BRACKETING AND MATRIXING DESIGNS (Q1D)


·         To reduce the total number of samples to be tested, the ICH guidelines introduced the concept of bracketing and matrixing.
·         BRACKETING
·         Definition: Bracketing is the design of a stability schedule such that only samples on the extremes (high level) of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design.
·         The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that,
o   the strengths or container sizes and/or fills selected for testing are actually the extremes
o   Bracketing can be applied to studies with multiple strengths where the relative amounts of drug substance and excipients change in a formulation.
·         An example of a bracketing design is given in following Table. 
o   This example is based on a product available in three strengths and three container sizes. 
o   In this example, it should be demonstrated that the 15 ml and 500 ml high-density polyethylene container sizes truly represent the extremes.
o   The batches for each selected combination should be tested at each time point as in a full design. Here, T = Sample tested
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



MATRIXING:
·         Definition: 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, and possibly, in some cases, different container closure systems.
·         Each storage condition should be treated separately under its own matrixing design.
·         Matrixing designs can be applied to strengths with identical or closely related formulations.
·         Examples include are (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).
·         Design Examples:
·         Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are in table.
·         The terms “one-half reduction” and “one-third reduction” refer to the reduction strategy initially applied to the full study design.
o   “One-half reduction” eliminates one in every two time points from full study design &
o   “One-third reduction” initially removes one in every three time points.
o   In the examples shown in Table, 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
o   These examples include full testing at the initial, final, and 12-month time points.
o   The ultimate reduction in testing is therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48, respectively.
·         Table 2:   Examples of Matrixing Designs on Time Points for a Product withTwo Strengths
·         “One-Half Reduction” Key: T = Sample tested
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
·         “One-Third Reduction” , Key: T = Sample tested
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


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