# Presentation: 535644

## Predicting Physical Stabilityin 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

## Stress Testing of Drug Substance

- Elevated temperature (in 10°C increment above accelerated temperature)
- Humidity (75% or greater)
- Effect of pH
- Oxidation
- Light

## 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

## 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

## 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

## Low Temperature Storage Conditions

***	******	******	******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

## 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

## 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

## 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

## 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