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吴京谢楠结婚新原料药和制剂稳定性试验的括号设计法和矩阵设计法 【双语阅读】Q1D-新药研发分析

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新原料药和制剂稳定性试验的括号设计法和矩阵设计法 【双语阅读】Q1D-新药研发分析
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“职场老司机,都喜欢钻研各种指导原则,不论国内的,还是国外的,只要能指导实际的,都是好原则郑子豪 。”
爱搞事情的老王,今天要来钻研Q1D 新原料药和制剂稳定性试验的括号设计法和矩阵设计法

Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
01

INTRODUCTION
1.1Objectives 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 of New Drug Substances and Products (hereafter referred to as the parent guideline).
1.1本指导原则的目的
本指导原则的目的是:在按照ICH Q1A(R)新原料药和制剂稳定性试验三方协调指导原则(下文”)进行稳定性研究时,如何应用括号设计法(括号法)及矩阵设计法(矩阵法)钟海源 。
1.2Background
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.
Q1A指出了矩阵法和括号法在经过验证的情况下可以应用于新原料药及制剂的稳定性试验,但并未提供进一步的指南。
1.3Scope 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.
本指导原则涉及的范围
本文件阐述了括号法与矩阵法研究设计的指导原则。在可以应用括号法和矩阵法时,本指导原则给出了专门的规则。指导原则中提到的设计样例仅仅是用来举例说明,不应当认为是唯一或最佳的设计。
02

GUIDELINES
2.1General
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.
2.1总则
一项完整的设计方案就是在所有时间点对样品的全部设计因子的每个组合都进行试验。简化的设计方案则是在所有的时间点并非对每个因子组合的样品都进行试验。当涉及到多种因子时,简化的设计方案可替代完整设计方案。任何一种简化设计方案必须具备足够的预测重检期或有效期的能力。在考虑一种简化设计方案以前,需要评估和验证相关的假设。还需要考虑由于数据收集量的减少而得出与完整设计方案比较相对短的重检期或有效期的潜在风险。
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.
在进行简化设计研究期间,如果有合理的依据,并且试验仍符合完整设计和简化设计的原则薛中行 ,可将简化方案改为完整的试验方案,或者改为简化程度少的设计方案。然而,如果因为设计的改变而造成样本量的增加,则应对统计分析作合理的调整。一旦改变了设计方案,在稳定性研究的剩余时间点,就应该采用改变后的完整试验方案或简化程度少的方案进行试验。
2.2Applicability 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.
2.2 简化设计的适用性
简化设计可应用于绝大多数药物制剂的正式稳定性研究。对于某些复杂的给药系统,因为有很多潜在的药物与装置的相互作用,则应提供进一步的合理性验证后才可应用。对原料药而言,矩阵法的应用有一定的限制,而括号法则通常不适用。
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贺顺顺 , 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冫冖, as shown by supporting data,董翠婷 should be considered when a matrixing design is applied.
在什么情况下可以使用括号法与矩阵法,取决于下文所述的条件。任何简化设计方案都需要验证。某些情况下,本指导原则中描述的条件已经为应用提供了足够的验证。但有些情况下,则应提供进一步的验证。进行验证的类型和程度,取决于可得到的支持性数据。应用矩阵法时,应当考虑由支持性数据所显示的的数据波动性和产品的稳定性。
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.
括号法与矩阵法是基于不同原理的简化设计法。因此,若在一个设计方案中同时使用括号法与矩阵法,需谨慎考虑并进行科学验证。
2.3Bracketing
As defined in the glossary to the parent guideline, bracketing is the design of a 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.
2.3 括号法
如同Q1A(R)中术语所定义的,括号法是一种稳定性试验的设计方案,它仅对某些设计因子(如规格、包装容器大小和/或装量)处在极端状态的样品,与完整设计方案一样,在所有时间点进行试验。这种方案假设:任何中间状态样品的稳定性可以用被试验的极端状态样品的稳定性所代表。
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.
如果无法确证被选择受试的规格、容器尺寸和/或装量确实是处在极端状态,那么使用括号法是不适当的。
2.3.1Design Factors
Design factors are variables (e.g., strength强项令董宣, container size and/or fill) to be evaluated in a study design for their effect on product stability.
2.3.1 设计因子
设计因子是需要在稳定性研究中评估其对产品稳定性影响的变量(如规格、容器大小和/或装量)。
2.3.1.1Strength
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).
2.3.1.1 规格
括号法可用于处方相同或相近的多个规格样品稳定性研究中。例子包括但不限于(1)由相同粉末混合物、不同填充量制成的不同规格的胶囊;(2)由不等量的同种颗粒压制成的不同规格的片剂;和(3)处方仅在某些微量辅料(如着色剂、矫味剂)上有差别的不同规格的口服溶液剂。
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.
In cases where different excipients are used among strengths暴力和亲指南, bracketing generally should not be applied.
经过验证,可将括号法应用于处方中原辅料比例不同的多个规格的研究中。这样的验证可以包括在临床试验或产品研发中所用批次的产品不同规格间稳定性情况的比较结果。
如果各规格之间使用了不同的辅料,就不能应用括号法。
2.3.1.2Container 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.
容器大小和/或装量可将括号法应用于容器大小或者装量不同而其他保持不变的同种包装容器系列的研究。但是,如果在容器大小和装量均发生变化的情况下考虑使用括号法,就不能假设最大和最小的容器代表了所有包装形态的极端状态。应通过比较包装容器系统中可能影响产品稳定性的各种特性来仔细选择包装形态的极端状态。这些特性包括容器壁厚度、闭塞物的几何形状,表面积与体积之比,上部空间与总体积之比,每个剂量单位或单位装量体积的水蒸气透过率或氧气透过率等。
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.
经过验证,括号法可以用于同种容器、不同闭塞物的研究。验证内容可以包括该系列容器密闭系统的相对通透率的讨论。
2.3.2Design 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.
2.3.2设计上的考虑和潜在风险
在研究工作开始以后,如果其中一种极端状态样品不再打算用于上市销售,那么该研究方案可以维持下去用以支持中间状态样品。还应承诺获得批准后,继续对已上市的极端状态样品进行稳定性研究。
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).
在应用括号设计法前,应评估它对判断重检期或有效期的影响。如果极端状态样品的稳定性不同,就不能认为中间样品比最不稳定的极端样品更稳定(即,中间样品的有效期不应超过最不稳定的极端样品的有效期)。
2.3.3Design 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 container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design.
2.3.3设计示例在表1中给出了一个括号法的设计示例。该实例为某种有三个规格和三种容器大小的制剂。在本例中,应证明15mL和500mL 高密度聚乙烯(HDPE)容器确实代表了极端状态。对于每一选定组合的批次,应如同在完整设计中一样,在每个时间点都进行试验。
Table 1: Example of a Bracketing Design

2.4Matrixing
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水浒仙途, and possibly, in some cases, different container closure systems.
2.4矩阵设计法
如同Q1A(R)中词汇表定义的一样,矩阵法是一种稳定性试验的设计方案,它在指定的某些时间点对所有具有全部因子组合的总样品中的一个选定子集进行试验。在后续的时间点,对另一个具有全部因子组合的样品子集进行试验。该设计方案假设受试的每个样品子集的稳定性代表着所给时间点上所有样品的稳定性。对于同一种制剂,受试样品间的各种差异应一一确定,如:批次不同,规格不同,包装容器相同但大小不同,在某些情况下,可能包装容器也不同。
When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems.
当一种次级包装系统影响到制剂的稳定性时,可以将该包装系统归入矩阵。
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.
每个贮存条件都应该在它自身的矩阵设计中分别设置。不能对试验项目进行矩阵设计吴京谢楠结婚 。但是,经过验证后,对于不同试验项目,可选用另外的矩阵设计方案。
2.4.1Design 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).
2.4.1设计因子
可将矩阵设计法应用到具有相同或相似处方的不同规格。例子包括但不限于:(1)由相同的粉末混合物用不同的填充量制成的不同规格的胶囊;(2)由不等量的同种颗粒压制成的不同规格的片剂;以及(3)处方中仅在某些微量辅料(如着色剂或矫味剂)上有差别的口服溶液剂。
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.
可以应用矩阵设计的其他例子有:使用相同的工艺和设备制成的、采用相同包装的不同批次产品。
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.
经过验证,可以把矩阵设计运用到原辅料比例不同的、使用不同辅料的、或使用不同包装的不同规格制剂。
Justification should generally be based on supporting data. For example, to matrix across two different closures or container closure systems, supporting data could be 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.
验证通常应有相关数据的支持。例如,针对两种不同的闭塞物或包装容器应用矩阵法时,就应提供它们相对的水气透过率或具有相似的避光保护措施的数据恶龙传说。或者,可以提供制剂不受氧气,湿度和光照影响的相关数据。
2.4.2Design 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.
2.4.2设计上需考虑的因素
矩阵方案的设计应尽可能均衡,以使每个因子组合在整个拟定的研究期间和在申报前最后一个时间点能被试验到同等的程度。然而,如下所述,推荐的完全试验是在那些固定的时间点进行的,所以在对时间点进行矩阵的设计方案中,要达到完全的均衡可能是困难的。
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.
在对时间点进行矩阵设计的方案中,应该在起始和结束的时间点对所有选定的因子组合进行测定,而在每个中间时间点仅仅对某些指定组合进行试验。如果在申报时无法提供用来确定有效期的完整的长期试验数据,则关于批次、规格、容器大小和装量以及其他因子的所有选定组合,应该在第12个月或在申报前的最后一个时间点均进行试验。而且,对于每个选定的组合,应申报在研究的前12个月中至少3个时间点(包括起始时间点)的数据。在加速试验条件或中间储存条件下进行矩阵设计时,对于每个选定的因子组合,应注意确保进行最少三个时间点的试验,包括最初和最终时间点。
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.
当已进行关于设计因子的矩阵时,如果某个规格或容器尺寸和/或装量不再打算用于上市销售,对该规格或容器尺寸和/或装量的稳定性试验可继续下去,以支持设计方案中的其他规格或容器尺寸和/或装量。
2.4.3Design 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 2.4.2. 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.
2.4.3 设计实例
表2为某种两个规格(S1和S2)制剂的针对时间点的矩阵设计示例。术语“1/2简化”和“1/3简化”,是指对完整研究设计进行的简化策略。比如,1/2简化是在完整研究设计的每两个时间点中去掉一个,而1/3简化则是在每三个时间点去掉一个秦素妍 。在表2的示例中,其简化程度少于1/2或1/3。这是因为如同2.4.2节所述,所有因子组合在某些时间点要进行完全试验。这些示例包括在起始、结束和第12个月时间点的完全试验。所以最终的简化要比1/2(24/48)或1/3(16/48)少,实际上分别是15/48和10/48。
Table 2: Examples of Matrixing Designs on Time Points for a Product withTwo Strengths


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.
表3a、3b给出了另一个有3种规格、3种容器尺寸的某种制剂的矩阵设计示例。表3a是一种仅对时间点进行矩阵的设计,而表3b则是对时间点和因子均进行矩阵的设计方案。在表3a中,批次、规格以及容器尺寸的所有组合都被试验;而在表3b中,某些组合不被试验。Tables 3a and 3b:Examples of Matrixing Designs for a Product with ThreeStrengths and Three Container Sizes
3a Matrixing on Time Points

3b Matrixing on Time Points and Factors


S1, S2, and S3 are different strengths. A, B, and C are different container sizes.
T = Sample tested
2.4.4Applicability and Degree of Reduction
The following, although not an exhaustive list, should be considered when a matrixing design is contemplated:
·knowledge of data variability
·expected stability of the product
·availability of supporting data
·stability differences in the product within a factor or among factors
and/or
·number of factor combinations in the study
2.4.4 简化的适用性和程度
设计一个矩阵方案时,应考虑如下因素,虽然它们还不够全面:
(1)了解数据的变异性;
(2)产品预期的稳定性;
(3)支持性数据的有效性;
(4)在一个因子之内或多个因子之间产品稳定性的差异,和/或
(5)研究中因子组合的数量。
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.
一般来说,如果支持性数据指示了产品有可以预见的稳定性,则可采用矩阵设计。如果支持性数据变异性很小,则说明运用矩阵是适当的。但是,如果支持性数据显示了中等的波动性,就应该通过统计分析验证矩阵设计的合理性。如果支持性数据显示了很大的波动性,就不能采用矩阵设计方案。
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.
所谓统计方法验证,即对该矩阵设计检测因子间降解速率差异的能力或其估计有效期的准确程度进行评估。
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 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.
如果一个矩阵设计被认为是可采用的,那么其简化程度可根据被评估的因子组合的数量来决定。与产品相关的因子越多,每个因子的层次越多,可以考虑简化的程度就越大。然而,任何简化的设计都应有足够的预测产品有效期的能力。
2.4.5Potential 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.
2.4.5 矩阵设计的潜在风险
一个仅对因子而非对时间点的矩阵设计,与相应的完整设计方案相比,由于数据收集量的减少,通常在估测有效期的准确性上要差一些,得出的有效期要短一些。而且,这样的矩阵设计方案也许没有足够的能力检测出某些主要因子或因子间相互作用的影响,因此在评估有效期时,会导致将不同设计因子得来的数据进行不正确的合并。如果在因子组合的试验数量上简化过度,这些实验数据就不能合并以建立一个有代表性的有效期,也就不可能估测那些缺失的因子组合的有效期。
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.
一个仅对时间点进行的矩阵研究设计,在检测各因子之间变化率的差异和建立一个可靠的有效期方面,常常与完整设计方案有相似的能力米雪冥婚 。这是因为假设这些变化存在线性关系,而且还因为所有因子组合在起始时间点和申报前的最后时间点都仍然进行完全试验。
2.5Data Evaluation
Stability data from studies in a reduced design should be treated in the same manner as data from full design studies.
2.5 数据评估简化设计研究获得的稳定性数据的处理和评估方式与完整试验设计相同。
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