BRACKETING AND MATRIXING DESIGNS (Q1D) - 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 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. 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. And once changed it should be kept same henceforth throughout the studies.

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

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

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