Stability Trials ASEAN Guidelines

The Objective of a stability study To determine the shelf life, namely the time period of storage at a specified condition within which the drug product still meets its established specifications To determine the shelf life, namely the time period of storage at a specified condition within which the drug product still meets its established specifications

Design The design should be based on knowledge of the behavior and properties of the drug substance and dosage form. The design should be based on knowledge of the behavior and properties of the drug substance and dosage form. Photostability testing should be conducted on at least one primary batch of the product if appropriate. The standard conditions were described by ICH Photostability testing should be conducted on at least one primary batch of the product if appropriate. The standard conditions were described by ICH

Selection of Batches For NCE stability data should be provided on at least 3 primary batches of the drug products For NCE stability data should be provided on at least 3 primary batches of the drug products For generic and variations; For generic and variations; - For conventional dosage forms (immediate release solid and solutions), when the drug substances are known to be stable stabiliy data on at least 2 pilot scale batches are acceptable

Selection of Batches (contd) - For critical dosage forms (prolonged release forms) or when the drug substances are known to be unstable, stability data on 3 primary batches are to be provided. Two or 3 batches should be at least of a pilot scale; the third batch may be smaller

Testing parameter Stability study should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. Stability study should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. The testing should cover, the physical, chemical, biological and microbiological attributes, preservatives content (antioxidant & antimicrobial) and functionality test (dose delivery system) The testing should cover, the physical, chemical, biological and microbiological attributes, preservatives content (antioxidant & antimicrobial) and functionality test (dose delivery system)

Testing parameter (contd) The analytical procedures should be fully validated and stability indicating according to ASEAN guideline on Analytical validation. The analytical procedures should be fully validated and stability indicating according to ASEAN guideline on Analytical validation. 1. Tablet Should be evaluated for appearance, odor, color, assay, degradation products, dissolution, moisture and hardness/friability

Testing parameter (contd) 2. Capsules Hard gelatin capsules: appearance (incl brittleness), odor, color, assay, degradation products, dissolution, mosture and microbial content. Soft gelatin capsules: appearance (incl brittleness), odor, color, assay, degradation products, dissolution, mosture and microbial content, pH, leakage, and pellicle formation.

Testing parameter (contd) 3. Emulsions : Appearance (incl. phase separation), color, odor, assay, degradation products, pH, viscosity, microbial limits, preservative content, and mean size and distribution of dispersed globules

Testing parameter (contd) 4. Oral solutions and Suspensions Appearance (incl. formation of precipitate, clarity for solutions), color, odor, assay, degradation products, pH, viscosity, preservative content and microbial limits. Additional for suspensions: redispersibility, rheological properties, mean size and distrib of particles. After storage sample of suspensions should be prepared for assay according to the recommended labelling (shake well before using).

Testing parameter (contd) 5. Oral powders for reconstitution Oral powders: appearance, color, odor, assay, degradation products, moisture and reconstitution time. Reconstituted products (suspensions): as described in oral solutions and suspensions above, after preparation

Testing parameter (contd) 6. Metered dose inhalations and Nasal aerosols Appearance (content, container, valve), color, taste, assay, degrad. Products, assay for cosolvent, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distrib., microscopic evaluation, water content, leak rate, microbial limits, valve delivery, and extractable/leachables from plastic and elastomeric components

Testing parameter (contd) 7. Nasal Sprays: Solutions and Suspensions Appearance, color, clarity for solution, assay, degrad. Products, preservative and antioxidant content, microbial limits, pH, particulate matter, unit spray medication content uniformity, number of actuations meeting unit spray content uniformity per container, droplet and/or particle size distrib., weight loss, pump delivery, microscopic evaluation, foreign particulate matter, bleachable form plastic and closure & pump.

Testing parameter (contd) 8. Topical, Ophtalmic and Otic preparations (included ointments, cream, lotions, paste, gel, solutions and non-metered aerosols for application to the skin) Topical prep: appearance, clarity, color, homogenity, odor, pH, resuspendability (for lotions), consistency, viscosity, particle size distrib, assay, degrag. Products, preservative and antioxidant content, microbial limits/sterility and weight loss

Testing parameter (contd) Ophtalmic or otic products: additionally sterility, particulate matter and extractable Non-metered topical aerosols: appearance, assay, degrad. Products, pressure, weight loss, net weight dispensed, delivery rate, microbial limits, spray pattern, water content, and particle size distrib.

Testing parameter (contd) 9. Suppositories - appearance, color, assay, degradation products, particle size, softening range, dissolution (at 37 o C) and microbial limits.

Testing parameter (contd) 10. Small Volume Parenterals (SVPs) appearance, clarity, color, assay, preservative content (if present), degradation products, particulate matter, pH, sterility and pyrogen/endotoxin. (additional for injectable suspension/emulsion as in suspension/emulsion)

Testing parameter (contd) 11. Large Volume Parenterals (LVPs) appearance, color, assay, preservative content (if present), degradation products, particulate matter, pH, sterility, pyrogen/endotoxin, clarity and volume

Testing parameter (contd) 12. Drug Admixture should be evaluated for stability and compatibility in admixture with the other drug products or with dilents, both in upright and in inverted orrientations. A stability protocols should be conducted at 0-, 6- to 8- and 24 hour time points. Tests include appearance, color, clarity, assay, degradation products, pH, particulate matter, interaction w/ container, sterility.

Testing parameter (contd) 13. Transdermal Patches appearance, assay, degradation products, in-vitro release rates, leakage, sterility, peel and adhesive forces, and the drug release rates

Testing parameter (contd) 14. Freeze-dried Products appearance for both freeze-dried and its reconstituted products, pH, water content and rate of solution.

Testing Frequency Storage Condition Products Testing Frequency Real Time NCE, Generics, and variations 0, 3, 6, 9, 12, 18, 24 months and annually through the proposed shelf-life Accelerated NCE, Generics, and variations 0, 3 and 6 months Alternatives to accelerated study NCE, Generics, and variations 0, 1 and 3 months

Storage Condition Type of container/study Storage Condition Products in primary containers permeable to water vapour 30 o C + 2 o C/75% RH + 5% RH Products in primary containers impermeable to water vapour 30 o C + 2 o C/RH not specified Accelerated studies 40 o C + 2 o C/75% RH + 5% RH Stress studies 40 o C + 2 o C/75% RH + 5% RH

For NCE Drug Products Study Storage Condition Minimum time period covered by data at submission Number of Batches Real Time 30 o C + 2 o C/75% RH + 5% RH 12 months Min. 3 Accelerated 40 o C + 2 o C/75% RH + 5% RH 6 months Min. 3

For generics and variation products Study Storage Condition Minimum time period covered by data at submission Number of Batches Real Time 30 o C + 2 o C/75% RH + 5% RH 12 months Min.2 for conventional & stable drug subs Min 3 for critical dosage form or unstable drug s Accelerated 40 o C + 2 o C/75% RH + 5% RH 6 months Min 2

Drug Products Intended for storage in a refrigerator Study Storage Condition Minimum time period covered by data at submission Number of Batches Real Time 5 o C + 3 o C 12 months Min. 3 Accelerated 25 o C + 2 o C/60% RH + 5% RH 6 months Min. 3

Drug Products Intended for storage in a Freezer Study Storage Condition Minimum time period covered by data at submission Real Time -20 o C + 5 o C 12 months