Utilizing Stability and Analytical Tools to Improve Product Knowledge to Facilitate Support of a Global Clinical Program AAPS Roundtable

Stability Evaluations Using Alternate Accelerated Conditions Annual Meeting Los Angeles, California 11/10/09

Frank Diana Endo Pharmaceuticals

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Stability and Analytical Tools to Support Global Clinical Program

Analytical Tools

Stability Indicating Methods Forced Degradation (Stress) Studies Physical Evaluations

Accelerated and Stress Stability Studies Freeze/Thaw Studies Shelf Life Assessments

Stability Tools

Development Studies and Data

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Stability Indicating Methods

Quantitative analytical methods... that will distinguish each active ingredient from its degradation products so that the active ingredient content can be accurately measured. For clinical development, analytical methods should be stability indicating Specificity/Stability Indicating Nature of the analytical method should be established as early as feasible in a development program

Forced degradation studies are conducted to challenge the stability indicating characteristics of the method.
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Forced Degradation (Stress) studies

Stress studies for drug substance and the drug product should be performed to demonstrate the specificity of the potency assay and tests for impurities and degradation products Goals Generate typical degradation products which may be expected on stability at sufficient levels to allow identification Avoid secondary degradation Target range is 5-15 % loss of active as judged by assay relative to an un-degraded sample Look for purity and mass balance

Typical Stress Study Design

Drug Substance: Solid State: Heat: 60C for up to 1 month Photostability Solution State: depending on solubility Acid: 0.1-1N HCl up to 2 weeks and to 60C Base: 0.1-1N NaOH up to 2 weeks and to 60C Peroxide: 3% H2O2 up to 24 hours Photostability
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Typical Stress Study Design

Drug Product: Heat: 60C for up to 1 month Heat/moisture 40C/75%RH Photostability - note that degradation pathways could be different with UV and Visible light stress Use placebo as control For combination product (multiple active ingredients) Stress should be done for API individually and also in the presence of the other API (s).
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Evaluation of Stress Studies

Method should be selective for the main compound in the presence of the expected level of degradation products (stability-indicating) Primary degradation pathways need to be determined Only peaks which occur at or above the threshold under expected storage conditions need to be identified and qualified. Stress conditions may produce degradation products which are not observed under practical storage conditions; it is not likely that these peaks would need to be identified.

Physical Evaluation

Dosage Form dependent

Tablet breakage Capsule moisture content Phase separation Particle agglomeration Precipitation of particles Change in viscosity Backing separation Dose delivery
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Accelerated and Stress Stability Studies

Early development 50 or 60C Clinical development 40C/75%RH For refrigerated products, 25C/60%RH Photostability testing Thermal Cycling High Humidity

Stability Studies, additional considerations

Upright/Inverted orientation Open dish studies Homogeneity testing of Semi-solid products Stability of Reconstituted products Potential package interactions Change in penetration/solubility enhancers Biological Activity Stability long enough to cover clinical study
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Thermal Cycling and Freeze/Thaw Studies

Effects of temperature variation Storage and Shipping conditions Temperature cycling (2-3 cycles) Susceptible drug products, e.g. semi-solids, suspensions, biologics Refrigerated followed by 25 or 40C storage conditions Freezer (e.g. -20C) followed by 25 or 40C storage conditions
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Shelf Life Assessments

For clinical product, shelf life will be based on available data and product knowledge Concurrent stability especially early in a development program or with changes in formulation Re-test date established, extension as additional data are collected Notification of clinical sites
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Development Studies and Data

Pre-formulation studies Forced Degradation studies Early stress studies Clinical stability studies Packaging Studies Shipping studies

Shipping route and mode of transportation Qualification

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Development Studies and Data

Product Knowledge based on development studies

Summarize degradation products observed at release and stability Identify degradation products and perform safety qualification as needed Understand potential physical changes Package selection
Light sensitivity Sensitive to moisture Shipping containers/monitors

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Development Studies and Data

Product Knowledge based on development studies Identify acceptable temperature range for shipping and distribution; particularly important for global clinical studies Options if product goes outside of temperature range for a short period of time
Justify no impact Re-test Reduce dating Physical evaluation (e.g. particulates) Discard/Replace

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