1. Stability Studies - Evaluation of Outcomes and Development of Documentation For Regulatory Submissions
Bob Seevers

2. Outcomes of Stability Studies
Retest date or shelf-life for APIs
Shelf-life for drug products
Stability-indicating analytical methods
Appropriately protective packaging for API and drug product
Understanding the impact of temperature excursions during distribution

3. ICH Q1E Evaluation of Stability Data
Presentation of data
Extrapolating from existing data
Decision Trees

4. ICH Q1E
Stability data from 3 lots of drug substance or drug product may used to establish a shelf-life or retest date.
This is a statistical prediction
Increased variability among lots means less confidence in the shelf-life/retest date
More lots provide greater confidence
Extrapolation from available data is limited

5. ICH Q1E: Data to Provide
Results from the physical, chemical, biological, and microbiological tests such as:
Dissolution
Degradants
Assay
Preservative content
The adequacy of the mass balance should be assessed. Factors that can cause an apparent lack of mass balance should be considered
Mechanisms of degradation
Stability-indicating capability of analytical methods

6. ICH Q1E Extrapolation
Can extend expiration dating or retest date beyond available long-term stability data if
Sufficient long-term data is available to assess any trends
No significant change is observed under accelerated conditions
This process is spelled out in Q1E decision trees
Shelf-lives/retest dates established based on extrapolation must be confirmed by long-term data when available

8. ICH Q1E Additional Analysis
For each parameter set a regression line with 95% confidence interval

10. ICH Q1E Additional Analysis
Testing if data from all batches can be pooled to determine shelf-life/retest date
Slopes and intercepts for each batch should be the same to be pooles
Analysis of Covariance used
Analysis of Bracketing studies
Assumes stability of the intermediate strengths or sizes is represented by the stability at the extremes.
If the statistical analysis indicates that the stability of the extreme strengths or sizes is different, the intermediate strengths or sizes should be considered no more stable than the least stable extreme.

11. ICHQ1E Additional Analysis
Matrixing
Important to ascertain that all factors and factor combinations that can have an impact on shelf life estimation have been appropriately tested.
Statistical analysis should clearly identify the procedure and assumptions used.
Assumptions underlying the model in which interaction terms are negligible should be stated.
If a preliminary test is performed for the purpose of eliminating factor interactions from the model, the procedure used should be provided and justified.
The final model on which the estimation of shelf life will be based should be stated.
Use of a matrixing design can result in an estimated shelf life shorter than that resulting from a full design.

12. ICH Q5C Stability Testing of Biotechnological/Biologic Products
Applies to well-characterised proteins and polypeptides, their derivatives and products of which they are components, and which are isolated from tissues, body fluids, cell cultures, or produced using rDNA technology.
Does not provide specific data analysis recommendations
Therefore the principles of ICH Q1E should be applied to biotech/biologic drugs

13. Curent WHO Guidance
Annex 2 Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (2009)
Provides limited recommendations for data evaluation that are consistent with ICH Q1E

14. Documentation For Regulatory Submissions

15. Which is Better: This?
RHS
Model Stability QOS

16. And This…
RHS
Model Stability QOS

17. And So On for Page After Page…
RHS
Model Stability QOS

18. Or This?
Figure 1. API degradation rate (%/ 12 mo) vs. change in mean 25°C/60% RH.
RHS
Model Stability QOS

19. And This
Figure 2. API degradation rate (%/ 6 mo) vs. change in mean 40°C/75% RH
RHS
Model Stability QOS

20. And This
Drug Product Degradation Product 25C/60%RH. Results of ICH Q1E analysis. All pkg studied; only worst case shown.
RHS
Model Stability QOS

21. Graphical Presentation of Data
All data presented as points on graphs
Full data tables available if requested
Important convention: Y-axis of data plots scaled to
either the upper bound of the acceptance criteria
or to accommodate the maximum value of the data if it exceeds the acceptance criteria.
Rationale for specifications becomes very clear
RHS
Model Stability QOS

22. How Has This Worked? Regulators have asked for the tables of data
There is an FDA-Industry group working on a data standard for submitting stability results
Some state that they want to do their own analysis of the stability data
In practice this is extremely rare

23. What is Needed Stability data in tables or graphs or both
2nd person verified
Be prepared to submit electronically
Statistical analysis
Justify parameters tested
Validation reports for analytical methods
Conclusions
Retest date for drug substance
Shelf-Life for drug product

24. Immediate Release Solid Orals
Assay
Appearance
Degradants
Dissolution
Moisture

25. Modified Release Dosage Forms
Enteric coated to release in intestine not stomach
Delayed release
Assay
Appearance
Degradants
Dissolution
Moisture

26. Parenteral Products Assay Appearance Preservative Content
Degradation Products
Particulate matter pH

27. Creams, Ointments, and Suppositories
Assay
Appearance
Degradants pH
Resuspendibility for lotions
Viscosity
Particle size
Preservative and Antioxidant Content

28. Non-parenteral Liquids
Assay
Degradants
Preservative Content
Degradation Products
Particulate matter pH