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1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE 새로운원료의약품과완제의약품의안정성시험을위한브라켓방법과매트릭스방법 (Bracketing & Matrixing Designs for Stability Testing ) Q1D Current Step 4 version dated 7 February 2002 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 1

2 adoption to the regulatory bodies of the European Union, Japan and USA. 2

3 Q1D Document History First Codification Q1D History Date New Codification November 2005 Approval by the Steering Committee under 10 Q1D Step 2 and release for public consultation November 2000 Current Step 4 version Q1D Approval by the Steering Committee under 7 Q1D Step 4 and recommendation for adoption February to the three ICH regulatory bodies

4 BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS ICH Harmonised Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 7 February 2002, this guideline is recommended for adoption to the three regulatory parties to ICH. 목차 1. 서론 (INTRODUCTION) 1.1 목표 (Objectives of the Guideline) 1.2 배경 (Background) 1.3 적용범위 (Scope of the Guideline) 2. 가이드라인 (GUIDELINES) 2.1 공통 (General) 2.2 단축디자인의적용 (Applicability of Reduced Designs) 2.3 브라켓방법 (Bracketing) 2.4 매트릭스방법 (Matrixing) 2.5 데이터평가 (Data Evaluation) 4

5 BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS 1. 서론 (INTRODUCTION) 1.1 목표 (Objectives of the Guideline) This guideline is intended to address recommendations on the application of bracketing and matrixing to stability studies conducted in accordance with principles outlined in the ICH Q1A(R) Harmonised Tripartite guideline on Stability Testing (hereafter referred to as the parent guideline). 이가이드라인은 ICH Q1A(R) 새로운원료의약품과완제의약품의안정성시험가이드라인 ( 이하 " 모가이드라인 ") 에기술된원칙에의거한안정성시험에적용할브라켓방법과매트릭스방법에대한권고사항을제시한다. 1.2 배경 (Background) The parent guideline notes that the use of matrixing and bracketing can be applied, if justified, to the testing of new drug substances and products, but provides no further guidance on the subject. 모가이드라인은타당성이있는경우에새로운원료의약품과완제의약품의안정성시험에매트릭스방법과브라켓방법을적용할수있다고했지만, 이에관하여더이상의가이드라인을제시하지않았다. 1.3 적용범위 (Scope of the Guideline) This document provides guidance on bracketing and matrixing study designs. Specific principles are defined in this guideline for situations in which bracketing or matrixing can be applied. Sample designs are provided for illustrative purposes, and should not be considered the only, or the most appropriate, designs in all cases. 브라켓방법과매트릭스방법에따른안정성시험에대한가이드라인을제공한다. 브라켓방법또는매트릭스방법의적용상황에대한구체적인원칙을규정한다. 샘플디자인은하나의예로제시된것이며, 모든상황에적용해야하는유일하거나가장적절한것으로생각해서는안된다. 5

6 2. 가이드라인 (GUIDELINES) 2.1 공통 (General) A full study design is one in which samples for every combination of all design factors are tested at all time points. A reduced design is one in which samples for every factor combination are not all tested at all time points. A reduced design can be a suitable alternative to a full design when multiple design factors are involved. Any reduced design should have the ability to adequately predict the retest period or shelf life. Before a reduced design is considered, certain assumptions should be assessed and justified. The potential risk should be considered of establishing a shorter retest period or shelf life than could be derived from a full design due to the reduced amount of data collected. 모든디자인요소의모든조합에해당되는검체를모든시점에시험하는것이 " 완전시험디자인 " 이다. 반면모든요소조합의검체를모든시점에시험하지않는것을 " 단축디자인 " 이라한다. 다수의디자인요소가관련된경우에는완전시험디자인대신에단축디자인을채택할수있다. 단축디자인은재시험기간또는유효기간을적절하게예측할수있어야한다. 단축디자인을검토하기에앞서, 몇가지가정을평가하고타당성을입증해야한다. 데이터수집량의감축으로인해완전디자인에서도출되는것보다재시험기간이나유효기간이더짧게설정될리스크도고려한다. During the course of a reduced design study, a change to full testing or to a less reduced design can be considered if a justification is provided and the principles of full designs and reduced designs are followed. However, proper adjustments should be made to the statistical analysis, where applicable, to account for the increase in sample size as a result of the change. Once the design is changed, full testing or less reduced testing should be carried out through the remaining time points of the stability study. 단축디자인으로안정성시험을진행하는도중에, 타당성이있고완전디자인과단축디자인의원칙을따른다면, 완전시험또는강화단축디자인으로변경할수도있다. 하지만그와같은변경에따른검체규모의증가를감안하여통계분석방법을적절하게조정해야한다. 안정성시험디자인을변경하면, 남은안정성시험기간동안완전시험또는강화단축시험을실시한다. 6

7 2.2 단축디자인의적용 (Applicability of Reduced Designs) Reduced designs can be applied to the formal stability study of most types of drug products, although additional justification should be provided for certain complex drug delivery systems where there are a large number of potential drug-device interactions. For the study of drug substances, matrixing is of limited utility and bracketing is generally not applicable. 대다수의약품의공식안정성시험에단축디자인을적용할수있다. 하지만약물-의료기기상호작용가능성이큰일부복잡한약물전달시스템은타당성이추가적으로증명되어야한다. 원료의약품안정성시험인경우에는매트릭스방법의효용성이제한적이며, 브라켓방법은일반적으로적용되지않는다. Whether bracketing or matrixing can be applied depends on the circumstances, as discussed in detail below. The use of any reduced design should be justified. In certain cases, the condition described in this guideline is sufficient justification for use, while in other cases, additional justification should be provided. The type and level of justification in each of these cases will depend on the available supporting data. Data variability and product stability, as shown by supporting data, should be considered when a matrixing design is applied. 아래에자세히기술한바와같이, 브라켓또는매트릭스방법의적용여부는상황에따라다르다. 단축디자인의타당성이입증되어야한다. 이가이드라인에기술된조건을충족하면충분한경우도있지만, 추가적으로타당성을입증해야하는경우도있다. 타당성입증의수준과유형은활용가능한근거데이터에따라달라진다. 매트릭스디자인을적용할때는근거데이터에서알수있는제품안정성과데이터변동성을고려해야한다. Bracketing and matrixing are reduced designs based on different principles. Therefore, careful consideration and scientific justification should precede the use of bracketing and matrixing together in one design. 브라켓방법과매트릭스방법은서로다른원칙을바탕으로하는단축디자인이다. 그러므로브라켓방법과매트릭스방법을하나의안정성시험에함께사용하려면, 신중한검토와과학적인타당성입증이전제되어야한다. 2.3 브라켓방법 (Bracketing) As defined in the glossary to the parent guideline, bracketing is the design of a 7

8 stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. 모가이드라인의용어정의에규정되어있는바와같이, 브라켓방법은특정디자인요소 ( 예, 함량, 용기크기, 충전량 ) 의극한조건에해당되는검체만완전디자인과마찬가지로모든시점에시험하는안정성시험디자인을의미한다. 이때극한조건의안정성이중간수준의안정성을대표한다고가정한다. The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes. 선정된함량, 용기크기, 충전량이실제로극한조건에해당됨을증명하지못하면, 브라켓디자인의사용은적절하다고볼수없다 디자인요소 (Design Factors) Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability. 디자인요소는안정성시험시에제품안정성에미치는영향을평가할변수 ( 예, 함량, 용기크기, 충전량 ) 를의미한다 함량 (Strength) Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Examples include but are not limited to (1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings). 동일조성또는밀접하게연관된조성의여러함량제품을상대로한안정성시험에브라켓방법을적용할수있다. 일부예를들면다음과같지만이에국한되지는않는다. (1) 동일파우더블렌드로만든서로다른플러그크기의함량이서로다른캡슐제품. (2) 동일과립의양을다르게하여압착해만든서로다른함량의정제. (3) 일부중요하지않은첨가제 ( 예, 착색제, 향미제 ) 만다르게한조제물로만든서로다른함량의내용액제. 8

9 With justification, bracketing can be applied to studies with multiple strengths where the relative amounts of drug substance and excipients change in a formulation. Such justification can include a demonstration of comparable stability profiles among the different strengths of clinical or development batches. 타당성이있으면원료의약품과첨가제의상대적인양이다른경우에도, 함량이여러가지인제품의안정성시험에브라켓방법을적용할수있다. 이때서로다른함량의임상배치또는개발배치사이의안정성프로파일이동등함을증명하는식으로타당성을입증할수있다. In cases where different excipients are used among strengths, bracketing generally should not be applied. 함량이여러가지인제품의첨가제가서로다른경우에는, 일반적으로브라켓방법을적용하지않는다 용기마개크기와충전량 (Container Closure Sizes and/or Fills) Bracketing can be applied to studies of the same container closure system where either container size or fill varies while the other remains constant. However, if a bracketing design is considered where both container size and fill vary, it should not be assumed that the largest and smallest containers represent the extremes of all packaging configurations. Care should be taken to select the extremes by comparing the various characteristics of the container closure system that may affect product stability. These characteristics include container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate or oxygen permeation rate per dosage unit or unit fill volume, as appropriate. 다른조건은동일한상태에서용기크기나충전량이다른경우, 동일용기마개시스템의안정성시험에브라켓방법을적용할수있다. 하지만용기크기와충전량이모두다른경우에브라켓디자인을고려한다면, 가장큰용기와가장작은용기가모든포장구조가운데극한조건에해당된다고가정해서는안된다. 제품안정성에영향을미칠가능성이있는용기마개시스템의다양한특성을비교하여극한조건을신중하게선정한다. 이때고려해야할특성으로는용기벽두께, 마개의기하구조, 표면적-부피비율, 헤드스페이스- 부피비율, 단위제품당수증기투과율또는산소투과율, 또는단위충전량이있다. 9

10 With justification, bracketing can be applied to studies for the same container when the closure varies. Justification could include a discussion of the relative permeation rates of the bracketed container closure systems. 타당성이있으면용기는동일하고마개가다른경우의안정성시험에브라켓방법을적용할수있다. 이때브라켓방법을적용한용기마개시스템의상대투과율평가를통해타당성을입증하는방법이있다 디자인고려사항과잠재리스크 (Design Considerations and Potential Risks) If, after starting the studies, one of the extremes is no longer expected to be marketed, the study design can be maintained to support the bracketed intermediates. A commitment should be provided to carry out stability studies on the marketed extremes post-approval. 안정성시험을시작한다음에극한조건가운데하나에해당되는제품을판매할가능성이없는것으로예상되어도, 브라켓방법에의거한중간조건의제품안정성을뒷받침하기위해시험디자인을그대로유지할수있다. 제품승인이후에판매제품의극한조건을대상으로안정성시험을실시하겠다는이행약속을제공해야한다. Before a bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e., the shelf life for the intermediates should not exceed that for the least stable extreme). 브라켓디자인을적용하기전에, 재시험기간또는유효기간추정에미치는영향을평가한다. 극한조건의안정성이다른것으로밝혀지면, 중간조건의제품이극한조건의제품보다더안정하다고간주해서는안된다 ( 즉극한조건제품의안정성보다중간조건제품의안정성이더좋다고간주하고유효기간을극한조건제품보다더길게잡아서는안된다 ) 디자인예 (Design Example) An example of a bracketing design is given in Table 1. This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 ml and 500 ml high-density polyethylene 10

11 container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design. 표 1은브라켓디자인의한예이다. 이예는 3종류의함량과 3종류의용기크기로판매되는제품을대상으로한다. 여기서 15 ml와 500 ml의 HDPE 용기크기가실제로극한조건임이증명되어야한다. 각선정조합에해당되는배치를완전디자인과마찬가지시점에시험한다. Table 1: 브라켓디자인의예 (Example of a Bracketing Design) 함량 (Strength) 50 mg 75 mg 100 mg 배치 (Batch) 용기크기 15 ml T T T T T T (Container Size) 100 ml 150 ml T T T T T T T = 검체시험 (Sample tested) 2.4 매트릭스방법 (Matrixing) As defined in the glossary of the parent guideline, matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and possibly, in some cases, different container closure systems. 모가이드라인의용어정의에규정되어있는바와같이, 매트릭스방법은모든요소조합에해당되는검체전체가운데일부세트를선정하여지정시점에시험하는안정성시험방법이다. 다음시점에는모든요소조합에해당되는검체가운데다른세트를시험한다. 이방법은특정시점에서시험대상검체세트의안정성이모든검체의안정성을대표한다고가정한것이다. 동일의약품의검체차이로는배치차이, 함량차이, 동일용기 / 마개의크기차이, 그리고경우에따라서는용기 / 마개시스템차이등이있다. When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems. 11

12 이차포장시스템이의약품안정성에영향을준다면, 포장시스템전체에걸쳐매트릭스 방법을적용할수있다. Each storage condition should be treated separately under its own matrixing design. Matrixing should not be performed across test attributes. However, alternative matrixing designs for different test attributes can be applied if justified. 자체매트릭스디자인에의거해각보관조건을별도로처리한다. 매트릭스방법을시험항목에적용하지않는다. 하지만타당성이있는경우에는시험항목별매트릭스디자인을적용할수도있다 디자인요소 (Design Factors) Matrixing designs can be applied to strengths with identical or closely related formulations. Examples include but are not limited to (1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants or flavourings). 동일조성또는밀접하게연관된조성의여러함량제품에매트릭스방법을적용할수있다. 일부예를들면다음과같지만이에국한되지는않는다. (1) 동일파우더블렌드로만든서로다른플러그크기의함량이서로다른캡슐제품. (2) 동일과립의양을다르게하여압착해만든서로다른함량의정제. (3) 일부중요하지않은첨가제 ( 예, 착색제, 향미제 ) 만다르게한조제물로만든서로다른함량의내용액제. Other examples of design factors that can be matrixed include batches made by using the same process and equipment, and container sizes and/or fills in the same container closure system. 이외에도동일한공정과설비로만든배치와동일용기마개시스템의용기크기및 / 또는충전량에매트릭스방법을적용할수있다. With justification, matrixing designs can be applied, for example, to different strengths where the relative amounts of drug substance and excipients change or where different excipients are used or to different container closure systems. Justification should generally be based on supporting data. For example, to matrix across two different closures or container closure systems, supporting data could be 12

13 supplied showing relative moisture vapour transmission rates or similar protection against light. Alternatively, supporting data could be supplied to show that the drug product is not affected by oxygen, moisture, or light. 타당성이있는경우에는예를들어서로다른용기마개시스템또는원료의약품과첨가제의상대적인양이변하거나다른첨가제를사용하는경우의서로다른함량에매트릭스디자인을적용할수있다. 일반적으로타당성입증은근거데이터로바탕으로한다. 예를들어두개의서로다른마개또는용기마개시스템에매트릭스방법을적용할때는, 상대수증기전파율또는유사한차광효과를보여주는근거데이터를제공할수있다. 아니면산소, 습기또는빛이의약품에영향을주지않음을보여주는근거데이터를제시할수있다 디자인고려사항 (Design Considerations) A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. However, due to the recommended full testing at certain time points, as discussed below, it may be difficult to achieve a complete balance in a design where time points are matrixed. 안정성시험예정기간동안과제출직전의마지막시점까지각요소조합을동일수준에서시험할수있도록, 최대한균형잡힌매트릭스디자인을설계한다. 하지만아래에서설명하는바와같이, 특정시점에서는모든시험이필요하므로, 시험시점의매트릭스디자인시에완벽한균형을달성하기어려울수있다. In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study. For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors. 시점매트릭스디자인에서는초기와말기에모든선정요소조합을시험하며, 중간 13

14 시점에는지정조합의일부만시험한다. 승인받기이전에예정유효기간에대한전체장기안정성데이터를제출할수없다면, 무엇보다도배치, 함량, 용기크기, 충전량등선정조합전체에대하여 12개월시점또는제출직전마지막시점에시험해야한다. 이외에도첫 12개월시험기간동안각선정조합에대하여초기를포함해최소 3개시점의시험데이터가있어야한다. 가속조건또는중간보관조건시험에매트릭스방법을적용할때는각선정요소조합에대하여초기및말기를포함해최소 3개시점에시험할수있도록한다. When a matrix on design factors is applied, if one strength or container size and/or fill is no longer intended for marketing, stability testing of that strength or container size and/or fill can be continued to support the other strengths or container sizes and/or fills in the design. 매트릭스방법을적용할때특정함량또는용기크기및 / 또는충전량에해당되는제품을판매할가능성이없어도, 매트릭스디자인에포함된다른함량또는용기크기및 / 또는충전량을뒷받침하기위해해당함량또는용기크기및 / 또는충전량의안정성시험을계속진행할수있다 디자인예 (Design Examples) Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are shown in Table 2. The terms one-half reduction and one-third reduction refer to the reduction strategy initially applied to the full study design. For example, a one-half reduction initially eliminates one in every two time points from the full study design and a one-third reduction initially removes one in every three. In the examples shown in Table 2, the reductions are less than one-half and one-third due to the inclusion of full testing of all factor combinations at some time points as discussed in section These examples include full testing at the initial, final, and 12-month time points. The ultimate reduction is therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48, respectively. 표 2는 2개함량 (S1, S2) 제품의시험시점매트릭스디자인의예이다. "1/2 단축 (onehalf reduction)" 과 "1/3 단축 (one-third reduction)" 은완전시험디자인에대비한단축전략을의미한다. 예를들어 "1/2 단축 " 은완전시험디자인에서 2개시점가운데한개를초기에제외하고, "1/3 단축 " 은 3개시점가운데한개를초기에제외한다. 표 2의예에서는 2.4.2에서설명했듯이일부시점에서모든요소조합의전체시험을포함시켰기 14

15 때문에 1/2 단축과 1/3 단축보다단축규모가더적다. 이예에서는초기, 말기, 12 개월 시점에전체시험을실시하는것으로했다. 그러므로실제단축규모는 1/2(24/48) 또는 1/3(16/48) 보다적은 15/48 또는 10/48 이다. Table 2: 2 개함량제품의시험시점매트릭스디자인의예 (Examples of Matrixing Designs on Time Points for a Product with Two Strengths) 1/2 단축 (One-Half Reduction) 시점 ( 월 ) 함량 S1 Batch 1 T T T T T T Batch 2 T T T T T T Batch 3 T T T T T S2 Batch 1 T T T T T Batch 2 T T T T T T Batch 3 T T T T T T = 검체시험 (Sample tested) 1/3 단축 (One-Third Reduction) 시점 ( 월 ) 함량 S1 Batch 1 T T T T T T Batch 2 T T T T T T Batch 3 T T T T T T T S2 Batch 1 T T T T T T T Batch 2 T T T T T T Batch 3 T T T T T T T = 검체시험 (Sample tested) Additional examples of matrixing designs for a product with three strengths and three container sizes are given in Tables 3a and 3b. Table 3a shows a design with matrixing on time points only and Table 3b depicts a design with matrixing on time points and factors. In Table 3a, all combinations of batch, strength, and container size are tested, while in Table 3b, certain combinations of batch, strength and container size are not tested. 3개함량과 3개용기크기제품의매트릭스디자인에대한예가표 3a와 3b에정리되어있다. 표 3a는시험시점만대상으로한매트릭스디자인이며, 표 3b는시험시점과요소 15

16 모두의매트릭스디자인이다. 표 3a 는배치, 함량, 용기크기의모든조합을시험하며, 표 3b 는배치, 함량, 용기크기의일부조합은시험하지않는다. Tables 3a and 3b: 3 개함량과 3 개용기크기제품의매트릭스디자인예 (Examples of Matrixing Designs for a Product with Three Strengths and Three Container Sizes) 3a 시험시점매트릭스 (Matrixing on Time Points) 함량 (Strength) S1 S2 S3 용기크기 (Container size) A B C A B C A B C Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2 Batch 2 T2 T3 T1 T3 T1 T2 T1 T2 T3 Batch 3 T3 T1 T2 T1 T2 T3 T2 T3 T1 3b 시험시점 / 요소매트릭스 (Matrixing on Time Points and Factors) 함량 (Strength) S1 S2 S3 용기크기 (Container size) A B C A B C A B C Batch 1 T1 T2 T2 T1 T1 T2 Batch 2 T3 T1 T3 T1 T1 T3 Batch 3 T3 T2 T2 T3 T2 T3 주 : 시험시점 (Time Point)( 월 ) T1 T T T T T T T T2 T T T T T T T3 T T T T T T S1, S2, and S3 are different strengths. A, B, and C are different container sizes. S1, S2, S3는다른함량을의미하고, A, B, C는다른용기크기를의미한다. T = 검체시험 (Sample tested) 적용및단축정도 (Applicability and Degree of Reduction) The following, although not an exhaustive list, should be considered when a matrixing design is contemplated: 16

17 매트릭스디자인을고려할때는다음사항을고려한다 ( 모든것을포괄하는리스트는 아니다 ). knowledge of data variability 데이터변동성에관한지식 expected stability of the product 제품의예상안정성 availability of supporting data 근거데이터의활용성 stability differences in the product within a factor or among factors and/or 특정요소또는여러요소측면의제품안정성차이 number of factor combinations in the study 시험대상요소조합의수 In general, a matrixing design is applicable if the supporting data indicate predictable product stability. Matrixing is appropriate when the supporting data exhibit only small variability. However, where the supporting data exhibit moderate variability, a matrixing design should be statistically justified. If the supportive data show large variability, a matrixing design should not be applied. 일반적으로근거데이터로제품안정성을예측할수있는경우에매트릭스디자인을적용할수있다. 근거데이터가매우적은수준의변동성을보여줄때만매티릭스방법이적절하다. 하지만근거데이터가중간수준의변동성을보여줄때는, 매트릭스디자인의타당성을통계적으로입증해야한다. 근거데이터가큰변동성을보여줄때는매트릭스디자인을적용할수없다. A statistical justification could be based on an evaluation of the proposed matrixing design with respect to its power to detect differences among factors in the degradation rates or its precision in shelf life estimation. 분해속도나유효기간추정의정밀성측면에서요소사이의차이를검출할수있는능력과관련된예정매트릭스디자인의평가결과를바탕으로통계적타당성을입증할수있다. If a matrixing design is considered applicable, the degree of reduction that can be made from a full design depends on the number of factor combinations being evaluated. The more factors associated with a product and the more levels in each 17

18 factor, the larger the degree of reduction that can be considered. However, any reduced design should have the ability to adequately predict the product shelf life. 매트릭스디자인을적용할수있다고판단되는경우, 평가대상요소조합의수를고려하여완전디자인에대비한단축수준을결정한다. 제품관련요소가많고요소별수준이많으면, 단축수준을더크게할수있다. 하지만어떤단축디자인을선택하건, 제품유효기간을적절하게예측할수있어야한다 잠재리스크 (Potential Risk) Due to the reduced amount of data collected, a matrixing design on factors other than time points generally has less precision in shelf life estimation and yields a shorter shelf life than the corresponding full design. In addition, such a matrixing design may have insufficient power to detect certain main or interaction effects, thus leading to incorrect pooling of data from different design factors during shelf life estimation. If there is an excessive reduction in the number of factor combinations tested and data from the tested factor combinations cannot be pooled to establish a single shelf life, it may be impossible to estimate the shelf lives for the missing factor combinations. 수집데이터의양이감소되므로, 시험시점이외다른요소의매트릭스디자인은일반적으로유효기간예측의정밀도가떨어지며완전디자인보다더짧은유효기간이도출된다. 이외에도그와같은매트릭스디자인은일부주영향또는상호작용영향을감지하는능력이충분하지않아, 유효기간추정시에각종디자인요소의데이터를부정확하게처리할수있다. 시험대상요소조합의수를과도하게단축하고시험한요소조합에서확보한시험데이터를처리하여하나의유효기간을설정할수없는경우에는생략한요소조합에대하여유효기간을추정하기가불가능할것이다. A study design that matrixes on time points only would often have similar ability to that of a full design to detect differences in rates of change among factors and to establish a reliable shelf life. This feature exists because linearity is assumed and because full testing of all factor combinations would still be performed at both the initial time point and the last time point prior to submission. 시험시점매트릭스디자인은각종요소사이의변화율차이를감지하고신뢰성있는유효기간을설정하는데있어서완전디자인과유사한효과를가질수있다. 이와같은특징은직선성을가정하고모든요소조합의모든시험을초기와제출직전의마지막시점에실시하기때문에가능하다. 18

19 2.5 데이터평가 (Data Evaluation) Stability data from studies in a reduced design should be treated in the same manner as data from full design studies. 단축디자인의안정성시험데이터를완전시험디자인의데이터와동일한방식으로처리한다. 19

Microsoft Word - Q1FStabilityDataPackage.doc

Microsoft Word - Q1FStabilityDataPackage.doc INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE III 및 IV 기후지역에서의등록신청을위한안정성데이터패키지 (Stability Data