Bracketing and Matrixing Methods for Stability analysis

About the methods of bracketing and matrixing ICH Q1D guideline

1. 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

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

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

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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 11

12. 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. 12

13. 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

14. 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. 14

15. Design Example Time points (months) 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

16. Time points (months) 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

17. 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). 17

18. 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 … 18

19. 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

20. 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. 20

21. 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. 21

22. 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. 22

23. 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 23

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