許，可以采用單批藥物進(jìn)行 3 個月之內(nèi)的試驗(yàn)，試驗(yàn)期間 增加檢測頻率，以使佐證討論內(nèi)容。如果加速試驗(yàn) 3 個月以內(nèi)發(fā)生顯著性變化，則認(rèn) 為不必繼續(xù)完成 6 個月的試驗(yàn)。2.173 Drug substances intended for storage in a freez 需 冷凍貯藏的藥物StudyStorage con diti onMinimum time period covered by data atsubmissi onLong term-20 C 5 C12 mon ths研究內(nèi)容放置條件申報文件涵蓋的最少時間周期長