Predicting Physical Stability in Q1A(R)

1. Predicting Physical Stabilityin Q1A(R) Chi-wan Chen, Ph.D. Office of New Drug Chemistry Center for Drug Evaluation and Research Food and Drug Administration Pharmaceutical Science Advisory Committee November 28, 2001

2. Stress Testing of Drug Substance • Elevated temperature (in 10°C increment above accelerated temperature) • Humidity (75% or greater) • Effect of pH • Oxidation • Light

3. 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

4. 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

5. 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 Room Temperature Storage Conditions Data at submission 12 mos from an ongoing study 6 mos from a 6-mo study 6 mos from a 12-mo study

6. Study Refrigerator Long-term Accelerated Freezer Long-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 Low Temperature Storage Conditions

7. 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

8. 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

9. 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

10. 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