Bracketing and its application to quality testing
Bracketing is a testing design approach recognized by USP, FDA, and ICH for assessing the quality of pharmaceutical products. It involves testing certain quality attributes at the lowest and highest extremes and assumes that intermediate levels are represented by the extreme test values. This design strategy reduces the samples needed for testing while ensuring product integrity.
Bracketing can be applied to compounded drug products with multiple strengths of identical or closely related formulations. Bracketing can also be applied to formulations of the same container closure system, where either container size or fill varies while the other remains constant. If both container size and fill vary, it's critical not to assume that the largest and smallest containers represent the extremes of all packaging configurations. Compounders must carefully select the extremes by comparing container closure system characteristics that may affect product stability.
Examples where bracketing may be applied to drug products with one variable change:
Bracketing should not be applied in cases where:
- Different excipients are used among strengths
- Strengths, container sizes, and/or fills selected for testing are not the extremes
Bracketing in a Stability Study Design
Bracketing is a risk-based approach and requires scientific justification before implementation. Considerations include, but are not limited to:
- Product Characteristics
- Regulatory Requirements
- Test Parameters
- Data Analysis
ICH Harmonized Guideline for Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products, Table 1 provides an example of a product available in three strengths and container sizes. The 15 mL and 500 mL container sizes represent the extremes, and batches for each selected combination should be tested at each time point, similar to a full design.
If a product has different storage conditions, each storage condition should be treated separately under its design.
Compounders must thoroughly evaluate the bracketing stability data before applying a beyond-use date. This assessment should consider the stability of the extremes. If they differ, it is important to consider the intermediates no more stable than the least stable extreme.
To request a bracketing stability study design, request a quote.
Additional Bracketing Applications
Bracketing may also be applied to tests and method validations with scientific justification.
Antimicrobial Effectiveness Testing:
Both 795 and 797 state antimicrobial effectiveness testing must be conducted and passed once for each formulation in accordance with USP 51 for the particular container closure system in which it will be packaged. A bracketing design may be used to test a low concentration and a high concentration of the active ingredient in the formulation to establish preservative effectiveness across various strengths of the same formulation. The concentration of all other ingredients (including preservatives) must be the same throughout the bracketing study.
ARL requires method suitability for each formulation tested.
Endotoxin Method Validation:
Method validation is recommended to ensure there is no inhibition or enhancement of endotoxins. When multiple concentrations of the sample product family are received, a bracketing design may be performed during validation. ARL will test the highest and lowest extreme concentrations. If an appropriate method for both formulations can be identified where the test method is the same, intermediate products can be referenced using the same test method.
For more information on bracketing, contact ARL at 800-393-1595 or info@arlok.com.