Excipient Compatibility as Predicted by ASAP

Excipient Compatibility as Predicted by ASAP - Description

A Case Study. 1. Jerusha Thompson. Science of Stability 2015. October 12-14, 2015 Connecticut, US. . Getting To K. no. w Faster. 2. Outline. Introduction. Overview of Traditional Excipient Compatibility Studies. ID: 616000 Download Presentation

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Excipient Compatibility as Predicted by ASAP

A Case Study. 1. Jerusha Thompson. Science of Stability 2015. October 12-14, 2015 Connecticut, US. . Getting To K. no. w Faster. 2. Outline. Introduction. Overview of Traditional Excipient Compatibility Studies.

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Excipient Compatibility as Predicted by ASAP




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Presentation on theme: "Excipient Compatibility as Predicted by ASAP"— Presentation transcript:

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Excipient Compatibility as Predicted by ASAP

A Case Study

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Jerusha Thompson

Science of Stability 2015

October 12-14, 2015 Connecticut, US

Slide2

Getting To Know Faster

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Outline

IntroductionOverview of Traditional Excipient Compatibility StudiesAccelerated Stability Assessment Program (ASAP)Case StudyAlternate Analytical TechniqueComparison of Analytical TechniquesConclusionAcknowledgement

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Slide4

Introduction

Provide a rational for excipient selectionICH Q8(R2): Pharmaceutical DevelopmentThe compatibility of the drug substance with excipients listed should be evaluatedImpact on stability of APIRisk managementRegulatory RequirementQOS: What evidence supports compatibility between the excipients and the drug substance?

Jerusha Thompson

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Traditional Excipient Compatibility Studies

Binary mixture of active pharmaceutical ingredient (API) and excipient prepared in a 1:1 ratio Excipients showing incompatibility at the 1:1 ratio tested at a ratio more typical of the final formulationTwo vial types (duplicate vials for each) prepared for each drug-excipient blendAssay vial (pre-weighed for moisture)Composite vial (for additional tests)

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Traditional Excipient Compatibility Study

Three controlled conditions200 vials prepared for 7 excipients studied open dish

One Excipient = 25 Vials T=0  T=2 weeks  T=4weeks  T=8 weeks Test ConditionsAssayDupl.Comp.AssayDupl.Comp.AssayDupl.Comp.AssayDupl.Comp.Accelerated - 40ºC / 75% RHXXXXXXXXXXXXCRT - 25ºC / 60% RHXXXXXXXXXXXXLight2 XXXN/AN/AN/AN/AN/AN/AN/AN/AN/ATotal Vial Counts =433222222222Grand Totals = 10  6  6  6 

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Traditional Excipient Compatibility Studies

The analytical testing includes:AssayImpuritiesDescriptionLoss on Drying (LOD)Results compared to a control (API) across all time points and conditions to look for any trending Any unexplained or unexpected loss in potency, or increase in impurities over time mandated further investigationsExcipient ratio screening, at the levels typical of the final formulation.

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Traditional Excipient Compatibility Studies

Limitations1:1 Binary blends not representative of formulationMay not pick up on incompatibilitiesManufacturingProcessingTableting Sample LoadResourcesIncreased time-lineInconclusive resultsNot an indicator of formulation stability

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Accelerated Stability Assessment Plan: Excipient Compatibility Study

Rapid approach to determine incompatibilitiesMultiple prototype formulations screened simultaneouslyProvides greater understanding of drug product stabilityImpurity profileAllows rapid entry in full formulation developmentPredicts impact of container/closure on product stability

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ASAP: Excipient Compatibility Study

Sample count depends on study 21 samples for 3 batches testedAmebis Incubation SystemIncubation flask controls temperature/humidity

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Case Study

aNDA programPresence of lactose in reference listed drug (RLD)Maillard reactionChemical reaction between amine and sugarOne known degradation productSpecification limit defined by ICH Q3B(R2) and monographDrug product: oral tabletStrength: 0.5mg, 1mg, and 2mgCommercial packaging configuration: 100 and 1000 count HDPE bottleTimeline12 months to develop final formulation

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Case Study

API determined to be stableThree prototype formulations pressed into tabletsManufactured at bench scaleFormulation 1 approximates RLD formulation

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Case Study

ASAP design parameters7 samples per prototype formulationContainer closure system selected based on appropriate sized bottle for 100 tablets

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Jerusha Thompson

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Case Study

Testing designScreening design for excipient selectionMinimal approach taken comparing three prototypesOnce prototype formulation selected and optimized then additional more robust ASAP study conducted

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Case Study

Stability indicating UHPLC methodReporting impurities equal or greater then 0.02% label claim2 days for analytical analyses with a developed method

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Chromatogram

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Raw Data: % Impurity

Formulation 1: Lactose

Deg ProductControl50ºC/75%RH14 days60ºC/50%RH14 days70ºC/11%RH14 days70ºC/75%RH1 days70ºC/75%RH3 days80ºC/30%RH2 daysKnown 1ND0.0320.0780.0760.0390.0650.099RRT 3.21ND0.1410.2620.1080.1500.3250.192RRT 3.31ND0.0580.2560.0640.0860.0590.179

Formulation 2: Dicalcium Phosphate

Deg ProductControl50ºC/75%RH14 days60ºC/50%RH14 days70ºC/11%RH14 days70ºC/75%RH1 days70ºC/75%RH3 days80ºC/30%RH2 daysKnown 1 0.0240.3920.6210.6220.3140.6140.629

Formulation 3: Starch 1500

Deg ProductControl50ºC/75%RH14 days60ºC/50%RH14 days70ºC/11%RH14 days70ºC/75%RH1 days70ºC/75%RH3 days80ºC/30%RH2 daysKnown 1ND0.0550.0360.0430.0460.1150.040

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Case Study

Predicted results from ASAP®Prime meeting acceptance criteria of 0.2% label claimAll degradation productsPackaging assessedWith and without desiccantICH accelerated and CRTRRT 3.31 poor correlationPotential secondary degradation

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Case Study

Formulation 2-Known-1 40°C/75% RH no desiccant

Formulation 2-Known-1 25°C/60%RH

no desiccant

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Case Study

Formulation 1- RRT 3.31 40°C/75% RH Higher error propagation

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Jerusha Thompson

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Case Study

ResultsFormulation 1 (RLD)Two unique unidentified degradation products observedFormulation 2Known 1 would have difficulty meeting a shelf-life of 24 months without a desiccantFailure at accelerated conditions would require additional testing at an intermediate conditionFormulation 3Highest probability of passing all conditions without desiccantStudy results will help justify the excipient and packaging selection in CMC section of submission

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Alternative Analytical Technique

Rapid entry into full formulation development with ASAP allows decreased timelineTraditional approach to excipient studies ~3-6 monthsASAP ~ 2-4 weeksRate limiting step can become analytical technologyStability indicating HPLC method can take time to develop~1-2 monthsResponse of degradation products to parent compound criticalQuantitative NMR (qNMR)One method for all drug productsNo method development requiredNo response of degradation product neededNo quantitative reference standard required

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Alternative Analytical Technique

qNMR Parameters

Pauli, G. F. et al. J. Med Chem. 2014, 57, 9220-9231

Weber, M. et al. J. Pharm. Biomed. Anal. 2014, 93, 102-110

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Alternative Analytical Technique

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Alternative Analytical Technique

Predicted results for meeting acceptance criteria of 0.2%

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Alternative Analytical Technique

Known 1 data for each prototype formulation analyzed using qNMR The results of the analysis predict prototype formulation 3 (Starch 1500) would have the greatest probability of meeting an acceptance criteria of 0.2% label claimAnalysis of unknown degradation products not performed during this analysisFurther optimization of extraction process necessaryBoth analytical techniques selected prototype formulation 3 as the most stable formulation

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Conclusion

The data generated from the excipient compatibility study predicted prototype formulation 3 would be the best candidate to move forward into full formulation developmentAnalysis of each of the prototype formulation in the ASAP study also provided an early profile of likely degradation products present in each formulationBoth analytical techniques investigating selected prototype formulation 3qNMR analysis may allow for faster determination of instabilities in a drug productThe predictions from the ASAP study will be further monitored through the project, and confirmed through traditional ICH stability studiesASAP approach to excipient compatibility testing allows faster entry into full formulation development ~2-5 month

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Acknowledgement

Patrick Nelson, Chemist IILimin Shi, Scientist IISze Leung, Associate Chemist ITyler Blanke, Associate Chemist IByrant Gay, Ph.D., Scientist IMark Gherke, Ph.D., Associate Director

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