What is Bracketing in Pharmacology? A Reduced Design for Efficient Drug Testing

October 5, 2025 •

3 min read

Saving time and resources during stability testing is a major objective for pharmaceutical companies. In this context, understanding what is bracketing in pharmacology is crucial for optimizing stability and validation studies by testing only the extremes of a product range.

Quick Summary

Bracketing is a pharmaceutical study design where only samples at the extreme ends of a variable, such as drug strength or container size, are tested to infer stability and performance across the entire range. This approach minimizes testing volume.

Key Points

Definition: Bracketing is a reduced study design used in pharmaceuticals to test only the extreme points of a product range, such as the highest and lowest strengths.
Core Assumption: The method relies on the assumption that the stability of intermediate product levels can be accurately represented by the stability of the tested extremes.
Primary Use: Its most frequent application is in stability testing to determine a drug product's shelf life, as outlined in ICH Q1D guidelines.
Application Factors: Bracketing can be used for variations in drug strength, container size, or fill volume, provided the formulation is identical or closely related.
Resource Efficiency: This testing approach significantly reduces the time, cost, and resources required for product development and quality assurance.
Scientific Justification: Successful implementation of a bracketing design requires strong scientific rationale and regulatory approval to ensure product quality is maintained.
Comparison to Matrixing: Unlike matrixing, which staggers testing over time points, bracketing tests all selected extreme samples at every time point.

The Core Concept of Bracketing

Bracketing is a scientifically justified, reduced study design primarily used in pharmaceutical stability testing and other validation studies. It involves testing only the highest and lowest extremes of a product range when a drug product is available in multiple variations, such as different strengths or container sizes. The underlying assumption is that the stability and characteristics of any intermediate level will fall within the performance of the two extremes. For example, if a drug is available in 50 mg, 100 mg, and 200 mg strengths, a bracketing study would typically test the 50 mg and 200 mg tablets, inferring the stability of the 100 mg strength.

Scientific justification is essential to demonstrate that intermediate levels will behave predictably. According to ICH Q1D guidelines, this design is most suitable for formulations that are identical or very closely related. An ideal candidate for bracketing would be a range of capsules made with the same powder blend but different shell sizes. Conversely, using different excipients for different strengths generally makes bracketing unsuitable.

Applications in Pharmaceutical Development

Bracketing has several key applications in the pharmaceutical industry:

Stability Testing: This is its most common use. Bracketing reduces the number of samples needed in formal stability studies where products are stored under specific conditions to determine shelf life. It can be applied to different strengths (e.g., 10 mg and 50 mg) or container sizes (e.g., 15 mL and 500 mL). The selected combinations are tested at all time points, similar to a full study but with fewer combinations overall.
Analytical Method Validation: Bracketing can validate only the lowest and highest concentrations when validating a method over a range, assuming intermediate concentrations are also validated.
Process Validation: For processes handling a range of batch sizes, bracketing allows validation of only the smallest and largest sizes, assuming intermediate sizes are covered.
Exposure-Bracketing: In clinical pharmacology, this specialized application uses known pharmacokinetics (PK) and pharmacodynamics (PD) of a drug to support the use of a new formulation. This can expedite development and reduce clinical trial size.

Bracketing vs. Matrixing: A Comparison

Bracketing and matrixing are both reduced stability study designs aimed at increasing efficiency, but they differ in principle.


Factor	Bracketing	Matrixing
Design Principle	Tests all samples at the extremes of factors like strength or container size for all time points.	Tests only a subset of all possible factor combinations at each specified time point.
Assumption	Assumes intermediate levels are represented by the extremes.	Assumes the stability of a subset represents all samples at a given time point.
Ideal for	Products with a limited number of factors and strong stability profiles.	Products with many variables (e.g., batches, strengths, container types) and strong stability profiles.
Resource Reduction	Reduces the total number of combinations to test, but each selected combination is tested frequently.	Reduces the total number of tests performed at each time point by staggering the testing schedule.
Complexity	Relatively simple to design and manage.	More complex, involving statistical design to ensure all combinations are covered over the study's duration.

Advantages and Limitations

Bracketing offers benefits but also has limitations.

Advantages:

Cost and Resource Savings: Reduces expenditure on materials, equipment, and personnel by testing fewer samples.
Faster Development: Can shorten development timelines and accelerate market entry.
Efficiency: Streamlines the stability testing process.

Limitations:

Not Universal: Not suitable for all products, especially those with non-linear degradation or complex drug-device interactions.
Risk-Based: Relies on the linearity assumption. If extremes show different stability, the shelf life of intermediates cannot exceed that of the least stable extreme.
Requires Justification: Needs scientific justification and regulatory approval; a full study may be required if justification is insufficient.

Regulatory Perspective and Requirements

Regulatory agencies like the FDA and EMA accept bracketing under specific conditions, guided by ICH Q1D. The guidelines emphasize that reduced designs must be scientifically justified and based on the product's stability profile to ensure quality and safety.

Conclusion

What is bracketing in pharmacology is a risk-based strategy balancing scientific rigor and efficiency. It allows pharmaceutical manufacturers to accelerate development and reduce costs by testing product range extremes. While beneficial for resource savings and faster timelines, successful implementation depends on a thorough understanding of product characteristics and robust scientific justification. Adhering to guidelines like ICH Q1D makes bracketing a valuable tool for bringing safe and effective medicines to market more efficiently without compromising quality.

For more detailed technical specifications, refer to the official ICH guidelines(https://database.ich.org/sites/default/files/Q1D%20Guideline.pdf).

Frequently Asked Questions

A company should consider using bracketing when a drug product comes in multiple strengths or container sizes with identical or very closely related formulations. It's particularly useful for products with strong stability profiles, allowing for significant resource reduction while maintaining reliable data.

The primary risk is that the stability of the intermediate levels may not fall predictably between the extremes. If the stability of the extremes proves to be different, the shelf life for all intermediates must be limited to that of the least stable extreme, which could be less than initially projected.

Standard bracketing focuses on stability and quality factors in manufacturing. Exposure-bracketing is a more specialized clinical pharmacology concept that extrapolates efficacy and safety data from existing knowledge of a drug's pharmacokinetics and pharmacodynamics to a new formulation.

The International Council for Harmonisation (ICH) Q1D guideline, specifically titled 'Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products,' provides the international regulatory framework for this practice.

While bracketing and matrixing are based on different principles, they can potentially be used together in a single study design. However, this requires careful consideration and additional scientific justification, as advised by regulatory guidelines.

Yes, bracketing should generally not be applied if different excipients are used among different product strengths, or if the drug product exhibits non-linear degradation or complex drug-device interactions that could compromise the linearity assumption.

A company must provide robust scientific justification demonstrating that the extremes chosen are truly representative and that the stability profiles of the different strengths or package sizes are identical or closely related.