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Predicting Physical Stabilityin Q1A(R)
Chi-wan Chen, Ph.D.Office of New Drug Chemistry
Center for Drug Evaluation and ResearchFood and Drug Administration
Pharmaceutical ScienceAdvisory CommitteeNovember 28, 2001
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Stress Testing of Drug Substance
• Elevated temperature (in 10°C increment above accelerated temperature)
• Humidity (75% or greater)
• Effect of pH
• Oxidation
• Light
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Batch Selection of Drug Product
• A minimum of 3 batches: 2 should be at least pilot scale; 3rd can be smaller
• Same formulation and container/closure as proposed for marketing
• Using manufacturing process simulating that for production batches
• Meeting same specifications as proposed for marketing
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Test Specification
• Q1AR: Attributes that are susceptible to change during storage and likely to influence quality, safety, and/or performance
• Q1AR: Physical, chemical, microbiological, and biological attributes; functionality test
• Q3A/B: Identification and qualification of impurities/degradation products
• Q6A: Establishing acceptance criteria for polymorphic forms, particle size, dissolution
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Room Temperature Storage Conditions
Study
Long-term
Accelerated
Intermediate
Storage Condition
25°C ± 2°C/ 60% RH ± 5% RH
40°C ± 2°C/ 75% RH ± 5% RH
30°C ± 2°C/ 60% RH ± 5% RH
Data at submission
12 mos from an ongoing study
6 mos from a 6-mo study
6 mos from a 12-mo study
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Low Temperature Storage Conditions
Study
• Refrigerator
Long-term
Accelerated
• FreezerLong-term
Accelerated**(optional)
Storage Condition
5°C ± 3°C
25°C ± 2°C/60% RH ± 5% RH
-20°C ± 5°C
5°C ± 3°C or 25°C ± 2°C
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Significant Change Criteria
• 5% change in assay, or failure to meet acceptance criteria for potency using biological or immunological procedures
• Degradation products exceeding acceptance criteria
• Failure to meet pH acceptance criteria
• Failure to meet acceptance criteria for appearance, physical attributes, functionality test
• Failure to meet acceptance criteria for dissolution for 12 dosage units
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Consequence of Significant Change
• If significant change occurs at accelerated condition, conduct intermediate testing, where applicable; extrapolation of shelf life beyond real-time data may not be granted
• If significant change occurs at intermediate condition, consider reformulation, more protective container/closure, shorter shelf life, qualification of higher impurity level
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Shelf Life Establishment
• Extrapolation of shelf life beyond real-time data can be granted if no significant change at accelerated condition and if supported by supporting data and/or statistical analysis
• Post-approval, tentative shelf life should be confirmed by 3 production batches on stability
• In the U.S., at least one batch should be put on long-term stability annually thereafter
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Predictability of Physical Stability
• Predictability of long-term behavior based on physical attributes at accelerated condition
• Predictability of future production batch behavior based on data from primary stability batches– Complexity of formulation and dosage form– Robustness of manufacturing process, scale-up– Soundness of sampling plan– Reproducibility of analytical procedure– Meaningful acceptance criteria– Experience; number of primary and supporting batches