Braketing and matrixing designs for stability testing of new drug substances and products

1. PRESENTED BY: Mrunal More
M.Pharmacy (Pharmaceutics)
AISSMS College of Pharmacy
Pune-411001
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2.  INTRODUCTION
 APPLICABILITY OF THE REDUCED DESIGNS
 BRACKETING
 MATRIXING
 DATA EVALUATION
 SUMMARY
 REFERENCES
BONUS
CONTENTS
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3. 1.International Conference of Harmonisation of technical requirements for
registration of pharmaceuticals for human use.
2. ICH Topics are divided into four categories :
ICH
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4. 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
Q1 - STABILITY
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5.  1.1 Objectives of the Guideline
This guideline is intended to address recommendations on the application of
bracketing and matrixing to stability studies conducted in accordance with
principles outlined in the ICH Q1A(R) Harmonised Tripartite guideline on Stability
Testing of New Drug Substances and Products (hereafter referred to as the parent
guideline).
 1.2 Background
The parent guideline notes that 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
This document 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. Sample designs are provided for illustrative purposes,
and should not be considered the only, or the most appropriate, designs in all
cases.
INTRODUCTION
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6.  These are reduced designs in which all samples are not
tested at all time points.
 Alternatively used when multiple design factors are
involved.
 Certain assumptions should be made and justified.
 Potential risk should be considered before assuming the
shorter retest period and shelf life.
 A change from full to reduced test design should be
considered, if the justification is done and principles of both
the designs are followed.
 During the test study, once the design is changed from the
full to reduced it should be carried out through the
remaining study.
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7. 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.
Applicability of the Reduced designs
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8.  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
Bracketing
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9. 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) (pic)
 If different excipients are used among strengths,
bracketing should not be applied.
STRENGTH
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10. 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.
Container size or fills
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11.  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.
 Retest period and shelf life should be assessed before
applying this design.
 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.
Design consideration and Potential Risk
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12. DESIGN EXAMPLE
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Total = 27
Tested = 12

13.  It is the stability schedule in which selected samples
for all combinations are tested at a time point.
 At subsequent time point, another set of samples of all
combinations are tested.
 This design 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.
MATRIXING
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14. This design can be 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.
DESIGN FACTORS
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15. In this design, each sample should be tested at intended
time points and should be tested at last time point before
the submission.
Because 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.
Design ConsiderationS
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16. Table 2: Examples of Matrixing Designs on Time Points for a
product with two strengths One half reduction
Design example
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Total= 48
½= 24
Reduced =15

17. 17
Total = 48
1/3 = 16
Reduced = 10

18. The one half reduction in which one in two time points is
eliminated from testing.
The one third reduction in which 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).
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19.  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.
 If the variability in the supporting data is less and moderate
matrixing can be done.
 If the variability is high matrixing cannot be done.
contd…
Applicability and Degree of reduction
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20. The matrixing design can be justified with respect to its
power to detect differences among factors of degradation
and its precision in shelf life estimation.
 If the design is applicable, the degree of reduction depends
on the number of factors involved.
 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.
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21. Due to the insufficient data collected for the testing, the
matrixing design may get lesser shelf life than the shelf life
got from the full test design.
That matrixing 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.
Potential Risk
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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.
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23. 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 and
Matrixing design in which selected samples are tested.
Bracketing is mainly used to pursue a trend initially in pre
clinical studies and clinical trials. Matrixing is used to
confirm a prediction of the stability information.
The reduced designs should be used after the proper
justification and scientific consideration.
They may not get precise shelf life values as the full test
design.
CONCLUSION
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24. 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
REFERENCE
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25. THANK YOU
FOR YOUR
ATTENTION
ANY QUESTION?
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