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

1. Introduction Bracketing and Matrixing Designs

Bracketing: The stability of drug substances and products is essential for ensuring their quality, safety, and efficacy over time. Stability testing helps determine the shelf life, appropriate storage conditions, and expiration dates of pharmaceutical products. Bracketing and matrixing are two types of reduced study designs that allow for more efficient stability testing while still providing reliable results. These strategies, however, require a careful understanding and application to ensure that the stability data generated accurately reflects the product’s true performance over time.

This guideline is intended to provide recommendations for applying bracketing and matrixing to stability studies in line with the principles outlined in the ICH Q1A(R) guideline on stability testing of new drug substances and products. Although the parent guideline mentions the application of bracketing and matrixing, it does not offer detailed guidance, making this document a crucial tool for researchers and pharmaceutical professionals seeking to optimize their stability testing procedures.

1.1 Objectives of the Guideline

The primary objective of this guideline is to:

Define the concepts of bracketing and matrixing in the context of stability testing for new drug substances and products.
Provide specific recommendations and examples of how these designs can be implemented effectively and scientifically.
Offer guidance on how to assess and justify the applicability of these designs based on data variability, product stability, and other relevant factors.

This document aims to ensure that pharmaceutical manufacturers can employ bracketing and matrixing designs while ensuring the reliability and accuracy of their stability data.

1.2 Background

The ICH Q1A(R) guideline on stability testing provides the framework for stability studies of new drug substances and products. The guideline mentions that reduced study designs like bracketing and matrixing may be applicable, but it does not elaborate on how they should be applied. This has led to the need for more detailed instructions on when and how these strategies can be used without compromising the integrity of the stability testing process.

The use of bracketing and matrixing allows for a reduction in the number of samples tested and time points monitored, thus improving the efficiency of stability studies. However, these designs must be applied carefully, and their assumptions must be justified with solid scientific reasoning.

1.3 Scope of the Guideline

This guideline covers the application of bracketing and matrixing study designs for stability testing. The document provides:

An overview of when and how these designs can be used.
Specific examples to illustrate the application of these designs.
Guidance on how to justify the use of reduced designs based on the available data and product characteristics.

It is important to note that these sample designs are for illustrative purposes, and their application may vary depending on the specifics of the product being tested.

2. Guidelines: Bracketing and Matrixing Designs

2.1 General Overview

Stability studies can follow two main approaches: full designs and reduced designs. In a full design, samples are tested for every combination of all design factors (such as strength, container size, fill, and time point) across all time points. This provides a comprehensive view of how different factors impact stability, but it can be resource-intensive and time-consuming.

A reduced design, on the other hand, tests only a subset of these combinations. This can be an effective alternative when there are multiple factors involved, and it can still yield reliable data if the design is carefully selected. However, reduced designs carry some risk, as they may not capture all the variations in product stability. Before adopting a reduced design, it is critical to assess and justify its assumptions, particularly how it might affect the shelf life or retest period.

If the reduced design yields insufficient data, it may be necessary to switch to a full design for the remaining time points. Any adjustments to the design must be properly justified and accounted for in the statistical analysis.

2.2 Applicability of Reduced Designs

Reduced designs, such as bracketing and matrixing, can be applied to most drug product stability studies. However, for complex drug delivery systems—particularly those involving drug-device interactions—additional justification is required. For drug substances, matrixing may be useful in some cases, but bracketing is generally not applicable.

Whether bracketing or matrixing can be used will depend on the specific circumstances of the study. For example, the variability of the product, the number of factors involved, and the available supporting data will all influence whether a reduced design is appropriate.

2.3 Bracketing

Bracketing is a stability study design where only the extreme values of certain factors (such as strength, container size, or fill) are tested across all time points. The assumption is that the stability of intermediate values between these extremes can be inferred based on the stability of the extreme values.

The design factors for bracketing generally include:

Strength: For drug products available in multiple strengths, bracketing can be applied to test only the extreme strengths (e.g., the highest and lowest) and assume the stability of the intermediate strengths based on the extreme values.
Container Size and Fill: Bracketing can also be used to test only the largest and smallest container sizes or fill volumes. If there are multiple factors (e.g., container size and closure type), careful consideration must be given to ensure that the extremes selected truly represent the boundaries of the product’s stability.

2.3.1 Example of Bracketing Design

An example of a bracketing design is shown in Table 1, where a product is available in three strengths and three container sizes. In this design, only the extreme strengths and container sizes (15 ml and 500 ml) are tested at each time point.

Table 1: Example of a Bracketing Design

Strength	50 mg	75 mg	100 mg
Container Size	15 ml	100 ml	500 ml
Batch 1	T	T	T
Batch 2	T	T	T
Batch 3	T	T	T
Key: T = Sample tested

2.4 Matrixing

Matrixing is another reduced design where a subset of all possible factor combinations is tested at each time point. Over time, different subsets of combinations are tested at subsequent time points. The design assumes that the stability of the untested combinations can be inferred from the results of the tested combinations.

In matrixing, the design factors can include:

Strength: As with bracketing, matrixing can be applied to products with multiple strengths, especially if they have similar formulations.
Container Size: Matrixing can be applied to products with different container sizes or closures, with the assumption that certain combinations of factors (e.g., different strengths and container sizes) represent the overall stability.
Time Points: For matrixing, it is common to reduce the number of time points tested. This allows for a more efficient study design while still capturing enough data to make reliable stability predictions.

2.4.1 Example of Matrixing Design

An example of matrixing on time points is provided in Table 2, where a product is available in two strengths (S1 and S2). In this example, only a subset of batches is tested at each time point.

Table 2: Example of Matrixing Design on Time Points

“One-Half Reduction”

Time Point (Months)	0	3	6	9	12	18	24	36
Strength S1 Batch 1	T	T	T	T	T	T	T	T
Strength S2 Batch 1	T	T	T	T	T	T	T	T
Key: T = Sample tested

2.5 Data Evaluation

Stability data collected from a reduced design should be treated in the same way as data from a full design. This includes statistical analysis and interpretation to ensure that the product’s shelf life can be accurately estimated based on the available data.

Conclusion

Bracketing and matrixing are valuable tools for optimizing the efficiency of stability testing for new drug substances and products. While these designs reduce the number of samples and time points that need to be tested, they must be used carefully to ensure that the results remain scientifically valid and that the stability of the product is accurately represented. The appropriate use of these designs requires solid justification, supporting data, and a clear understanding of the potential risks involved. By following these guidelines, pharmaceutical manufacturers can achieve reliable stability data while minimizing testing resources.