Stability testing is crucial for product development, but it can be expensive and time-consuming. Luckily, there are well-established and accepted procedures to reduce the number of stability samples required: bracketing and matrixing. These procedures can greatly decrease the amount of testing needed, reduce the cost of testing and management, and free up time and resources. By using these methods, you can optimize stability study design and ensure regulatory approval. Let's explore the power of bracketing and matrixing in this article, and see how they can be applied for maximum efficiency.
What is Bracketing?
- 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.
- 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.
1. Design Factors
a. Strength:
- Bracketing can be applied when studying multiple strengths of closely related formulations, such as different capsule strengths made with varying fill plug sizes, tablets with varying drug amounts from the same granulation, or oral solutions with minor excipient differences.
- Justification for bracketing can include demonstrating comparable stability profiles among different strength batches. However, bracketing is generally not recommended when different excipients are used among strengths.
b. Container Closure Sizes and/or Fills:
- Bracketing can be employed in studies involving the same container closure system, where either container size or fill volume varies while the other remains constant. When both container size and fill vary, careful selection of extreme conditions is necessary, considering factors like container wall thickness, closure geometry, and permeation rates.
- Justification for bracketing in cases where the closure varies should include a discussion of the relative permeation rates of different closure systems.
2. Design Considerations and Potential Risks
- If one of the extreme conditions is no longer expected to be marketed during the study, the design can still support the remaining bracketed intermediates. However, a commitment should be made to conduct stability studies on the marketed extremes post-approval.
- Before applying a bracketing design, its impact on retest periods or shelf life estimation should be assessed. If stability differences exist among extremes, the intermediates should not be considered more stable than the least stable extreme.
3. Design Example
- An example in Table 1 demonstrates a bracketing design for a product with three strengths and three container sizes. In this case, it is essential to establish that the 15 ml and 500 ml high-density polyethylene container sizes genuinely represent the extremes.
- Each combination should be rigorously tested at various time points, similar to a full design study.
Table 1: Example of a Bracketing Design
|
Strength |
50
mg |
75
mg |
100
mg |
|||||||
|
Batch |
1 |
2 |
3 |
1 |
2 |
3 |
1 |
2 |
3 |
|
|
Container
size |
15
ml |
T |
T |
T |
|
|
|
T |
T |
T |
|
100
ml |
|
|
|
|
|
|
|
|
|
|
|
500
ml |
T |
T |
T |
|
|
|
T |
T |
T |
|
T : Sample Tested
What is Matrixing?
- Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested.
- Matrixing is a strategy in stability testing where a specific subset of potential samples, encompassing various factors such as batches, strengths, container sizes, and closures, is tested at defined time intervals.
- It assumes that the stability of this tested subset accurately represents the stability of all samples at a given time point. Matrixing can also be extended to include different packaging systems. Each storage condition is managed independently within its own matrixing plan, and matrixing should not be applied across different test attributes unless justified.
1. Design Factors:
- Matrixing designs can be applied to similar formulations, including different strengths, batches, and container sizes.
- Justification for matrixing should be supported by data, such as moisture transmission rates or product stability.
2. Design Considerations:
- Matrixing designs should aim for balance in testing across different factors over the study duration.
- Full testing is recommended at specific time points, but achieving complete balance can be challenging when matrixing time points.
- Testing requirements include initial, final, and 12-month time points for selected combinations.
- Accelerated or intermediate storage conditions require testing at multiple time points.
3. Design Examples:
- Examples in the theory demonstrate matrixing designs for different strengths, showing reductions in testing time points.
- Reduction strategies like "one-half" or "one-third" refer to the initial elimination of specific time points.
- These examples include full testing at the initial, final, and 12-month time points, resulting in ultimate reductions in testing points.
ALSO READ: SOP for Stability/Shelf Life Determination
Table 2: Examples of Matrixing Designs on Time Points for a Product with Two Strengths
“One-Half Reduction”
|
Time
point (months) |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
||
|
Strength |
S1 |
Batch
1 |
T |
T |
|
T |
T |
|
T |
T |
|
Batch
2 |
T |
T |
|
T |
T |
T |
|
T |
||
|
Batch
3 |
T |
|
T |
|
T |
T |
|
T |
||
|
S2 |
Batch
1 |
T |
|
T |
|
T |
|
T |
T |
|
|
Batch
2 |
T |
T |
|
T |
T |
T |
|
T |
||
|
Batch
3 |
T |
|
T |
|
T |
|
T |
T |
||
T : Sample Tested
“One-Third Reduction”
|
Time
point (months) |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
||
|
Strength |
S1 |
Batch
1 |
T |
T |
|
T |
T |
|
T |
T |
|
Batch
2 |
T |
T |
T |
|
T |
T |
|
T |
||
|
Batch
3 |
T |
|
T |
T |
T |
T |
T |
T |
||
|
S2 |
Batch
1 |
T |
|
T |
T |
T |
T |
T |
T |
|
|
Batch
2 |
T |
T |
|
T |
T |
|
T |
T |
||
|
Batch
3 |
T |
T |
T |
|
T |
T |
|
T |
||
T : Sample Tested
- Tables 3a and 3b offer further insights into matrixing designs tailored for a product featuring three strengths and three container sizes. Table 3a showcases a design strategy that employs matrixing solely on time points, while Table 3b presents a more intricate approach integrating matrixing both on time points and factors.
- In Table 3a, an exhaustive examination includes all possible combinations of batch, strength, and container size. Conversely, Table 3b introduces selectivity by omitting certain combinations of batch, strength, and container size from testing, thereby optimizing the overall design.
Tables 3a and 3b: Examples of Matrixing Designs for a Product with Three Strengths and Three Container Sizes
"3a Matrixing on Time Points"
|
Strength |
S1 |
S2 |
S3 |
||||||
|
Container size |
A |
B |
C |
A |
B |
C |
A |
B |
C |
|
Batch 1 |
T1 |
T2 |
T3 |
T2 |
T3 |
T1 |
T3 |
T1 |
T2 |
|
Batch 2 |
T2 |
T3 |
T1 |
T3 |
T1 |
T2 |
T1 |
T2 |
T3 |
|
Batch 3 |
T3 |
T1 |
T2 |
T1 |
T2 |
T3 |
T2 |
T3 |
T1 |
"3b Matrixing on Time Points and Factors"
|
Strength |
S1 |
S2 |
S3 |
||||||
|
Container size |
A |
B |
C |
A |
B |
C |
A |
B |
C |
|
Batch
1 |
T1 |
T2 |
|
T2 |
|
T1 |
|
T1 |
T2 |
|
Batch
2 |
|
T3 |
T1 |
T3 |
T1 |
|
T1 |
|
T3 |
|
Batch
3 |
T3 |
|
T2 |
|
T2 |
T3 |
T2 |
T3 |
|
T = Sample tested
S1, S2, and S3 are different strengths.
A, B, and C are different container sizes.
Key:
|
Time-point
(months) |
0 |
3 |
6 |
9 |
12 |
18 |
24 |
36 |
|
T1 |
T |
|
T |
T |
T |
T |
T |
T |
|
T2 |
T |
T |
|
T |
T |
|
T |
T |
|
T3 |
T |
T |
T |
|
T |
T |
|
T |
Applicability of Reduced Designs
- Reduced designs can be applied to almost every type of drug product in the formal stability study. This includes a planning process that balances design to the intended study period. Reduced designs such as bracketing and matrixing offer great benefits but require additional justification for complex drug delivery systems, particularly for products providing several potential drug-device interactions.
- The applicability of these methods will depend on the available supporting data. Therefore, the type and level of justification, in each case, differ based on available data variability and product stability.
Benefits of Bracketing and Matrixing
- Bracketing and matrixing procedures play a crucial role in streamlining drug stability testing, significantly cutting costs and saving time in product development. These methods reduce the required testing, leading to smaller sample production, streamlined management, and substantial time and cost savings, making them a preferred choice among developers.
- Additionally, regulatory authorities widely accept these procedures, aligning with ICH guidelines, making them a trusted tool for optimizing stability studies across the industry. Whether you're passionate about regulations or tired of paperwork, bracketing and matrixing offer relief.
- In summary, their cost-effectiveness, ease of application, regulatory acceptance, and workload reduction make them indispensable in stability protocol design, ensuring you don't have to rush data collection anymore.
Conclusion
Bracketing and matrixing are powerful tools for optimizing stability protocols in product development. When applied correctly, they can significantly reduce costs and time spent on stability studies without compromising on data quality or regulatory compliance. With their ease of application and widespread acceptance by regulatory authorities, there's simply no reason not to use these procedures in the pharmaceutical industry. So go ahead, give them a try and experience the benefits for yourself!
ALSO READ: SOP for Stability Study of Products
Tags
Quality Control
