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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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