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-Term 25 º C, 60% RH 30 º C, 65% RH 30 º C, 75% RH 12 months or 6 months Intermediate 30 º C, 65% RH 6 months Accelerated 40 º C, 75% RH 6 months Long-Term 5ºC5ºC 12 months Accelerated 25 º C, 60% RH or 30 º C, 65% RH or 30 º C, 75% RH 6 months Long-Term -20 º C 12 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) “Store below 30ºC” 25ºC/60% RH (long-term) 30ºC/65% RH (intermediate) “Store below 25ºC” 30ºC/75% RH (long-term)“Store below 30ºC” 30ºC/65% RH (long-term)“Store below 30ºC” 25ºC/60% RH (long-term)“Store below 25ºC” 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: ◦ A pplicable: 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: ◦ A pplicable: 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

 Bracketing - Considerations:  I f 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:  - D esign 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)