1. STABILITY TESTING Dr. Laila Khairy PhD, Chairman, NODCAR NATIONAL ORGANIZATION FOR DRUG CONTROL AND RESEARCH Dr. Laila Khairy PhD, Chairman, NODCAR NATIONAL ORGANIZATION FOR DRUG CONTROL AND RESEARCH

2. PURPOSE OF STABILITY STUDIES FOR TYPE OF STUDY OBJECTIVE Development of product Accelerated - To select adequate formulation & container closure Development of product and registration dossier Accelerated and / or real-time - To determine shelf life and storage conditions Registration dossier Real-time - To substantiate the claimed shelf life Quality assurance in general including quality control. Accelerated and real time - To verify that no changes have been introduced in the formulation or manufacturing process.

3. Intended Market Four climatic zones can be distinguished for the purpose of worldwide stability testing Measured data in open (C o ) (RH%) Type Climatic zone 18.7 45 18.8 10.9 75 TemperateI 21.1 52 17.0 70 Sub-tropicII 26.0 54 24.4 39 Hot / dry III 28.4 70 26.5 77 Hot / humid IV

4. Points of Consideration During A Stability Study Storage Conditions. Storage Conditions. Container Closure Container Closure Extreme Temperature Fluctuations Extreme Temperature Fluctuations Storage Temperatures Storage Temperatures Microbial Quality Microbial Quality Degradation Degradation Statistical consideration Statistical consideration

5. On-going stability studies – WHO  One batch every other year may be tested for formulations considered to be stable ( otherwise one batch per year)  One batch every 3 – 5 years may be tested for formulations when the stability profile has been established unless a major product change has been made.

6. CONTENT OF STABILITY REPORTS A. General Product Information. B. Specifications and test methodology. C. Study Design and Study Conditions. D. Stability Data / Information. E. Analytical Methods F. Data Analysis and Conclusions.

7. Before You Start  Rugged and robust methods.  Trained analysts.  Effective technology transfer.  Qualified equipment and instruments.  Pre-Determined and Written. -Protocol -Acceptance Criteria

8. Pre-validation Assay Acceptance Criteria Assay Characterized for: Assay Characterized for: –Accuracy -Specificity -Ruggedness -Robustness -Precision and other parameters as appropriate -SST parameters. Passes repeated SST SETS Passes repeated SST SETS

9. Quantitation Limit Lowest amount of analyte in a samples which can be quantitatively determined with suitable Lowest amount of analyte in a samples which can be quantitatively determined with suitable - Precision. - Accuracy. Approaches. Approaches. - Visual evaluation. - By signal to noise ratio (10:1) - Based on SD and slope of response.

10. Accuracy Closeness to reference value. Closeness to reference value. Methods. Methods. - Assay of reference material. - Comparison of results to reference procedure. - Infer from precision, linearity, and specificity data.

11. Specificity for ID Tests Discrimination may be shown by. Discrimination may be shown by. Obtaining Obtaining - Positive results from samples containing the analyte. AND Negative results from samples not containing the analyte. Negative results from samples not containing the analyte. - Obtaining negative results on materials similar in structure to the analytes.

12. Specificity for Assay & Impurity Tests Spike with impurities and demonstrate resolution. Spike with impurities and demonstrate resolution. - From active - From each other Spike with degradation product standards Spike with degradation product standards Perform peak purity tests Perform peak purity tests - Collection and analysis - Detection (DAD.MS)

13. Ruggedness and Robustness Ruggedness: ability of assay to perform. Ruggedness: ability of assay to perform. - Person to person - Instrument to instrument - Day – to day Robustness: capacity to remain unaffected Robustness: capacity to remain unaffected - By small, deliberate changes in parameters

14. Linearity Ability to obtain test results which are directly proportional to the concentration of analyte in the sample. Ability to obtain test results which are directly proportional to the concentration of analyte in the sample. Establish across the range (5 conc. Min.). Establish across the range (5 conc. Min.). Dilution or separate weighings. Dilution or separate weighings. Visual inspection of plot. Visual inspection of plot. Statistical analysis of regression line. Statistical analysis of regression line.

15. Reproducibility Expresses precision between laboratories. Expresses precision between laboratories. Inter – laboratory trial. Inter – laboratory trial. Used for assay standardization. Used for assay standardization. Not necessarily part of marketing application dossier. Not necessarily part of marketing application dossier.

16. Repeatability ( AKA intra-assay precision) Precision under Precision under - Same operating conditions - Over a short time interval Methods Methods - 9 determinations (minimum) covering range - 6 determinations at 100% test concentration

17. Generally Acceptable Design Considerations 1.Tablets: A stability study should include tests for the following characteristics of the tablet: Appearance, friability, hardness, color, odor, moisture, strength, disintegration and dissolution. etc …… capsules …………………………

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