Current Practices In Shelf Life Estimation

Shelf Life Estimation ICH estimation methodsCurrent Practices in Shelf Life Estimation Typical stability study Shelf Life paradigmJames Schwenkeg IngelheimgPharmaceuticals,, Inc.Boehringer Regression methods for estimating shelf lifePQRI Stability Shelf Life Working Group Actual stability study results Summarize empirical distribution of estimated shelf life Extend to random batch analysesPharmaceutical Stability Shelf LifeAugust 1, 20101Definitions of Shelf Life – ICH Q1E ICH Guideline Q1E defines shelf life as ICH Guideline Q1A defines “Shelf Life (also referred to asexpiration dating period)” as“The shelf life of a pharmaceutical product is the maximumtime at which the true mean response of a stability limitingcharacteristic crosses the acceptance criterion.”“The shelf life for a pharmaceutical product is the maximumtime at which a stability limiting characteristic stays withinacceptancepcriteria.”– basis for the current ICH/FDA shelf life estimation procedure– limited assurance that individual test results will comply withthe specification up to m months– focus on the mean response implies the risk to fail specificationat shelf life will be 50% Also in Q1A, “Specification Shelf Life” is defined as“The combination of physical, chemical biological, andmicrobiological tests and acceptance criteria that determinethe suitability of a drug substance throughout its re-testperiod, or that a drug product should meet throughout itsshelf life.”Pharmaceutical Stability Shelf LifeAugust 1, 20102Typical Stability StudyPharmaceutical Stability Shelf LifeAugust 1, 20103The Shelf Life Paradigm Minimum of 3 stability batches– can be 6 or more batches included in study– can be several studies combined togetherStability Limiting RResponseAcceptance Criterion Study duration can be 6-12-24-36-48 months– longerlstudiest di can hhave iinterimt i reportst– length of study can depend on shelf life desired Various environmental conditions– more severe environmental condition can act as an acceleratedtesting for milder conditionsProductShelf LifeStorage Time (Months)Pharmaceutical Stability Shelf LifeAugust 1, 20104Pharmaceutical Stability Shelf LifeAugust 1, 20105

The Shelf Life ParadigmICH Shelf Life Estimation Methods General concerns– Exactly what should be modeled and how does it relate to theproduct shelf life? individual tablet compositepsamplep of several tablets packaged unit (bottle or blister pack) stability batches or all future batches– How does results of content uniformity studies affect thedecision process?– If focused on the mean response, when the mean crosses theacceptance criteria, 50% of product out of specification. ICH methodology– minimum of three batches– batches are considered fixed effects for the analysis– batches can be pooled if no significant differences 0.25 level of significance for tests involving batches 0.05 level of significance for tests involving other factors· package type, storage orientation, coating, etc.– construct 95% confidence intervals on individual (or pooled)batch means– find minimal storage time where confidence interval crossesacceptance criteriaAugust 1, 2010Pharmaceutical Stability Shelf Life6ICH Shelf Life Estimation – No PoolingStability Limiting RResponseStability Limiting RResponseAcceptance CriteriaBatchMeanResponseLabeledShelf LifeConfidence Bandon Pooled Batch MeanProductShelf LifeAugust 1, 2010Pooled BatchMeanResponseLabeledShelf LifeStorage TimePharmaceutical Stability Shelf Life7ICH Shelf Life Estimation – Pooled BatchesAcceptance CriteriaConfidence Bandon Worst BatchAugust 1, 2010Pharmaceutical Stability Shelf LifeProductShelf LifeStorage Time8Pharmaceutical Stability Shelf LifeAugust 1, 20109ICH Estimation MethodologyICH Estimation Methodology usually a simple linear (straight line) regression model isassumed to characterize the response-time continuum– first-order nonlinear models are more appropriate for somestability limiting characteristics– we will focus on simple linear regression models ICH methodology suggest to test for equal regression slopesamong stability batches first– if batch slopes are nonsignificant (α 0.25) common regression slope is assumed among batchesp are tested batch intercepts· if batch intercepts are nonsignificant (α 0.25)- common intercept is assumed among batches- batches are pooled– if batch slopes are significant, no further testing is considered– ICH does not allow for a model with a common batch interceptand unequal slopes (which can be an important model) simple linear modelyij b0i b1i (monthj) εij yij observation at jth month for ith batch b0i batch intercept and b1i batch regression slope εij residual error with Normal assumptionsPharmaceutical Stability Shelf LifeAugust 1, 201010Pharmaceutical Stability Shelf LifeAugust 1, 201011

ICH Estimation IssuesICH Estimation Issues Regression model selection– there are four possible linear regression models1) full model: unequal intercepts and slopes among batches2) common intercept with unequal slopes among batches3) unequal intercepts with common slope among batches4) common intercept and slope (pooled batches)– Model #2 is not allowed following ICH guidelines still considered an important model to consider by colleagues for stability limiting characteristics that should be at 0% or100% at 0-months storage time Batch poolability– if batches cannot be pooled, shelf life is estimated on results ofthe worst batch– if batches can be pooled, between and within batch variation iscombinedPharmaceutical Stability Shelf LifeAugust 1, 201012Real-Life Example Data Set Random batch effects– the 0.25 level of significance used to test hypotheses involvingfixed batch effects is intended to accommodate batch-to-batchvariation– available software allows for random batch analysis– would avoid batch poolability issueAugust 1, 2010Pharmaceutical Stability Shelf Life13Product Shelf LifeIndustry Example: 26 Stability BatchesConsidered as Total Population to Define Product Shelf Life of 37.8 Real-life example contributed by one of our PQRI members– 26 stability batches– all on same product– most kept on study for 24 months– assay was measured115Stability Limiting Response (Assay)110 will use to study empirical distributional properties of estimatedshelf life using 3- and 6-batch studies1051009590850612182430Storage Time (Months)Pharmaceutical Stability Shelf LifeAugust 1, 201014Pharmaceutical Stability Shelf Life364248“Product Shelf Life”August 1, 2010Empirical Study of Distributional PropertiesEmpirical Study of Distributional Properties use real-life stability batch data set– consider entire 26-batch data set defines the productpopulation of batches– use all batches to product shelf life estimate regressiongline assumingg batches are random product shelf life is storage time where regression line crossesacceptance criteria 3-batch analysis– consider all possible combinations of 3 batches from the 26– there are 2,600 combinations– conduct regression analysis allowing for all four models does not follow ICH allows for common intercept / unequal slope model model is included by my analytical scientists– estimate shelf life from best fitted model consider all possible sets of 3 and 6 batches– conduct ICH estimation methods for shelf life– summarize resultsPharmaceutical Stability Shelf LifeAugust 1, 201015 6-batch analysis– there are 230,230 possible combinations (7.5 days to run)– randomly chose 20,000 (15.5 hours to run)16Pharmaceutical Stability Shelf LifeAugust 1, 201017

3-Batch Estimate of Shelf Life6-Batch Estimate of Shelf LifeComparison of ICH Shelf Life Estimation Methodology Using Industry DataUsing 3 Batches with 24 Months of Data, Extrapolating to 48 Months of Storage TimeConsidering All Possible Response ModelsProduct Shelf Life 37.8450Comparison of ICH Shelf Life Estimation Methodology Using Industry DataUsing 6 Batches with 24 Months of Data, Extrapolating to 48 Months of Storage TimeConsidering All Possible Response ModelsProduct Shelf Life .31% 14.016.018.020.022.026.028.030.032.034.00.35% 0.20% 0.08% 0.04%36.038.040.042.044.0ICH Estimated Shelf Life (Total 230230)ICH Estimated Shelf Life (Total 2600)August 1, 2010Pharmaceutical Stability Shelf Life24.018August 1, 2010Pharmaceutical Stability Shelf Life193-Batch Estimate of Shelf Lifen 466 (18%) mean 22.9 monthsICH Estimation MethodologySD 5.86Comparison of ICH Shelf Life Estimation Methodology Using Industry DataUsing 3 Batches with 24 Months of Data, Extrapolating to 48 Months of Storage TimeConsidering All Possible Response Models, Model 11: Full ModelProduct Shelf Life 37.8 Comparing the two empirical distributions– there is a shifting toward shorter estimated shelf lives with anincrease in the number of batches included in the analysis counterintuitive increase in the number of batches should reflect an increasein the amount of information about the product increase in the amount of information about the productshould reflect a better estimate of shelf life· should see a shift in distribution toward longer shelf lives· better estimates of product shelf life (37.8 months)– disincentive for industry to include more stability .040.042.044.0ICH Estimated Shelf Life (Total 2600)August 1, 2010Pharmaceutical Stability Shelf Life206-Batch Estimate of Shelf Lifen 5035 (25%) mean 19.9 monthsAugust 1, 2010Pharmaceutical Stability Shelf Life213-Batch Estimate of Shelf Lifen 788 (30%) mean 23.3 monthsSD 4.60Comparison of ICH Shelf Life Estimation Methodology Using Industry DataUsing 6 Batches with 24 Months of Data, Extrapolating to 48 Months of Storage TimeConsidering All Possible Response Models, Model 11: Full ModelProduct Shelf Life 37.8SD 5.71Comparison of ICH Shelf Life Estimation Methodology Using Industry DataUsing 3 Batches with 24 Months of Data, Extrapolating to 48 Months of Storage TimeConsidering All Possible Response Models, Model 01: Common InterceptProduct Shelf Life 12.014.0ICH Estimated Shelf Life (Total 230230)Pharmaceutical Stability Shelf Life978224321612.01098780August 1, .040.042.044.0ICH Estimated Shelf Life (Total 2600)22Pharmaceutical Stability Shelf LifeAugust 1, 201023