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1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE 새로운원료의약품과완제의약품의안정성시험 (Stability Testing of New Drug Substances and ) Q1A (R2) Current Step 4 dated 6 February 2003 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 1

2 Q1A(R2) Document History First Codification Q1 Q1A Q1A(R) Q1A(R) History Date New Codification November 2005 Approval by the Steering Committee under Step 2 and release for public consultation. Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies. Q1 was renamed Q1A. Approval by the Steering Committee of the first revision under Step 2 and release for public consultation. Approval by the Steering Committee of the first revision under Step 4 and recommendation for adoption to the three ICH regulatory bodies. 16 Q1 September Q1A October October Q1A(R1) Q1A(R1) November 2000 Current Step 4 version Q1A(R2) Approval by the Steering Committee of the 6 Q1A(R2) second revision directly under Step 4 February without further public consultation, to 2003 include consequences of the adoption of Q1F (Stability Data Package for Registration Applications in Climatic Zones III and IV), and recommendation for adoption to the three ICH regulatory bodies. 2

3 COVER NOTE FOR REVISION OF Q1A(R) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS The purpose of this note is to outline the changes made in Q1A(R) that result from adoption of ICH Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV. These changes are: ICH Q1F " 기후지역 III 및 IV의등록신청문서중안정성데이터패키지 " 채택에따른 Q1A(R) 의변경사항을정리하면다음과같다. 1. The intermediate storage condition has been changed from 30 C ± 2 C/60% RH ± 5% RH to 30 C ± 2 C/65% RH ± 5% RH in the following sections: 다음섹션에서중간보관조건을 30 C ± 2 C/60% RH ± 5% RH에서 30 C ± 2 C/65% RH ± 5% RH로변경했다 Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case Drug products packaged in semi-permeable containers 3 Glossary - Intermediate testing C ± 2 C/65% RH ± 5% RH can be a suitable alternative long-term storage condition to 25 C ± 2 C/60% RH ± 5% in the following sections: 다음섹션에서장기보관조건을 25 C ± 2 C/60% RH ± 5% 대신 30 C ± 2 C/65% RH ± 5% RH로할수도있다 Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case C ± 2 C/35% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25 C ± 2 C/40% RH ± 5% and the corresponding example for the ratio of water-loss rates has been included in the following section: 다음섹션에서장기보관조건으로 25 C ± 2 C/40% RH ± 5% 이외에도 30 C ± 2 C/35% RH ± 5% RH를추가했으며수분손실율의예를포함시켰다 Drug products packaged in semi-permeable containers 3

4 Mid-stream switch of the intermediate storage condition from 30 C ± 2 C/60% RH ± 5% RH to 30 C ± 2 C/65% RH ± 5% RH can be appropriate provided that the respective storage conditions and the date of the switch are clearly documented and stated in the registration application. 중간보관조건을 30 C ± 2 C/60% RH ± 5% RH에서 30 C ± 2 C/65% RH ± 5% RH로중도에전환할수있지만, 각각의보관조건과전환일자를명확하게기록하고등록신청문서에도기재해야한다. It is recommended that registration applications contain data from complete studies at the intermediate storage condition 30 C ± 2 C/65% RH ± 5% RH, if applicable, by three years after the date of publication of this revised guideline in the respective ICH tripartite region. 각 ICH 지역에서이개정가이드라인이공표된날로부터 3년이내에, 해당되는경우에는 30 C ± 2 C/65% RH ± 5% RH의중간보관조건에서실시한안정성시험데이터를등록신청문서에포함시킬것을권고한다. 4

5 STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS ICH Harmonised Tripartite Guideline First Recommended for Adoption at Step 4 of the ICH Process on 27 October Revised under Step 2 of the ICH Process on 7 October 1999 and Recommended for Adoption at Step 4 of the ICH Process on 8 November This guideline has been Revised a second time and has reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 6 February It is recommended for adoption to the three regulatory parties to ICH. 목차 1. 서론 (INTRODUCTION) 1.1. 목표 (Objectives of the Guideline) 1.2. 적용범위 (Scope of the Guideline) 1.3. 일반원칙 (General Principles) 2. 가이드라인 (GUIDELINES) 2.1. 원료의약품 (Drug Substance) 공통 (General) 가혹시험 (Stress Testing) 배치선정 (Selection of Batches) 용기마개시스템 (Container Closure System) 규격 (Specification) 시험주기 (Testing Frequency) 보관조건 (Storage Conditions) 안정성이행약속 (Stability Commitment) 평가 (Evaluation) 표시사항 (Statements/Labeling) 2.2. 완제의약품 (Drug Product) 공통 (General) 광안정성시험 (Photostability Testing) 배치선정 (Selection of Batches) 용기마개시스템 (Container Closure System) 규격 (Specification) 시험주기 (Testing Frequency) 5

6 보관조건 (Storage Conditions) 안정성이행약속 (Stability Commitment) 평가 (Evaluation) 표시사항 (Statements/Labeling) 3. 용어정의 (GLOSSARY) 4. 참고문헌 (REFERENCES) 6

7 STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS 1. 서론 (INTRODUCTION) 1.1. 목적 (Objectives of the Guideline) The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States. It does not seek necessarily to cover the testing for registration in or export to other areas of the world. 이가이드라인은 ICH Q1A 가이드라인의개정판이며, EC, 일본, 미국등 3개지역의등록신청에필요한신규원료의약품또는완제의약품의안정성데이터기준을규정한다. 기타국가의등록이나수출에필요한안정성시험까지대상으로할의도는없다. The guideline seeks to exemplify the core stability data package for new drug substances and products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons. 신규원료의약품과완제의약품의핵심안정성데이터패키지기준을규정한다. 하지만평가대상물품의특성과과학적인특정사유로인해발생할가능성이있는다양한실무적상황을감안하여충분히유연하게작성했다. 과학적타당성이있는경우에는다른방법을채택할수도있다 적용범위 (Scope of the Guideline) The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products. This guideline does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc. 이가이드라인은 NME(new molecular entity) 와관련의약품의등록신청시에제출해야하는정보에관한것이다. 약식허가신청, 변경신청, 임상시험신청등을위해제출하는정보는대상이아니다. 7

8 Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline. 예정용기 / 마개시스템에포장한특정제형제품의검체채취와시험에관한구체적인사항은이가이드라인의대상이아니다. Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively. 신규제형과생물공학 / 생물학적제품에관한자세한사항은각기 ICH 가이드라인 Q1C와 Q5C를참고한다 일반원칙 (General Principles) The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product 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 drug product and recommended storage conditions. 안정성시험의목적은온도, 습도, 빛등각종환경요소의영향아래에서시간경과에따른원료의약품또는완제의약품의품질변화에대한증거를확보하고, 그에따라원료의약품의재시험기간또는완제의약품의유효기간과권장보관조건을설정하는것이다. The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II. The principle has been established that stability information generated in any one of the three regions of the EC, Japan and the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guideline and the labeling is in accord with national/regional requirements. 이가이드라인에규정된시험조건은 EC, 일본, 미국등 3개지역의기후조건분석결과에근거한것이다. 다른지역의 MKT(mean kinetic temperature) 는기후데이터를토대로구하며, 모두 4개기후지역 (I~IV) 으로구분할수있다. 이가이드라인은기후지역 I과 II를대상으로한다. EC, 일본, 미국등 3개지역가운데한곳에서생산한 8

9 안정성정보는다른두개지역에서도인정할수있다는원칙이설정되었다. 다만그 정보는이가이드라인에따른것이고라벨표시정보도국가 / 지역기준에부합해야한다. 2. 가이드라인 (GUIDELINES) 2.1. 원료의약품 (Drug Substance) 공통 (General) Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. 원료의약품의안정성에관한정보는체계적인안정성평가에서필수적인부분이다 가혹시험 (Stress Testing) Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. 원료의약품의가혹시험은분해산물을파악하는데도움이되며, 이결과는다시원료의약품분자의분해경로와본질적인안정성을조사하고분석방법의안정성지시성을밸리데이션하는데도움이된다. 관련완제의약품의유형과개개원료의약품을고려하여가혹시험방법을결정한다. Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10 C increments (e.g., 50 C, 60 C, etc.) above that for accelerated testing), humidity (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 wide range of ph values when in solution or suspension. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B. 원료의약품한배치를상대로가혹시험을실시할수있다. 온도 ( 가속시험온도를기준으로 10 C 단위로증가 ( 예, 50 C, 60 C 등 )), 습도 ( 예, 75%RH 이상 ), 산화, 광분해가 9

10 원료의약품에미치는영향을조사한다. 또한용액또는현탁액상태에서각종 ph 값을 대상으로원료의약품의가수분해민감성을평가한다. 광안정성시험도가혹시험의중요한 부분이다. 광안정성시험조건은 ICH Q1B 를참고한다. Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long term storage conditions. 가혹조건에서분해산물조사는분해경로를파악하고적합한분석방법을개발해밸리데이션하는데유용하다. 하지만특정분해산물이가속또는장기보관조건에서형성되지않는것으로증명되면, 그와같은분해산물을조사할필요는없을것이다. Results from these studies will form an integral part of the information provided to regulatory authorities. 시험결과는규제기관에제출하는정보의중요한부분을구성한다 배치선정 (Selection of Batches) Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale. 최소 3개원료의약품기본배치를대상으로실시한공식안정성시험데이터를제공한다. 안정성시험배치는실제생산배치제조공정을시뮬레이션한제조방법과절차를적용하고동일한합성경로에따라최소한파일럿규모로제조한다. 공식안정성시험대상원료의약품배치의전반적인품질은실제생산규모로제조되는물품의품질을대표할수있어야한다. Other supporting data can be provided. 기타근거데이터를제공할수있다. 10

11 용기마개시스템 (Container Closure System) The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. 보관과유통에사용할예정포장시스템과동일하거나그시스템을시뮬레이션한용기마개시스템에원료의약품을포장하여안정성시험을실시한다 규격 (Specification) Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, is addressed in ICH Q6A and Q6B. In addition, specification for degradation products in a drug substance is discussed in Q3A. 시험항목, 분석방법정보, 예정허용기준으로구성된목록인규격문서에대해서는 ICH Q6A와 Q6B를참고한다. 또한원료의약품의분해산물에대한규격은 Q3A를참고한다. Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed will depend on the results from validation studies. 보관중에변화될수있고품질, 안전성및 / 또는유효성에영향을줄가능성이있는원료의약품의특성을안정성시험시에평가한다. 물리적, 화학적, 생물학적, 미생물학적특성을시험한다. 밸리데이션된안정성지시성분석방법을사용한다. 밸리데이션결과에따라반복실시여부와정도를결정한다 시험주기 (Testing Frequency) For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed retest period. 장기안정성시험인경우에시험주기는원료의약품의안정성프로파일을결정하는데 11

12 충분해야한다. 예정재시험기간이최소 12 개월인원료의약품인경우에장기보관조건 시험주기를일반적으로첫해에 3 개월로하고, 두번째해에는 6 개월로하며, 그 이후부터는예정재시험기간전체에걸쳐연 1 회로한다. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design. 가속보관조건인경우에는 6개월시험기간동안최소한 3회 ( 초기와말기포함 )( 예, 0, 3, 6개월 ) 시험할것을권장한다. ( 개발경험에근거하여 ) 가속시험결과가 " 중대한변화 " 에대한기준에근접할것으로예상되는경우, 마지막시점에검체를추가하거나 4번째시험시기를포함시키는방식으로시험을확대하여실시한다. When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended. 가속보관조건에서중대한변화가발생하여중간보관조건시험이필요한경우, 12개월시험기간을설정하고최소 4회 ( 초기와말기포함 )( 예, 0, 6, 9, 12개월 ) 시험할것을권장한다 보관조건 (Storage Conditions) In general, a drug substance should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. 일반적으로열안정성과해당되는경우에는습기민감성을시험할수있는보관조건 ( 적정허용범위포함 ) 에서원료의약품을평가한다. 보관조건과시험기간은보관, 운송, 사용상황을감안하여충분하게설정한다. The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a 12

13 period of time sufficient to cover the proposed re-test period. Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested. Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short term excursions outside the label storage conditions (such as might occur during shipping). 장기안정성시험은제출시점에최소 3개기본배치를상대로최소 12개월간실시한상태여야하며, 이후에도예정재시험기간을포함해충분한기간동안계속진행해야한다. 요청이있는경우에는등록신청문서의평가기간동안축적된추가데이터를규제기관에제출한다. 가속보관조건에서확보한시험데이터와적절한경우에는중간보관조건에서확보한시험데이터를활용하여 ( 운송도중발생할수있는것과같이 ) 표시보관조건을단기적으로벗어나는일탈상황의영향을평가할수있다. Long term, accelerated, and, where appropriate, intermediate storage conditions for drug substances are detailed in the sections below. The general case applies if the drug substance is not specifically covered by a subsequent section. Alternative storage conditions can be used if justified. 원료의약품안정성시험을위한장기, 가속, 그리고적절한경우에는중간보관조건을아래에서자세히설명한다. 아래항목에서별도로다루지않은원료의약품에대해서는일반기준이적용된다. 타당성이있는경우에는다른보관조건을채택할수도있다 일반기준 (General case) 시험 (Study) 장기 (long term)* 보관조건 (Storage Condition) 25 C ± 2 C/60% RH ± 5% RH 또는 30 C ± 2 C/65% RH ± 5% RH 최소제출자료 (Minimum time period covered by data at submission) 12개월 중간 (intermediate)** 30 C ± 2 C/65% RH ± 5% RH 6개월 가속 (accelerated) 40 C ± 2 C/75% RH ± 5% RH 6개월 * It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2 C/60% RH ± 5% RH or 30 C ± 2 C/65% RH ± 5% RH. 13

14 장기안정성시험조건 (25 ± 2 C/60% RH ± 5% RH 또는 30 C ± 2 C/65% RH ± 5% RH) 을신청업체가결정한다. ** If 30 C ± 2 C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition. 30 C ± 2 C/65% RH ± 5% RH를장기안정성시험조건으로한다면, 중간조건은해당되지않는다. If long-term studies are conducted at 25 C ± 2 C/60% RH ± 5% RH and significant change occurs at any time during 6 months testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Testing at the intermediate storage condition should include all tests, unless otherwise justified. The initial application should include a minimum of 6 months data from a 12-month study at the intermediate storage condition. 장기안정성시험을 25 C ± 2 C/60% RH ± 5% RH 조건에서실시하며가속조건 6개월시험기간에 " 중대한변화 " 가발생하면, 중간조건에서추가시험을실시하고중대한변화기준에대비하여평가한다. 별도로타당성이입증되지않으면, 중간보관조건안정성시험시에모든항목을시험한다. 첫신청문서제출시에중간보관조건 12개월시험가운데최소 6개월시험데이터를포함시켜야한다. Significant change for a drug substance is defined as failure to meet its specification. 원료의약품의 " 중대한변화 " 라함은원료의약품규격에부합하지않는것으로정의된다 냉장보관원료의약품 (Drug substances intended for storage in a refrigerator) 시험조건 (Study) 보관조건 (Storage Condition) 최소제출자료 (Minimum time period covered by data at submission) 장기 (long term) 5 C ± 3 C 12 개월 가속 (accelerated) 25 C ± 2 C/60% RH ± 5% RH 6 개월 14

15 Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below. 아래에서명확히기술한경우를제외하고이가이드라인의평가섹션에기술한바에따라냉장보관데이터를평가한다. If significant change occurs between 3 and 6 months testing at the accelerated storage condition, the proposed re-test period should be based on the real time data available at the long term storage condition. 가속보관조건에서 3개월시점과 6개월시점사이에중대한변화가발생하면, 장기보관조건의실시간안정성데이터를근거로예정재시험기간을설정한다. If significant change occurs within the first 3 months testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during shipping or handling. This discussion can be supported, if appropriate, by further testing on a single batch of the drug substance for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months. 가속보관조건에서첫 3개월사이에중대한변화가발생하면, 표시보관조건을단기적으로벗어나는일탈상황 ( 예, 운송또는취급시 ) 의영향에대한평가자료를제출한다. 이때 3개월보다짧은기간동안원료의약품한배치를추가로시험하되일반적인상황보다더빈번하게시험하여평가결과를뒷받침할수있다. 첫 3개월사이에중대한변화가발생한다면안정성시험을 6개월까지계속진행하는것은불필요하다고볼수있다 냉동보관원료의약품 (Drug substances intended for storage in a freezer) 시험조건 (Study) 보관조건 (Storage Condition) 최소제출자료 (Minimum time period covered by data at submission) 장기 (long term) - 20 C ± 5 C 12 개월 For drug substances intended for storage in a freezer, the re-test period should be based on the real time data obtained at the long term storage condition. In the 15

16 absence of an accelerated storage condition for drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5 C ± 3 C or 25 C ± 2 C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition, e.g., during shipping or handling. 냉동보관원료의약품인경우에는장기보관조건에서확보한데이터를근거로재시험기간을설정한다. 냉동보관원료의약품의가속보관조건이없는경우, 적정기간동안높은온도 ( 예, 5 C ± 3 C 또는 25 C ± 2 C) 조건에서한배치를시험하여, 예정표시보관조건을단기적으로벗어나는상황 ( 예, 운송또는취급시 ) 에따른영향을평가한다 C 이하보관원료의약품 (Drug substances intended for storage below - 20 C) Drug substances intended for storage below -20 C should be treated on a case-bycase basis. -20 C 이하에서보관할원료의약품은상황에따라처리한다 안정성이행약속 (Stability Commitment) When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period. 기본배치를대상으로한장기안정성시험데이터가승인시점에예정재시험기간을모두포괄하고있지않다면, 승인을받은이후에도안정성시험을계속진행하여재시험기간을입증하겠다는이행약속을해야한다. Where the submission includes long term stability data on three production batches covering the proposed re-test period, a post approval commitment is considered unnecessary. Otherwise, one of the following commitments should be made: 제출문서에예정재시험기간을포괄하는 3개생산배치대상장기안정성시험데이터가포함되어있다면, 승인이후의안정성시험약속은필요하지않다. 그렇지않으면다음가운데한가지이행약속을해야한다. 1. If the submission includes data from stability studies on at least three 16

17 production batches, a commitment should be made to continue these studies through the proposed re-test period. 최소 3개생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있다면, 이시험을예정재시험기간전체에걸쳐계속진행하겠다고이행약속을한다. 2. If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re-test period. 3개보다적은생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있다면, 이시험을예정재시험기간전체에걸쳐계속진행하고추가생산배치를포함시켜최소총 3개배치가되도록하여예정재시험기간동안장기안정성시험을진행하겠다고이행약속을한다. 3. If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period. 생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있지않다면, 첫 3개생산배치를상대로예정재시험기간동안장기안정성시험을실시하겠다고이행약속을한다. The stability protocol used for long term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified. 안정성이행약속에따른장기안정성시험용안정성프로토콜은, 달리과학적타당성이없으면기본배치시험에사용했던것과동일해야한다 평가 (Evaluation) The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological, and microbiological tests), a re-test period applicable to all future batches of the drug substance manufactured under similar circumstances. The degree of variability of 17

18 individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period. 안정성시험의목적은최소 3개원료의약품배치를시험하고안정성정보를평가하여 ( 물리적, 화학적, 생물학적, 미생물학적시험결과포함 ), 향후유사조건에서제조되는원료의약품배치모두에적용될재시험기간을설정하는것이다. 개개배치의편차정도는향후생산될배치가지정재시험기간동안규격범위이내로유지될것이라는신뢰에영향을준다. The data may show so little degradation and so little variability that it is apparent from looking at the data that the requested re-test period will be granted. Under these circumstances, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient. 데이터상으로분해와편차가거의없어데이터를살펴보기만해도재시험기간이승인될것이분명한경우도있다. 그와같은경우에는공식통계분석을할필요가없다. 다만통계분석생략의타당성을충분히제시해야한다. An approach for analyzing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the acceptance criterion. If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches. If it is inappropriate to combine data from several batches, the overall re-test period should be based on the minimum time a batch can be expected to remain within acceptance criteria. 시간경과에따라변할것으로예상되는정량적특성데이터를분석하는한가지방법은, 평균곡선의 95% 단측신뢰한계가허용기준과교차하는시점을정하는것이다. 분석을통해배치간편차가적은것으로밝혀지면, 데이터를종합하여하나의전체적인추정치를구한다. 이작업은회귀선의기울기와개개배치의 0 시간절편에적절한통계적검정 ( 예, 0.25 이상의유의기각수준에대한 p 값 ) 을적용하는식으로한다. 여러배치의데이터를조합하는것이부적절하다면, 특정배치가허용기준이내를유지할것으로예상되는최소시간을근거로전체재시험기간을정한다. The nature of any degradation relationship will determine whether the data should 18

19 be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale. Statistical methods should be employed to test the goodness of fit of the data on all batches and combined batches (where appropriate) to the assumed degradation line or curve. 분해관계의특성에따라선형회귀분석을위한데이터변형의필요성이결정된다. 일반적으로그관계를산술또는대수스케일에대한 1차, 2차또는 3차함수로표현할수있다. 모든배치와배치조합 ( 적절한경우 ) 의데이터가가정분해직선또는곡선에어느정도적합도를갖는지통계적방법으로검정한다. Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the re-test period can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanism of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data. 타당성이있는경우에는장기보관조건실시간데이터를관찰범위이상으로제한적인외삽을하여승인시점에재시험기간을연장하는것도가능하다. 이때의타당성은분해메커니즘에대한지식, 가속조건시험결과, 수학적모델의적합도, 배치규모, 관련안정성데이터의존재등을근거로해야한다. 하지만이러한외삽은동일분해관계가관찰데이터이상으로계속적용된다는점을가정으로한다. Any evaluation should cover not only the assay, but also the levels of degradation products and other appropriate attributes. 정량분석뿐만아니라, 분해산물의수준과기타특성까지포함하여평가한다 표시사항 (Statements/Labeling) A storage statement should be established for the labeling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug substance. Where applicable, specific instructions should be provided, particularly for drug substances that cannot tolerate freezing. Terms such as ambient conditions or room temperature should be avoided. 관련국가 / 지역기준에의거하여표시자재에기재할보관정보를설정한다. 보관정보는 19

20 원료의약품의안정성평가에근거해야한다. 해당되는경우에는구체적인정보를제공해야 한다. 동결되면안되는원료의약품인경우에특히그렇다. ' 외기조건 ' 이나 ' 실온 ' 과같은 표현은피한다. A re-test period should be derived from the stability information, and a retest date should be displayed on the container label if appropriate. 안정성정보에근거하여재시험기간을설정하며, 적절한경우에는재시험일자를용기라벨에표시한다 완제의약품 (Drug Product) 공통 (General) The design of the formal stability studies for the drug product should be based on knowledge of the behavior and properties of the drug substance and from stability studies on the drug substance and on experience gained from clinical formulation studies. The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated. 완제의약품의공식안정성시험디자인은원료의약품의특성과동태에대한지식, 그리고임상제제시험과원료의약품안정성시험정보를토대로정한다. 보관중에일어날변화와공식안정성시험에서시험할특성요소의선정근거를명기한다 광안정성시험 (Photostability Testing) Photostability testing should be conducted on at least one primary batch of the drug product if appropriate. The standard conditions for photostability testing are described in ICH Q1B. 적절한경우에최소 1개완제의약품기본배치를대상으로광안정성시험을실시한다. 광안정성시험조건은 ICH Q1B를참고한다 배치선정 (Selection of Batches) Data from stability studies should be provided on at least three primary batches of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. The 20

21 manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified. Where possible, batches of the drug product should be manufactured by using different batches of the drug substance. 최소 3개완제의약품기본배치를대상으로실시한안정성시험데이터를제공한다. 이때기본배치는판매를위한것과동일한조성이고동일한용기 / 마개시스템으로포장해야한다. 기본배치제조공정은생산배치에적용되는공정을시뮬레이션한것이어야하며, 판매용제품과동일한품질을갖추고동일한규격에부합하는제품을생산할수있어야한다. 3개배치가운데 2개는최소한파일럿규모배치여야하고나머지한개배치는타당성이있는경우에더작은규모일수있다. 가능하면서로다른원료의약품배치로완제의약품배치를제조한다. Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. 브라켓방법이나매트릭스방법을적용하지않는다면, 완제의약품함량과용기크기각각에대하여안정성시험을실시한다. Other supporting data can be provided. 기타근거데이터도제공할수있다 용기마개시스템 (Container Closure System) Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label). Any available studies carried out on the drug product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively. 판매용용기마개시스템으로포장한완제의약품으로안정성시험을실시한다 ( 적절한경우에는이차포장과용기라벨포함 ). 다른포장자재로포장한의약품이나직접용기를벗어난상태에있는완제의약품을대상으로한시험은, 각기근거정보로활용하거나완제의약품가혹시험의한부분이될수있다. 21

22 규격 (Specification) Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different acceptance criteria for release and shelf life specifications, is addressed in ICH Q6A and Q6B. In addition, specification for degradation products in a drug product is addressed in Q3B. 출하승인규격과유효기간규격등서로다른허용기준개념을포함하여, 시험항목, 분석방법정보, 예정허용기준으로구성된목록인규격문서에대해서는 ICH Q6A와 Q6B를참고한다. 또한완제의약품의분해산물에대한규격은 Q3B를참고한다. Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system). Analytical procedures should be fully validated and stability indicating. Whether and to what extent replication should be performed will depend on the results of validation studies. 보관중에변화될수있고품질, 안전성, 및 / 또는유효성에영향을줄가능성이있는완제의약품의특성을안정성시험시에평가한다. 물리적, 화학적, 생물학적, 미생물학적특성, 보존제함량 ( 예, 항산화제, 항미생물보존제 ), 그리고기능성 ( 예, 약물전달시스템인경우 ) 을시험한다. 분석방법을충분히밸리데이션하며안정성지시성방법이어야한다. 밸리데이션결과에따라반복실시여부와정도를결정한다. Shelf life acceptance criteria should be derived from consideration of all available stability information. It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage. Any differences between the release and shelf life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation (except for preservative concentration) intended for marketing. A single primary stability batch of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for 22

23 verification purposes, regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content. 유효기간허용기준은활용가능한모든안정성정보를검토하여설정한다. 보관중에관찰된변화와안정성평가결과를바탕으로, 유효기간허용기준과출하승인허용기준을다르게설정할수있다. 항미생물보존제함량의출하승인허용기준과유효기간허용기준이차이가나면, 판매용최종조성상태 ( 보존제농도제외 ) 의제품을대상으로개발과정에서확보한화학적함량과보존제효능사이의검증된상호관계를통해그차이를뒷받침한다. 보존제함량의출하승인허용기준과유효기간허용기준사이에차이가있건없건, 한개안정성시험기본배치를대상으로예정유효기한시점에항미생물보존제효과 ( 보존제함량시험에추가하여 ) 를시험해확인한다 시험주기 (Testing Frequency) For long term studies, frequency of testing should be sufficient to establish the stability profile of the drug product. For products with a proposed shelf life of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life. 장기안정성시험인경우에시험주기는완제의약품의안정성프로파일을결정하는데충분해야한다. 예정유효기간이최소 12개월인제품인경우에장기보관조건시험주기를일반적으로첫해에 3개월로하고, 두번째해에는 6개월로하며, 그이후부터는예정유효기간전체에걸쳐연 1회로한다. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated testing are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design. 가속보관조건인경우에는 6개월시험기간동안최소한 3회 ( 초기와말기포함 )( 예, 0, 3, 6개월 ) 시험할것을권장한다. ( 개발경험에근거하여 ) 가속시험결과가 " 중대한변화 " 에대한기준에근접할것으로예상되는경우, 마지막시점에검체를추가하거나 4번째시험시기를포함시키는방식으로시험을확대하여실시한다. When testing at the intermediate storage condition is called for as a result of 23

24 significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended. 가속보관조건에서중대한변화가발생하여중간보관조건시험이필요한경우, 12개월시험기간을설정하고최소 4회시험 ( 초기와말기포함 )( 예, 0, 6, 9, 12개월 ) 시험할것을권장한다. Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified. 타당성이있는경우에는시험주기를감축하거나특정요소조합은전혀시험하지않는축소방법 ( 예, 매트릭스방법또는브라켓방법 ) 을활용할수있다 보관조건 (Storage Conditions) In general, a drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. 일반적으로열안정성과해당되는경우에는습기민감성또는용매손실가능성을시험할수있는보관조건 ( 적정허용범위포함 ) 에서완제의약품을평가한다. 보관조건과시험기간은보관, 운송, 사용상황을감안하여충분하게설정한다. Stability testing of the drug product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product. This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the formal stability studies at initial and final time points and, if full shelf life long term data will not be available before submission, at 12 months or the last time point for which data will be available. In general, this testing need not be repeated on commitment batches. 해당되는경우에는재구성또는희석한상태로완제의약품안정성시험을실시하여, 재구성또는희석제품의조제, 보관조건, 사용기간에관한표시정보를확보한다. 재구성또는희석제품을대상으로기본배치의예정사용기간전체에걸쳐이시험을실시한다. 공식 24

25 안정성시험의한부분으로초기와말기시점에실시하며, 제출시점에유효기간전체에 걸친장기안정성데이터가없는경우에는 12 개월시점또는마지막시험시점에실시하여 데이터를확보한다. 일반적으로이시험을이행약속배치를상대로반복할필요는없다. The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested. Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short term excursions outside the label storage conditions (such as might occur during shipping). 장기안정성시험은제출시점에최소 3개기본배치를상대로최소 12개월간실시한상태여야하며, 이후에도예정유효기간을포함해충분한기간동안계속진행해야한다. 요청이있는경우에는등록신청문서의평가기간동안축적된추가데이터를규제기관에제출한다. 가속보관조건에서확보한시험데이터와적절한경우에는중간보관조건에서확보한시험데이터를활용하여 ( 운송도중발생할수있는것과같이 ) 표시보관조건을단기적으로벗어나는일탈상황의영향을평가할수있다. Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below. The general case applies if the drug product is not specifically covered by a subsequent section. Alternative storage conditions can be used, if justified. 완제의약품안정성시험을위한장기, 가속, 그리고적절한경우에는중간보관조건을아래에서자세히설명한다. 아래항목에서별도로다루지않은완제의약품에대해서는일반기준이적용된다. 타당성이있는경우에는다른보관조건을채택할수도있다 일반기준 (General case) 시험조건 (Study) 보관조건 (Storage Condition) 최소제출자료 (Minimum time period covered by data at submission) 장기 (long term)* 25 C ± 2 C/60% RH ± 5% RH 또는 12 개월 25

26 30 C ± 2 C/65% RH ± 5% RH 중간 (intermediate)** 30 C ± 2 C/65% RH ± 5% RH 6개월 가속 (accelerated) 40 C ± 2 C/75% RH ± 5% RH 6개월 * It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2 C/60% RH ± 5% RH or 30 C ± 2 C/65% RH ± 5% RH. 장기안정성시험조건 (25 ± 2 C/60% RH ± 5% RH 또는 30 C ± 2 C/65% RH ± 5% RH) 을신청업체가결정한다. ** If 30 C ± 2 C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition. 30 C ± 2 C/65% RH ± 5% RH를장기안정성시험조건으로한다면, 중간 조건은해당되지않는다. If long-term studies are conducted at 25 C ± 2 C/60% RH ± 5% RH and significant change occurs at any time during 6 months testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial application should include a minimum of 6 months data from a 12-month study at the intermediate storage condition. 장기안정성시험을 25 C ± 2 C/60% RH ± 5% RH 조건에서실시하며가속조건 6개월시험기간에 " 중대한변화 " 가발생하면, 중간조건에서추가시험을실시하고중대한변화기준에대비하여평가한다. 첫신청문서제출시에중간보관조건 12개월시험가운데최소 6개월시험데이터를포함시켜야한다. In general, significant change for a drug product is defined as: 일반적으로완제의약품의 " 중대한변화 " 는다음과같이정의된다. 1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures; 초기값에대비하여함량결과가 5% 변화또는생물학적또는면역학적방법으로역가를평가할때는역가허용기준에부합하지않는경우. 2. Any degradation product s exceeding its acceptance criterion; 26

27 분해산물이허용기준을초과하는경우. 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; 성상, 물리적특성, 기능성시험 ( 예, 색상, 상분리, 재현탁성, 케이킹, 경도, 액츄에이션당투여용량전달 ) 허용기준부적합. 하지만가속조건에서는일부물리적특성 ( 예, 좌약의연화, 크림의용해 ) 변화가예상되기도한다. and, as appropriate for the dosage form: 그리고제형에따라적절한경우에, 4. Failure to meet the acceptance criterion for ph; or ph 허용기준부적합. 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. 12개제품의용출허용기준부적합 불침투성용기포장완제의약품 (Drug products packaged in impermeable containers) Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition. 습기나용매통과를막는영구적인배리어를제공하는불침투성용기에포장된완제의약품인경우에는습기민감성이나용매손실가능성이우려되지않는다. 그러므로불침투성용기에보관하는제품의안정성시험은습도관리조건이나외기습도조건에서실시할수있다 반투성용기포장완제의약품 (Drug products packaged in semi-permeable containers) 27

28 Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation can be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-permeable containers can withstand low relative humidity environments. 반투성용기에포장되는수성제품인경우에는, 물리적, 화학적, 생물학적, 미생물학적안정성이외에도수분손실가능성을평가해야한다. 아래에설명하는바와같이, 낮은상대습도조건에서이평가를실시할수있다. 궁극적으로는반투성용기에포장된수성의약품이낮은상대습도환경도견딜수있음을증명해야한다. Other comparable approaches can be developed and reported for non-aqueous, solvent-based products. 비수성, 용매기반제품에대해서도다른동등한방법을개발해보고할수있다. 시험조건 (Study) 장기 (long term)* 보관조건 (Storage Condition) 25 C ± 2 C/40% RH ± 5% RH 또는 30 C ± 2 C/35% RH ± 5% RH 최소제출자료 (Minimum time period covered by data at submission) 12개월 중간 (intermediate)** 30 C ± 2 C/65% RH ± 5% RH 6 개월 가속 (accelerated) 40 C ± 2 C/ not more than (NMT) 25% RH 6 개월 * It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2 C/40% RH ± 5% RH or 30 C ± 2 C/35% RH ± 5% RH. 장기안정성시험조건 (25 ± 2 C/40% RH ± 5% RH 또는 30 C ± 2 C/35% RH ± 5% RH) 을신청업체가결정한다. ** If 30 C ± 2 C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition. 30 C ± 2 C/35% RH ± 5% RH를장기안정성시험조건으로한다면, 중간조건은해당되지않는다. 28

29 For long-term studies conducted at 25 C ± 2 C/40% RH ± 5% RH, additional testing at the intermediate storage condition should be performed as described under the general case to evaluate the temperature effect at 30 C if significant change other than water loss occurs during the 6 months testing at the accelerated storage condition. A significant change in water loss alone at the accelerated storage condition does not necessitate testing at the intermediate storage condition. However, data should be provided to demonstrate that the drug product will not have significant water loss throughout the proposed shelf life if stored at 25 C and the reference relative humidity of 40% RH. 장기안정성시험을 25 C ± 2 C/40% RH ± 5% RH 조건에서실시하는경우, 가속조건 6개월시험기간에수분손실이외의 " 중대한변화 " 가발생하면, 일반기준항목에서설명한바와같이중간조건에서추가시험을실시하여 30 C의온도영향을평가한다. 가속보관조건에서수분손실만중대한변화가발생하는경우에는, 중간보관조건시험이꼭필요한것은아니다. 하지만 25 C와참조상대습도 40%RH에서보관했을때예정유효기간전체에걸쳐중대한수분손실이발생하지않음을증명하는데이터를제공해야한다. A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months storage at 40 C/NMT 25% RH. However, for small containers (1 ml or less) or unitdose products, a water loss of 5% or more after an equivalent of 3 months storage at 40 C/NMT 25% RH may be appropriate, if justified. 40 C/NMT 25% RH 조건에서 3개월보관에해당되는노출이후, 반투성용기에포장한제품이초기값에대비하여 5% 수분손실을보이면중대한변화로간주된다. 하지만작은용기 (1 ml 이하 ) 에포장한제품이나단위투여용량제품인경우에 40 C/NMT 25% RH 조건에서 3개월보관에해당되는노출이후, 5% 이상의수분손실을보여도타당성이있으면적절할수있다. An alternative approach to studying at the reference relative humidity as recommended in the table above (for either long term or accelerated testing) is performing the stability studies under higher relative humidity and deriving the water loss at the reference relative humidity through calculation. This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of 29

30 water loss rates between the two humidity conditions at the same temperature. The permeation coefficient for a container closure system can be experimentally determined by using the worst case scenario (e.g., the most diluted of a series of concentrations) for the proposed drug product. 상기표의참조상대습도에서시험하는방법이외의다른방법은 ( 장기또는가속시험 ), 더높은상대습도에서안정성시험을실시하고참조상대습도에서의수분손실을계산하여구하는것이다. 용기마개시스템의침투계수를실험적으로결정하거나아래의예에서설명한바와같이동일온도조건에서두개습도조건사이의수분손실율계산값을이용해구할수있다. 용기마개시스템의침투계수는예정완제의약품의최악의시나리오 ( 예, 일련의농도가운데가장많이희석된것 ) 를적용하여실험적으로구할수있다. 수분손실결정방법의예 (Example of an approach for determining water loss): For a product in a given container closure system, container size, and fill, an appropriate approach for deriving the water loss rate at the reference relative humidity is to multiply the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio shown in the table below. A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated. 특정용기마개시스템, 용기크기, 충전량의제품을상대로참조상대습도조건에서수분손실율을구하는적절한방법은, 동일온도의다른상대습도에서측정한수분손실율을아래의표에제시된수분손실비율로곱하는것이다. 그리고보관기간동안다른상대습도조건에서선형수분손실율을증명한다. For example, at a given temperature, e.g., 40 C, the calculated water loss rate during storage at NMT 25% RH is the water loss rate measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio. 예를들어특정온도 ( 예, 40 C) 와 NMT 25% RH에서보관기간동안수분손실율계산값은, 75% RH에서측정한수분손실율을해당수분손실비율인 3.0을곱하여구한것이다. 다른상대습도 (alternative relative humidity) 참조상대습도 (reference relative humidity) 특정온도에서의수분손실 비율 (ratio of water loss rates at a given 30

31 temperature) 60% RH 25% RH % RH 40% RH % RH 35% RH % RH 25% RH 3.0 Valid water loss rate ratios at relative humidity conditions other than those shown in the table above can also be used. 표에제시된것이외의상대습도조건에서유효한수분손실비율을활용할수도있다 냉장보관완제의약품 (Drug products intended for storage in a refrigerator) 시험조건 (Study) 보관조건 (Storage Condition) 최소제출자료 (Minimum time period covered by data at submission) 장기 (long term) 5 C ± 3 C 12 개월 가속 (accelerated) 25 C ± 2 C/60% RH ± 5% RH 6 개월 If the drug product is packaged in a semi-permeable container, appropriate information should be provided to assess the extent of water loss. 반투성용기에포장되는완제의약품인경우에는수분손실정도평가에필요한정보를적절하게제공해야한다. Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below. 아래에서명확히기술한경우를제외하고는이가이드라인의평가섹션에기술한바에따라냉장보관데이터를평가한다. If significant change occurs between 3 and 6 months testing at the accelerated storage condition, the proposed shelf life should be based on the real time data available from the long term storage condition. 가속보관조건에서 3개월과 6개월사이에중대한변화가발생하면, 장기보관조건 31

32 실시간안정성시험데이터를근거로예정유효기간을설정한다. If significant change occurs within the first 3 months testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during shipment and handling. This discussion can be supported, if appropriate, by further testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a product through 6 months when a significant change has occurred within the first 3 months. 가속보관조건에서첫 3개월사이에중대한변화가일어나면, 표시보관조건을단기적으로벗어나는일탈상황 ( 예, 운송또는취급시 ) 의영향에대한평가자료를제출한다. 이때 3개월보다짧은기간동안완제의약품한배치를추가로시험하되일반적인상황보다더빈번하게시험하여평가결과를뒷받침할수있다. 첫 3개월사이에중대한변화가발생한다면안정성시험을 6개월까지계속진행하는것은불필요하다고볼수있다 냉동보관완제의약품 (Drug products intended for storage in a freezer) 시험조건 (Study) 보관조건 (Storage Condition) 최소제출자료 (Minimum time period covered by data at submission) 장기 (long term) - 20 C ± 5 C 12 개월 For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long term storage condition. In the absence of an accelerated storage condition for drug products intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5 C ± 3 C or 25 C ± 2 C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition. 냉동보관완제의약품인경우에는장기보관조건에서확보한데이터를근거로유효기간을설정한다. 냉동보관완제의약품의가속보관조건이없는경우, 적정기간동안높은온도 ( 예, 5 C ± 3 C 또는 25 C ± 2 C) 조건에서한배치를시험하여, 예정표시보관조건을단기적으로벗어나는상황 ( 예, 운송또는취급시 ) 에따른영향을평가한다. 32

33 C 이하보관완제의약품 (Drug products intended for storage below - 20 C) Drug products intended for storage below -20 C should be treated on a case-bycase basis. -20 C 이하에서보관할완제의약품은상황에따라처리한다 안정성이행약속 (Stability Commitment) When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life. 기본배치를대상으로한장기안정성시험데이터가승인시점에예정유효기간을모두포괄하고있지않다면, 승인을받은이후에도안정성시험을계속진행하여유효기간을입증하겠다는이행약속을해야한다. Where the submission includes long term stability data from three production batches covering the proposed shelf life, a post approval commitment is considered unnecessary. Otherwise, one of the following commitments should be made: 제출문서에예정유효기간을포괄하는 3개생산배치대상장기안정성시험데이터가포함되어있다면, 승인이후의안정성시험이행약속은필요하지않다. 그렇지않으면다음가운데한가지이행약속을해야한다. 1. If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months. 최소 3개생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있다면, 예정유효기간전체에걸친장기시험과 6개월가속시험을계속진행하겠다고이행약속을한다. 2. If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies 33

34 for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months. 3개보다적은생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있다면, 예정유효기간전체에걸친장기시험과 6개월가속시험을계속진행하고추가생산배치를포함시켜최소한총 3개배치가되도록하여예정유효기간전체에걸친장기안정성시험과 6개월가속시험을진행하겠다고이행약속을한다. 3. If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months. 생산배치를상대로실시한안정성시험데이터가제출문서에포함되어있지않다면, 첫 3개생산배치를상대로예정유효기간동안장기안정성시험과 6개월가속시험을실시하겠다고이행약속을한다. The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scientifically justified. 이행약속배치의안정성시험프로토콜은, 달리과학적타당성이없으면기본배치시험에사용했던것과동일해야한다. Where intermediate testing is called for by a significant change at the accelerated storage condition for the primary batches, testing on the commitment batches can be conducted at either the intermediate or the accelerated storage condition. However, if significant change occurs at the accelerated storage condition on the commitment batches, testing at the intermediate storage condition should also be conducted. 기본배치의가속보관조건에서중대한변화가발생하여중간조건시험이필요한경우, 중간보관조건또는가속보관조건에서이행배치를시험할수있다. 그러나가속보관조건에서이행배치가중대한변화를보인다면, 중간보관조건도시험을해야한다 평가 (Evaluation) A systematic approach should be adopted in the presentation and evaluation of the 34