Stability of FPPs- Conducting, Bracketing, MatrixingSultan Ghani

Stability of Finished Pharmaceutical Product (FPP)Bracketing & Matrixing

Pre-formulation studies on pilot scale batch should be conductedStress testing may be performed on the pharmaceutical productSelection of batches: At least two pilot scale batches and the third one can be smallerContainer closure system should be the same as proposed for marketing

Specification: Appropriate physical, chemical, biological and microbiological attributes, also preservative contentShelf-life acceptance criteria should be established, as well as difference between shelf-life and release specificationsA single stability batch should be tested for antimicrobial preservative effectivenessValidated stability indicating analytical procedure should be applied

Testing frequency: Frequency of testing should be sufficient to establish stability profile for product. For proposed shelf-life of 12 months, the frequency of testing should be three months over the first year, six months over the second year, and annually thereafter. For accelerated storage, a minimum of three time points (036) is recommended. Reduced design: Matrixing and bracketing principle can be used if justifiedStorage condition should be monitored and recorded (see Table 1)

Commitment: Long-term stability data do not cover the proposed shelf-life granted at the time of approval. Commitment should be made to continue stability studies (post-approval). Three production batches covering the proposed shelf-life.Evaluation: Systematic approach for the evaluation of the stability information, including all attributes. All results must remain within specification throughout the shelf-life. If the data are limited, it is unnecessary to go through the statistical analysis.

Table 1

StudyStorage ConditionTime PeriodLong-Term25C, 60% RH30C, 65% RH30C, 75% RH12 months or6 monthsIntermediate30C, 65% RH6 monthsAccelerated40C, 75% RH6 monthsLong-Term5C12 monthsAccelerated25C, 60% RH or30C, 65% RH or30C, 75% RH6 monthsLong-Term-20C12 months

Testing Conditions of Active Pharmaceutical IngredientsRecommended Statement25C/60% RH (long term)40C/75% RH (accelerated)Store below 25C30C/65% RH (long-term)40C/75% RH (accelerated)Store below 30C25C/60% RH (long-term)30C/65% RH (intermediate)Store below 25C30C/75% RH (long-term)Store below 30C30C/65% RH (long-term)Store below 30C25C/60% RH (long-term)Store below 25C5C 3CStore in a refrigerator(2C to 8C)-20CStore in a freezer

Q1D - Bracketing and Matrixing

Outlines recommendations, principles, and considerations for reduced designs.Terms:Full Design: samples for every combination of all design factors are tested at all time pointsReduced Design: not all samples for every factor combination are tested at all time pointsBracketing: testing samples on the extremes of certain design factors (e.g., strengths, container sizes and/or fills)

Terms (contd):Matrixing: testing a selected subset of the total number of possible samples for all factor combinations at a specified time point, while testing another subset of samples at a subsequent time point

Basic Principles:some reduced designs may need minimal justification, some designs may require more justificationassumptions should be assessed and justifiedpotential risks should be taken into considerationNote:if a reduced design is proposed to be implemented after approval of the original submission, a prior approval application should be filed (e.g., in Canada: a Level 2 - Notifiable Change)

Bracketing - Strengths:Applicable: strengths of identical or closely related formulationsApplicable with additional justification (e.g., supporting data): strengths where the relative amounts of the drug substance and excipients vary within the product lineNot applicable: different excipients among strengths

Bracketing Container Size, Fill:Applicable: same container closure system where either the container size or fill varies while the other remains constantApplicable with additional justification (e.g., supporting data): same container closure system but both the container size and fill vary Not applicable: different container closure systems

Strength

50 mg

75 mg

100 mg

Batch

B1

B2

B3

B4

B5

B6

B7

B8

B9

Tested?

T

T

T

T

T

T

Key: B1 B9 indicate batches, T = sample tested

Strength

50 mg

Batch

B1

B2

B3

Container Size

15 mL

T

T

T

100 mL

500 mL

T

T

T

Key: B1 B3 indicate batches, T = sample tested

Bracketing - Considerations:If stability of extremes are shown to be different, the intermediates should be considered no more stable than the least stable extremeSelected extreme may be dropped from proposed market presentations

Matrixing:applicable:strengths with identical or closely related formulationscontainer sizes or fills of the same C/C systemdifferent batches made with the same equipment and processapplicable with additional justification:where the relative amounts of excipients change or different excipients are usednot applicable:different storage conditionsdifferent test attributes

Matrixing - Considerations:- Design should be balanced as far as possible so that each combination is tested to the same extent over the intended duration of the study and through the last time point prior to submission- Where time points are matrixed, all selected factor combinations should be tested at the initial and final time points (and the last time point prior to submission)

Time point (months)

0

3

6

9

12

18

24

36

Strength 1

Batch 1

T

T

T

T

Batch 2

T

T

T

T

Batch 3

T

T

T

T

Strength 2

Batch 1

T

T

T

T

Batch 2

T

T

T

T

Batch 3

T

T

T

T

T = sample tested

Time point (months)

0

3

6

9

12

18

24

36

Strength 1

Batch 1

T

T

T

T

T

T

Batch 2

T

T

T

T

T

T

Batch 3

T

T

T

T

T

Strength 2

Batch 1

T

T

T

T

T

Batch 2

T

T

T

T

T

T

Batch 3

T

T

T

T

T

T = sample tested

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