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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

Stability and Analytical Tools to

Support Global Clinical Program

Analytical Tools

Stability Indicating Methods

Forced Degradation (Stress) Studies

Physical Evaluations

Stability Tools

Accelerated and Stress Stability Studies

Freeze/Thaw Studies

Shelf Life Assessments

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

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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

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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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