2 2 Stability FPPs

8/2/2019 2 2 Stability FPPs

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Stability of FPPs-Conducting, Bracketing, Matrixing

Sultan Ghani


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Stability of Finished Pharmaceutical Product(FPP)

Bracketing & Matrixing


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Pre-formulation studies on pilot scalebatch should be conducted

Stress testing may be performed on thepharmaceutical product

Selection of batches: At least two pilotscale batches and the third one can besmaller

Container closure system should be thesame as proposed for marketing


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Specification: Appropriate physical, chemical,biological and microbiological attributes, alsopreservative content

Shelf-life acceptance criteria should beestablished, as well as difference betweenshelf-life and release specifications

A single stability batch should be tested for

antimicrobial preservative effectiveness Validated stability indicating analytical

procedure should be applied


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Testing frequency: Frequency of testing should be sufficientto establish stability profile for product. For proposedshelf-life of 12 months, the frequency of testing should bethree months over the first year, six months over the second

year, and annually thereafter. For accelerated storage, aminimum of three time points (036) is recommended.

Reduced design: Matrixing and bracketing principle can beused if justified

Storage condition should be monitored and recorded (see

Table 1)


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Commitment: Long-term stability data do not coverthe proposed shelf-life granted at the time ofapproval. Commitment should be made tocontinue stability studies (post-approval). Threeproduction batches covering the proposed shelf-

life. Evaluation: Systematic approach for the evaluation

of the stability information, including all attributes.All results must remain within specificationthroughout the shelf-life. If the data are limited, itis unnecessary to go through the statisticalanalysis.


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Table 1Study Storage Condition Time Period

Long-Term 25C, 60% RH30C, 65% RH30C, 75% RH

12 months or

6 months

Intermediate 30C, 65% RH 6 months

Accelerated 40C, 75% RH 6 months

Long-Term 5C 12 months

Accelerated 25C, 60% RH or30C, 65% RH or30C, 75% RH

6 months

Long-Term -20C 12 months


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Testing Conditions of ActivePharmaceutical Ingredients

Recommended Statement

25C/60% RH (long term)40C/75% RH (accelerated)

Store below 25C

30C/65% RH (long-term)40C/75% RH (accelerated)

Store below 30C

25C/60% RH (long-term)30C/65% RH (intermediate)

Store below 25C

30C/75% RH (long-term) Store below 30C



5C 3C Store in a refrigerator(2C to 8C)

-20C Store in a freezer


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Q1D - Bracketing and Matrixing


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Outlines recommendations, principles, andconsiderations for reduced designs. Terms:

Full Design: samples for every combination of all designfactors are tested at all time points

Reduced Design: not all samples for every factorcombination are tested at all time points

Bracketing: testing samples on the extremes of certaindesign factors (e.g., strengths, container sizes and/orfills)


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Terms (contd): Matrixing: testing a selected subset of the total number

of possible samples for all factor combinations at aspecified time point, while testing another subset ofsamples at a subsequent time point


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Basic Principles: some reduced designs may need minimal justification,

some designs may require more justification

assumptions should be assessed and justified

potential risks should be taken into consideration Note:

if a reduced design is proposed to be implemented afterapprovalof the original submission, a prior approvalapplication should be filed (e.g., in Canada: a Level 2 -

Notifiable Change)


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Bracketing - Strengths: Applicable: strengths of identical or closely related

formulations

Applicable with additional justification (e.g., supportingdata): strengths where the relative amounts of the drug

substance and excipients vary within the product line

Not applicable: different excipients among strengths


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Bracketing Container Size, Fill: Applicable: same container closure system where either

the container size or fill varies while the other remainsconstant

Applicable with additional justification (e.g., supporting

data): same container closure system but both thecontainer size and fill vary

Not applicable: different container closure systems


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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


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Strength 50 mg

Batch B1 B2 B3

15 mL T T T

100 mL

Container Size

500 mL T T T

Key: B1 B3 indicate batches, T = sample tested


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Bracketing - Considerations:If stability of extremes are shown to be different, the

intermediates should be considered no more stablethan the least stable extreme

Selected extreme may be dropped from proposed

market presentations


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Matrixing: applicable:

strengths with identical or closely related formulations container sizes or fills of the same C/C system different batches made with the same equipment and process

applicable with additional justification: where the relative amounts of excipients change or different

excipients are used

not applicable: different storage conditions

different test attributes


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Matrixing - Considerations: - Design should be balanced as far as possible so that

each combination is tested to the same extent over theintended duration of the study and through the last timepoint prior to submission

- Where time points are matrixed, all selected factorcombinations should be tested at the initial and final time

points (and the last time point prior to submission)


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Time point (months) 0 3 6 9 12 18 24 36

Batch 1 T T T T

Batch 2 T T T T

Strength 1

Batch 3 T T T TBatch 1 T T T T

Batch 2 T T T T

Strength 2

Batch 3 T T T T

T = sample tested


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Time point (months) 0 3 6 9 12 18 24 36

Batch 1 T T T T T TBatch 2 T T T T T T

Strength 1

Batch 3 T T T T T

Batch 1 T T T T T

Batch 2 T T T T T T

Strength 2

Batch 3 T T T T T

T = sample tested


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2 2 Stability FPPs

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