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BRACKETING AND MATRIXING STABILITY STUDIES

BRACKETING AND MATRIXING STABILITY STUDIES. Dr Ray Munden GlaxoSmithKline Research and Development. 50mg. 10mg. 100mg. WHAT ARE MATRIXING AND BRACKETING?. Bracketing Complete removal of some batches from testing. ICH DEFINITION. Bracketing

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BRACKETING AND MATRIXING STABILITY STUDIES

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  1. BRACKETING AND MATRIXING STABILITY STUDIES Dr Ray Munden GlaxoSmithKline Research and Development

  2. 50mg 10mg 100mg WHAT ARE MATRIXING AND BRACKETING? Bracketing Complete removal of some batches from testing

  3. ICH DEFINITION Bracketing The design of a stability schedule so that at any time point only the sample on the extremes, for example strength, package size, are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels samples are represented by those at the extremes.

  4. 10mg 100mg WHAT ARE MATRIXING AND BRACKETING? Matrixing Removal of some testing from all batches 50mg

  5. ICH DEFINITION Matrixing The design of a stability schedule such that only a selected subset of the total number of possible samples for all factor combinations is tested at any specified sampling point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

  6. 10mg 100mg 50mg WHAT ARE MATRIXING AND BRACKETING? Can Matrix and Bracket

  7. OBJECTIVE OF MATRIXING AND BRACKETING The quest to reduce the resource required - without compromising the quality of the data.

  8. WHAT AFFECTS STABILITY? • Storage Time • Storage Condition (Temperature and %RH) • Dosage Form • Strength • Container • Closure • Overwrapping

  9. RATIONALE FOR BRACKETING • Interpolation between extremes is logical • No need for stability to be the same • Useful where large number of presentations • Probably fairly well accepted • Resource saving

  10. RATIONALE FOR MATRIXING • Can revert to full testing. • Full testing at accelerated conditions. • Long term trends are approximately linear. • Most useful for definitive stability. • Can design so that the effect of each factor • can be determined • May have some idea about comparative • stability. • Resource saving.

  11. Strength 123 Pack AD1 D2 D3 Pack B D2 D3 D1 Pack C D3 D1 D2 MATRIXING Already much historical use eg. 3 strengths 3 packs 3 batches of drug substance Full testing = 3 x 3 x 3 = 27 batches Would probably have applied the following matrix (not in the ICH definition, but still a matrix) Only 9 batches on test

  12. MATRIXING Matrixing can use experimental designs (eg. fractional factorial designs) which are accepted practice. x x x x x x x x x x x x x x x x x x x

  13. Month: 0 3 6 9 12 18 24 36 Batch 1 X X Batch 2 X X Batch 3 X X DESIGNING THE MATRIX What is the best way to allocate a fixed number of tests across the stability study? Only optimal in terms of tightening confidence intervals

  14. Month: 0 3 6 9 12 18 24 36 Totals Batch 1 X X X X X 5 Batch 2 X X X X X 5 Batch 3 X X X X X 5 Totals 3 1 2 1 2 1 2 3 15 A balanced matrix SIMPLE MATRIX 1 (37.5% Reduction)A ONE HALF MATRIX For one condition eg. 25 °C/60%RH and one presentation

  15. Pack 2 Batch 1 X X X X X 5 or Batch 2 X X X X X 5 Strength 2 Batch 3 X X X X X 5 EXTENSION OF MATRIX 1(37.5% Reduction) For two presentations Month: 0 3 6 9 12 18 24 36 Totals Pack 1 Batch 1 X X X X X 5 or Batch 2 X X X X X 5 Strength 1 Batch 3 X X X X X 5 Totals: 6 3 3 3 3 3 3 6 30

  16. Month: 0 3 6 9 12 18 24 36 Totals Pack 1 Batch 1 X X X X X 5 or Batch 2 X X X X X X 6 Strength 1 Batch 3 X X X X X 5 Pack 2 Batch 1 X X X X X X 6 or Batch 2 X X X X X 5 Strength 2 Batch 3 X X X X X X 6 Totals: 6 3 3 3 6 3 3 6 33 Becomes slightly unbalanced, but not important Significant imbalance is not acceptable though EXTENSION OF MATRIX 1Modified for 12 months regulatory submission (31% Reduction)

  17. Month: 0 3 6 9 12 18 24 36 Totals Strength 1 Batch 1 X X X X X 5 Batch 2 X X X X X X 6 Batch 3 X X X X X 5 Strength 2 Batch 1 Batch 2 Batch 3 Strength 3 Batch 1 X X X X X X 6 Batch 2 X X X X X 5 Batch 3 X X X X X X 6 INCLUSION OF BRACKETING For three presentations Totals: 6 3 3 3 6 3 3 6 30

  18. Medium Batch 1 X X X X X X strength Batch 2 X X X XX Batch 3 X X X X X X Lowest Batch 1 X X X X X strength Batch 2 X X X X X X Batch 3 X X X X X UNCERTAIN OF MARKETED STRENGTHS? Matrix medium against lowest and against highest strengths. If either extreme is dropped still left with a viable matrix. Month: 0 3 6 9 12 18 24 36 Highest Batch 1 X X X X X strength Batch 2 X X X X X X Batch 3 X X X X X

  19. For one condition eg. 25 °C/60%RH Month: 0 3 6 9 12 18 24 36 Totals Batch 1 X X X X X X X 7 Batch 2 X X X X X X 6 Batch 3 X X X X X X 6 Totals 3 2 2 2 3 2 2 3 19 SIMPLE MATRIX 2 (21% Reduction)A 2/3RD MATRIX (plus full testing at 12months)

  20. MATRIX (Complete Reduced Design) Strength 1 2 3 Package A B C A B C A B C Batch 1 T1 T2 T3 T1 T2 T3 T1 T2 T3 Batch 2 T2 T3 T1 T2 T3 T1 T2 T3 T1 Batch 3 T3 T1 T2 T3 T1 T2 T3 T1 T2 T1: 0 3 12 36 T2: 0 6 12 18 36 T3: 0 9 12 24 26 T1, T2, and T3 represent sampling times in months. Represents a 42% reduction in samples tested.

  21. MATRIX (Incomplete Reduced Design) Strength 1 2 3 Package A B C A B C A B C Batch 1 X T2 T3 T1 T2 T3 T1 T2 T3 Batch 2 T2 T3 T1 T2 X T1 T2 T3 T1 Batch 3 T3 T1 T2 T3 T1 T2 T3 T1 X T1: 0 3 12 36 T2: 0 6 12 18 36 T3: 0 9 12 24 36 T1, T2, and T3 represent sampling times in months. X is not tested. Represents a 48% reduction.

  22. Month: 0 3 6 9 12 18 24 36 Totals Pack 1 Batch 1 X X X X 4 or Batch 2 X X X X X 5 Strength 1 Batch 3 X X X X X 5 Pack 2 Batch 1 X X X X X 5 or Batch 2 X X X X X 5 Strength 2 Batch 3 X X X X 4 Totals: 6 2 2 2 6 2 2 6 28 WHY NOT GO FURTHER?(1/3rd matrix, 42% Reduction) More appropriate for multiple presentations.

  23. R.I.P 20mg Tablet Expired 21.10.98 PURPOSE OF STABILITY TESTING To ensure the quality and stability of drug products used by patients: - Establish expiration dating period - Establish storage conditions - Support label claims.

  24. KEY ISSUES If reduce testing too much: confidence intervals will probably widen, giving reduced shelf lives; may not pick up information on differences between batches (poolability)

  25. Assay Time POOLABILITY- a risk factor Design should allow statistical comparison of intercepts and slopes for different batches. Downside, if can’t pool then estimate shelf lives of individual batches and assign the shortest to all batches not tested. If can pool then good chance of a longer shelf life.

  26. Stability High Moderate Poor EP 36months EP ~24months EP 2months Very Small Moderate High Variability * * * * * * * * * * * * * * * * * * * * * * * * * * * * * JUDGING SIZE OF REDUCTION IN TESTING Variability across Strength, Pack, Closure or Assay EP = expiry period Large (60+%) Large reductions are also supported when there are many presentations Size of Reduction Small or None *

  27. Acceptable for Bracketing (ICH Q1D) • Strength eg capsules with different fill size, same blend; tablets of varying compression weight, same granulation; oral solutions differing only in minor excipients (eg colourants, flavourings); with justification, multiple strengths where the relative amounts of active and excipients change. Where different excipients are used among strengths, bracketing should not generally be applied.

  28. Acceptable for Bracketing (ICH Q1D) • Container Closure Sizes and/or Fills Same closure system where either container size or fill varies. If both size and fill vary, largest and smallest may not represent the extremes. With justification, same container when the closure varies. Justification could include a discussion of the relative permeation rates of the systems.

  29. Acceptable for Matrixing (ICH Q1D) • For example, different batches; different strengths; different sizes of the same container closure system; possibly different closure systems; secondary packaging (if contributes to stability).

  30. Acceptable for Bracketing and Matrixing(based upon CPMP guideline) • Strength (small or no change in proportions of • ingredients) • Strength (where obtained by changing/varying • amount of active and one or two major ingredients) • Container size (same contact materials) and fill volume • Closure systems (of demonstrated equivalence) • Manufacturing site (where same company) • Batch size • Intermediate observation times

  31. Normally Acceptable for Bracketing and Matrixing(based upon CPMP guideline) • Strength (significant change in proportions of • ingredients or change in one or two minor • components) • Closure systems (non equivalent performance) • Orientation of container during storage • Fill volume of containers • Containers (different contact materials) • Manufacturing process • Manufacturing site (different company)

  32. Currently Not Acceptable for Bracketing and Matrixing • Initial observation time • Final observation time (at or beyond desired ED) • Dosage form • Site of manufacture (different company) • Storage conditions

  33. WHAT IF IT STARTS TO GO WRONG?If a reduced design study becomes unsuitable (eg if the product is less stable than expected)a modified design, that either reverts to full testing or to a less reduced design, can be followed.However, once changed, you can not at subsequent time points revert back to the original design.

  34. ASSAY DISSOLUTION MATRIXING DIFFERENT TESTS CAN BE MATRIXED TO DIFFERENT EXTENTS

  35. You want MORE! MATRIXING Can matrix follow up (production, supplemental) studies even if original stability in marketing application was not matrixed. BfArM

  36. REFERENCES E Nordbrook J Biopharm Stat 1992 2 91-113 W Fairweather, T.D. Lin and R Kelly J Pharm Sci 1995 84 1322 - 1326 MH Golden, D Cooper, M Riebe and K Carswell J Pharm Sci 1996 86 240-244 The Matrixing Bible and of Bracketing

  37. EXAMPLES: Retrospective Analysis(from Golden reference) • Metered-dose Inhaler (MDI) • Capsule • Conventional statistical analysis • - Full data set • - Simulated matrix data set. • 1/2 matrix • Note that in the simulation the authors did not • include full testing at 12 months

  38. BATCH PERMUTATIONS Full Month: 0 3 6 9 12 18 24 36 Row 1 Batch 1 1 1 1 1 1 1 1 1 Row 2 Batch 2 2 2 2 2 2 2 2 2 Row 3 Batch 3 3 3 3 3 3 3 3 3 Permutation 123 Month: 0 3 6 9 12 18 24 36 Row 1 Batch 1 1 1 1 1 1 Row 2 Batch 2 2 2 2 2 2 Row 3 Batch 3 3 3 3 3 3 Other Permutations: 132, 213, 231, 312, 321

  39. MDI: Expiry Estimates (Months)from 12 month data Batch Permutations ConditionTest Full 123 132 213 231 312 321 AVG 30°C/50% RH Dose 13 12 17 11 8 16 9 12 Sum 21 21 19 13 17 17 20 18 IMPs >36 11 >36 >36 >36 >36 >36 32 Minimum 13 11 17 11 8 16 9 Dose = Delivered Dose Sum = Fine Particle Mass by Cascade Impaction (stages 4-6) IMPs = Total drug-related impurities

  40. MDI: Expiry Estimates (Months)from 24 month data Batch Permutations ConditionTest Full 123 132 213 231 312 321 AVG 30°C/50% RH Dose 34 29 29 29 27 >36 32 30 Sum 25 19 20 19 25 18 25 21 IMPs >36 >36 26 >36 25 >36 >36 33 Minimum 25 19 20 19 23 18 25 Dose = Delivered Dose Sum = Fine Particle Mass by Cascade Impaction (stages 4-6) IMPs = Total drug-related impurities

  41. CAPSULE: Expiry Estimates (Months)from 12 month data Batch Permutations ConditionTest Full 123 132 213 231 312 321 AVG 25°C/50% RH Dose 24 14 16 24 24 16 16 18 Diss. >36 >36 >36 22 21 >36 >36 31 IMPs 25 21 14 12 15 13 18 16 Minimum 24 14 14 12 15 13 16 Dose = Drug Content Diss = Dissolution (45 minutes) IMPs = Total drug-related impurities

  42. CAPSULE: Expiry Estimates (Months)from 24 month data Batch Permutations ConditionTest Full 123 132 213 231 312 321 AVG 25°C/50% RH Dose 23 24 24 21 25 29 29 25 Diss. >36 >36 >36 >36 >36 >36 >36 36 IMPs 17 18 18 21 22 18 14 19 Minimum 17 18 18 21 22 18 14 Dose = Drug Content Diss = Dissolution (45 minutes) IMPs = Total drug-related impurities

  43. FURTHER SIMULATION EXAMPLESEXPIRY ESTIMATES 1/2 Matrix, full testing at 12 months 12 month data Matrix ProductTest Full 123 132 213 231 312 321 AVG X Dose 17 16 18 16 16 18 17 16.8 MDI FPM 18 17 17 17 18 18 16 17.2 IMPs >24 >24 >24 >24 >24 >24 >24 24.0 Y FPM21 20 22 20 21 22 22 21.2 MDI IMPs >24 >24 >24 >24 >24 >24 >24 24.0 36 month data Matrix ProductTest Full 123 132 213 231 312 321 AVG X Dose >48 >48 >48 >48 >48 >48 >48 48.0 MDI FPM >48 >48 >48 >48 >48 >48 >48 48.0 IMPs >48 >48 >48 >48 >48 >48 >48 48.0 Y FPM24 23 22 26 24 24 23 23.7 MDI IMPs >48 >48 >24 >48 >48 >48 >48 48.0

  44. CASE HISTORIESthat have received regulatory approval Dr Ray Munden GlaxoSmithKline Research and Development

  45. CASE 1 ANTIBIOTIC TABLETSSUPPLEMENTAL SUBMISSION EXISTING • 36 MONTH DATA ON 200 MG TABLETS SUBMITTED • MANUFACTURED IN JAPAN IN PACK P0, • PACKED AT SITE S0 IN UK REQUIRED • 400 AND 600MG AS WELL AS 200MG • MANUFACTURED IN UK • TWO NEW PACKS, P1 AND P2 • ALTERNATIVE PACKING SITE, S1

  46. 200mg 400mg 600mg Batch S1,P1 S1,P2 S0,P1 S1,P1 S0,P2 S1,P2 S0,P1 S1,P1 S0,P2 S1,P2 1 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 2 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 0 3 6 9 12 18 24 36 48 60 T1 X X X X X X T2 X X (X) X X X X 600 400 200 CASE 1MATRIX FOR SUPPLEMENTAL SUBMISSION

  47. CASE 2 CONVENTIONAL TABLET, 1 MG NEW SUBMISSION Al FOILS AND HDPE BOTTLES 2 BOTTLE SIZES (50 & 80 CC) INITIALLY LOW AND HIGH FILLS PROBABLY ONLY 1 SIZE MARKETTED SUPPORTING DATA ON HIGHER STRENGTHS INDICATES GOOD STABILIY

  48. CASE 2The following 1/2 (approx) Matrix was praised by the FDA

  49. CASE 3 A METERED DOSE POWDER INHALERNEW SUBMISSION FOR CANADA • EXISTING DATA FOR OTHER MARKETS • CANADA REQUIRE SPECIFIC BATCHES • 4 STRENGTHS (50,100,250 & 500 MCG) • POTENTIALLY 12 BATCHES • CURRENTLY 18 MONTH SHELF LIFE • MAY WANT TO EXTEND TO 24

  50. CASE 3 STABILITY TEST PROTOCOL FOR MDPI, 50, 100, 250 and 500ug

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