Download - Stability of FPPs- Conducting, Bracketing, Matrixing Sultan Ghani.

Stability of FPPs -Conducting, Bracketing, Matrixing

Sultan Ghani

Stability of Finished Pharmaceutical Product (FPP)

Bracketing & Matrixing

Pre-formulation studies on pilot scale

batch should be conducted Stress testing may be performed on

the pharmaceutical product Selection of batches: At least two

pilot scale batches and the third one can be smaller

Container closure system should be the same as proposed for marketing

Specification: Appropriate physical, chemical, biological and microbiological attributes, also preservative content

Shelf-life acceptance criteria should be established, as well as difference between shelf-life and release specifications

A single stability batch should be tested for antimicrobial preservative effectiveness

Validated 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 justified

Storage 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 Period

Long-Term25ºC, 60% RH30ºC, 65% RH30ºC, 75% RH

12 months or

6 months

Intermediate30ºC, 65% RH6 months

Accelerated40ºC, 75% RH6 months

Long-Term5ºC12 months

Accelerated25ºC, 60% RH or30ºC, 65% RH or30ºC, 75% RH

6 months

Long-Term-20ºC12 months

Testing Conditions of Active Pharmaceutical Ingredients

Recommended Statement

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

“Store below 25ºC”

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


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


30ºC/75% RH (long-term)“Store below 30ºC”



5ºC ± 3ºC“Store in a refrigerator(2ºC to 8ºC)”

-20ºC“Store 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 points◦ Reduced Design: not all samples for every factor

combination are tested at all time points◦ Bracketing: testing samples on the extremes of

certain design factors (e.g., strengths, container sizes and/or fills)

Terms (cont’d):◦ 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 justification◦ assumptions should be assessed and justified◦ potential risks should be taken into consideration

Note:◦ 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

formulations◦ Applicable with additional justification (e.g.,

supporting data): strengths where the relative amounts of the drug substance and excipients vary within the product line

◦ Not 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 constant

◦ Applicable 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 mgBatch B1 B2 B3

15 mL T T T100 mL

Container Size

500 mL T T TKey: 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 extreme

Selected extreme may be dropped from proposed market presentations

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

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

Strength 1

Batch 3 T T T T Batch 1 T T T T Batch 2 T T T T

Strength 2

Batch 3 T T T T T = sample tested

Time point (months) 0 3 6 9 12 18 24 36Batch 1 T T T T T TBatch 2 T T T T T T

Strength 1

Batch 3 T T T T TBatch 1 T T T T TBatch 2 T T T T T T

Strength 2

Batch 3 T T T T TT = sample tested