Read an interesting information about Bracketing and Matrixing designs for stability testing of new drug substances and products by AISSMS College Of Pharmacy.

1. BRACKETING AND MATRIXING
DESIGNS (Q1D)
Dr. Mangesh Bhalekar
Mrunal More (M.Pharm Pharmaceutics)

2. CONTENTS:
● INTRODUCTION
● APPLICABILITY OF THE REDUCED DESIGNS
● BRACKETING
● MATRIXING
● DATA EVALUATION
● SUMMARY
● REFERENCES

3. ICH
1.International Conference of Harmonisation of technical requirements for
registration of pharmaceuticals for human use.
2. ICH Topics are divided into four categories :

4. Q1 - STABILITY
1. Q1A(R2)-Stability testing for new drug substances and products.
2. Q1B - Stability testing: Photo-stability testing of new drug
substances and products.
3. Q1C - Stability testing for new dosage forms.
4. Q1D - Bracketing and Matrixing designs for stability testing of
new drug substances and products.
5. Q1E - Evaluation of stability data.
6. Q1F- Stability data package for Registration applications in
Climatic zones III and IV

5. INTRODUCTION
1.1 Objectives of the Guideline
To address recommendations on the application of bracketing and matrixing to stability
studies performed under the principles outlined in the ICH Q1A(R) Harmonised
Tripartite guideline on Stability Testing of New Drug Substances and Products.
1.2 Background
The use of matrixing and bracketing can be applied,if justified,to the testing of new
drug substances and products, but provides no further guidance on the subject.
1.3 Scope of the Guideline
Provides guidance on bracketing and matrixing study designs. Specific principles are
defined in this guideline for situations in which bracketing or matrixing can be applied.
For illustrative purposes some sample designs are provided, and which should not be
considered the only, or the most appropriate, designs in all cases.

6. Alternatively used when multiple design factors are involved.
Certain assumptions should be made and justified.
A change from full to reduced test design should be considered, if the
justification is done and principles of both the designs are followed. And
once changed it should be kept same henceforth throughout the
studies.
Potential risk should be considered before assuming the shorter retest
period and shelf life.
These are reduced designs in which all samples are not tested at all time
points.

7. Applicability of the Reduced designs
➔ It can be applied for drug products,but additional justification
should be done for some complex substances which have
potential drug-device reaction.
➔ Whether bracketing or matrixing should be done, decided as per
the conditions.
➔ Data variability and product stability shown by the supporting
data should be considered for the application of matrixing
design.
➔ Careful consideration and scientific justification should be there
in selection of designs.

8. Bracketing
In this the samples in the extremes of design factors are only tested at all time
points.
It assumes that the stability of the intermediates is represented by the stability
of the extremes tested.
The use of this design is inappropriate if the selected samples are not the
extremes.
Design factors: These are variables which should be evaluated for their effect
on stability. They are:
1. Strength
2. Container size or fill

9. STRENGTH
➔ Applied for multiple strengths and closely related formulations.
➔ Examples:
a) Capsules - different fill plug sizes and strengths, made up of same
powder blend.
b) Tablets - different strengths manufactured with compressing
varying amounts of same granulation.
c) Oral solutions - different strengths which may differ in minor
excipients (colorants, flavourings)
➔ If different excipients are used among strengths, bracketing should not be
applied.

10. Container size or fills
➔ Either fill size or container size should be vary and other should be
constant.
➔ If both are varying, the smallest and largest are not considered as the
extremes of the packaging operations.
➔ In selecting the extremes, compare the characters carefully because it
may effect the stability of the product.
➔ The characters include container wall thickness, surface to volume
ratio, oxygen permeation rate per dosage unit, closure geometry.
➔ It is applied for the same container having different closures with
justification.

11. Design consideration and Potential Risk
➔ During the study, if one of the extreme is known to be no longer in the
market, then design is made for supporting the intermediates.
➔ If the stabilities of both the extremes are different, then the stability
of the intermediate will be considered as not more than the least
stable extreme.
➔ The shelf life of the intermediates will be less than the shelf life of the
least stable extreme.
➔ Retest period and shelf life should be assessed before applying this
design.

12. DESIGN EXAMPLE

13. MATRIXING
➔ It is the stability schedule in which selected samples for all combinations
are tested at a time point.
➔ Another set of samples of all combinations are tested at subsequent time
point.
➔ Assumes that the stability of each set of samples represents the stability
of the remaining samples at a given point.
➔ The differences in the same drug sample are different strengths, different
batches, different sizes of the same container closure system.
➔ When secondary packaging system contributes to the stability of the
system, then packaging materials should be tested.

14. DESIGN FACTORS
➔ Applied for different strengths of identical or closely related substances. Examples
are
a) Capsules - different fill plug sizes and strengths, made up of same powder
blend.
b) Tablets - different strengths and compressed with varying amounts of
same granulation.
c) Oral solutions - different strengths which may differ in minor excipients.
d) Different batches made by same process and same equipment.
➔ Justification should be done based on supporting data.

15. Design Considerations
➔ In this design, each sample should be tested at intended time
points and should be tested at last time point before the
submission.
➔ Reason: It is difficult to test at all time points as in full test,
some time points are matrixed.
➔ It should be tested for first and last time points for selected
factors, but for some factors intermediate time points should
also be tested.
➔ For accelerated or intermediate storage condition testing -
Atleast three points should be tested.

16. Design example
Table 2: Examples of Matrixing Designs on Time Points for a product with two strengths
One half reduction.

17. Table 3: Examples of Matrixing Designs on Time Points for a product with two strengths One
third reduction.

18. ➔ One half reduction - one in two time points is eliminated from testing.
➔ One third reduction - one in three time points is eliminated from
testing.
➔ These examples include the full testing for the initial, final and 12
month time period points.
➔ In one half reduction, the time points are reduced less than the one half
(24/48) that is actually (15/48).
➔ In one third reduction, the time points are reduced less than the one
third (16/48) that is actually (10/48).

19. Applicability and Degree of reduction
➔ The following should be followed when matrixing is applied:
• knowledge of data variability
• availability of supporting data
• stability differences in the product within a factor or among factors
• number of factor combinations in the study
➔ In general matrixing is done when the appropriate supporting data
indicate appropriate product stability.
➔ Variability in the supporting data is less and moderate matrixing can be
done.
➔ Variability high, matrixing cannot be done.
contd…

20. ➔ The degree of reduction depends on the number of
factors involved when the design is applicable.
➔ The more the factors involved, the more the degree of
the reduction.
➔ Any design should have the ability to calculate the
shelf life of a product appropriately.
➔ The design can be justified with respect to its power to
detect differences among factors of degradation and
its precision in shelf life estimation.

21. Potential Risk
➢ Due to the insufficient data collected for the testing, the matrixing
design may show lesser shelf life than the shelf life we got from
the full test design.
➢ This design has lesser efficiency to detect certain interaction
effects leading to incorrect pooling of data.
➢ If testing of factor combinations is reduced, the tested factor
combinations cannot give sufficient data for finding the shelf life.

22. Data Evaluation
➔ The data collected from the reduced design should be treated in
the same manner as collected from the full test design by using
statistical applications.

23. CONCLUSION
may not get precise values
05 Shelf life values as the full test design.
reduced designs -
04
● Should be used after the proper justification
and scientific consideration.
Matrixing is used to confirm a prediction of the
stability information.
Bracketing is mainly used to
pursue a trend initially in pre
clinical studies and clinical
trials.
03
lesser time -
01
The reduced test designs are used for the
testing the stability in lesser time than the full
test design by considering some risks.
Bracketing design in which
extremes are tested
02
And Matrixing design in which selected
samples are tested.

24. REFERENCES
• BRACKETING AND MATRIXING DESIGNS FOR STABILITY
TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1D :
ICH Harmonised Tripartite Guideline, current step 4 version,
7 February 2002, page no: 1-7.
• https://www.youtube.com/watch?v=Np6ulndf78Q

25. Thank You…!
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