INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
Q1D
Bracketing and matrixing designs for stability
testing of drug substances and drug products
Step 2 9 November 2000
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INTRODUCTION
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1.1Objectives of the Guideline
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The objective of this guideline is to provide harmonid guidance on the application of bracketing 13
and matrixing for stability studies conducted in accordance with principles outlined in the ICH 14
Q1A Harmonid Tripartite guideline covering Stability Testing of New Drug Substances and 15
Products (hereafter referred to as the parent guideline).
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1.2Background
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Q1A notes that the u of matrixing and bracketing can be applied, if justified, to the testing of 20
new drug substances and products, but provides no further guidance on the subject.
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1.3Scope of the guideline
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This document is an annex to the parent guideline and address recommendations for 25
bracketing and matrixing study designs. Specific principles are provided in this guideline for 26
situations in which bracketing or matrixing can be applied without further justification. In other 27
circumstances, bracketing or matrixing is applicable only if further justification is provided. 28
Sample designs are provided in this guideline for illustrative purpos, and should not be 29
considered the only, or the most appropriate, designs in all cas.
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2GUIDELINES
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2.1General
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A full study design is one in which samples for every combination of all design factors are tested 39
at all time points. A reduced design, is one in which samples for every factor combination are not 40
all tested at all time points. A reduced design can be a suitable alternative to a full design when 41
multiple design factors are involved in the drug substance or product being evaluated. Any 42
reduced design should retain the ability to adequately detect differences in stability resulting 43
from any of the design factors. Before a reduced design is considered, certain assumptions 44
should be assd and justified. The potential risk should be considered of establishing a shorter 45
shelf life than could be derived from a full design due to the reduced amount of data collected. 46
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During the cour of a reduced design study, if it becomes apparent that the reduced testing is 48
no longer appropriate becau, for example, the product appears less stable than expected, a 49
modified design, that either reverts to full testing or to a less reduced testing design, can be 50
followed. Once the design is reverted, full testing or less reduced testing should be carried out 51
through the propod retest period or shelf life.
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2.2Applicability of Reduced Designs
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Reduced designs can be applied to the stability study of most types of drug products, when 56
appropriate. For the study of drug substances, matrixing is of limited utility and bracketing is 57
generally not applicable.
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Bracketing or matrixing can be applied with or without justification depending on the 60
circumstances as discusd in detail below. The degree of justification in each of the cas will 61
depend on the available supporting data on the product. Data variability and product stability, as 62
shown by supporting data, should be considered when a matrixing design is applied.
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Bracketing and matrixing are reduced designs bad on different principles. Therefore, the u of 65
bracketing and matrixing together in one design should be considered and scientifically justified. 66
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Reduced designs can be ud for formal stability studies if the principles outlined below are 68
改变字体followed.
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2.3Bracketing
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As defined in the glossary to the parent guideline, bracketing is the design of a stability schedule 73
such that only samples on the extremes of certain design factors, e.g., strength, package size, are 74
tested at all time points as in a full design. The design assumes that the stability of any 75护理工作制度
intermediate levels is reprented by the stability of the extremes tested. Where a range of 76
strengths is to be tested, bracketing is applicable if the strengths are identical or very cloly 77
related in composition (e.g., for a tablet range made with different compression weights of a 78
similar basic granulation, or a capsule range made by filling different plug fill weights of the 79
same basic composition into different size capsule shells). Bracketing can be applied to different 80
container sizes of or different fills in the same container closure system.
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The u of a bracketing design would not be appropriate if it cannot be demonstrated that the 83
strengths or container sizes and fills lected for testing are indeed the extremes.
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2.3.1Design Factors
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Design factors are variables (e.g. strength, container size, fill) to be evaluated in a stability design 88
for their effect on product stability.
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2.3.1.1Strength
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Bracketing can be applied without further justification to studies with strengths of identical or 93
cloly related formulations. Examples include capsules of different strength made with different 94
fill plug sizes from the same powder blend, tablets of different strengths manufactured by 95
compressing varying amounts of the same granulation, and formulations that differ only in minor 96
excipients, e.g., colorants, flavourings.
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Bracketing can be applied with justification where the relative amounts of drug substance and 99
excipients change in a formulation. For cas where different excipients are ud amongst 100
strengths, generally bracketing should not be applied.
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2.3.1.2Container Closure Sizes and Fills
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Bracketing can be applied without further justification to studies of the same container closure 105
system where either container size or fill varies while the other remains constant. However, if a 106
bracketing design is considered where both container size and fill vary, it should not be assumed 107
that the largest and smallest containers reprent the extremes of all packaging configurations. 108
Care should be taken to lect the extremes of packaging configurations by comparing the 109
various characteristics of the container closure system that may affect the product stability. 110
The characteristics include container wall thickness, closure geometry, surface area to volume 111
ratio, head space to volume ratio, water vapour permeation rate or oxygen permeation rate per 112
dosage unit or unit fill volume, as appropriate.
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Bracketing can be applied with justification in studies for the same container when the closures 115
vary. Justification could include a discussion of the relative permeation rates of the bracketed 116
container closure system.十一的英语
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2.3.2Design Considerations and Potential Risks
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If, after starting the studies, one of the extremes is no longer expected to be marketed, the study 121
design can be maintained to support the bracketed intermediates. A commitment should be 122
provided to carry out stability studies on the marketed extremes.
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Before a bracketing design is applied, its effect on retest period or shelf life estimation should be 125
assd. If the stability of the extremes is shown to be different, the intermediates should be 126
considered to be no more stable than the least stable extreme, i.e., the shelf life for the 127
intermediates should not exceed that for the least stable extreme.
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2.3.3Design Example
131132 A typical bracketing example is given in Table 1. This example is bad on a product available in 133three strengths and three container sizes. In this instance it should be demonstrated that the 15134ml and 500 ml HDPE container sizes bracket the 100 ml size. The batches for each lected 135combination should be tested at each time point as in a full design.
136137Table 1. Example of a Bracketing Design
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Strength 50mg 75mg 100mg Batch B1B2B3B4
西红柿丝瓜汤
B5
B6
B7B8B915 ml T T T T T T 100 ml Container size
500 ml
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T
梦游症状T
T
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140Key: B1-B9 indicate batches T = sample tested
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Matrixing
143144As defined in the glossary to the parent guideline, matrixing is the design of a stability schedule 145such that a lected subt of the total number of possible samples for all factor combinations is 146tested at a specified time point. At a subquent time point, another subt of samples for all 147factor combinations is tested. The design assumes that the stability of each subt of samples 148tested reprents the stability of all samples at a given time point. The differences in the samples 149for the same drug product should be identified as, for example, covering different batches,150different strengths, different sizes of the same container closure system, and, possibly in some 151cas, different container closure systems.
152153When a condary packaging system contributes to the stability of the drug product, matrixing 154can be performed across the packaging systems.
155156Each storage condition should be treated parately under its own matrixing design. Matrixing 157should not be performed across test attributes. However, alternative matrixing designs for 158different test attributes can be applied, if justified, with different testing frequencies.159160 2.
4.1
Design Factors
161162Matrix designs can be applied without further justification to strengths with identical or cloly 163related formulations. Examples include capsules of different strength made with different fill 164plug sizes from the same powder blend, tablets of different strengths manufactured by 165compressing varying amounts of the same granulation, and formulations that differ only in minor 166excipients, e.g., colorants or flavourings.
167168Other examples of design factors that can be matrixed without further justification include:169batches made using the same process and equipment; container size and fill in the same container 170closure system.
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