Bracketing and Matrixing Methods for Stability analysis

BRACKETING AND MATRIXING DESIGNS
FOR STABILITY TESTING OF NEW DRUG
SUBSTANCES AND PRODUCTS
(Q1D)
Presented By
T V Sarath Chandra
M Pharm I Year SEM I
Regd. No. 170609008
1
Guided by
Dr. Swapnil J D
Assistant Professor
DEPARTMENT OF PHARMACEUTICAL QUALITY ASSURANCE
MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES
MANIPAL UNIVERSITY

CONTENTS
 INTRODUCTION
 APPLICABILITY OF THE REDUCED DESIGNS
 BRACKETING
 MATRIXING
 DATA EVALUATION
 SUMMARY
 REFERENCES
2

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

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

Introduction
 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.
5

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.
 For drug substances, bracketing is not applicable and matrixing is of limited use.
 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.
6

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
7

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.
8

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.
9

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.
 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 lives of the intermediates will be less than the shelf life of the least
stable extreme.
10

Design Example
Table 1
Strength 50mg 75mg 100mg
Batch 1 2 3 1 2 3 1 2 3
Container
size
15ml T T T T T T
100ml
500ml T T T T T T
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Matrixing
 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.
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Design factors
 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.
13

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.
 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.
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Design Example
Time points (months) 0 3 6 9 12 18 24 36
S
T
R
E
N
G
T
H
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
15
Table 2: Examples of Matrixing Designs on Time Points for a product with two strengths
One half reduction

Time points (months) 0 3 6 9 12 18 24 36
S
T
R
E
N
G
T
H
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
16
One third reduction

 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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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.
 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…
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 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.
19

Potential Risk
 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.
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 The design which have reduction in time points only have the ability of
establishing of shelf life as in full test design.
 It exists because the full testing of all the samples is done at initial and
final time point before the submission.
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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CONCLUSION
 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.
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Reference
 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
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