BRACKETING AND MATRIXING DESIGNS (Q1D) - AISSMS College Of Pharmacy

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BRACKETING AND MATRIXING DESIGNS (Q1D)

• Dr. Mangesh Bhalekar
• Mrunal More (M.Pharm Pharmaceutics)

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CONTENTS

• INTRODUCTION
• APPLICABILITY OF THE REDUCED DESIGNS
• BRACKETING
• MATRIXING
• DATA EVALUATION
• SUMMARY
• REFERENCES

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ICH

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

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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

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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.

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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.

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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

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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.

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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.

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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.

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DESIGN EXAMPLE
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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.

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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.

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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.

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Design example

• Table 2 Examples of Matrixing Designs on Time
  Points for a product with two strengths One half
  reduction.

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

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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.
• Variability in the supporting data is less and
  moderate matrixing can be done.
• Variability high, matrixing cannot be done.
• 
  
  contd

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• 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.

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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.

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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
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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?vNp6ulndf78Q

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