stability trials asean guidelines. the objective of a stability study to determine the shelf life,...

Stability TrialsStability Trials

ASEAN GuidelinesASEAN Guidelines

The Objective of a stability The Objective of a stability studystudy

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

DesignDesign

The design should be based on The design should be based on knowledge of the behavior and knowledge of the behavior and properties of the drug substance and properties of the drug substance and dosage form.dosage form.

Photostability testing should be Photostability testing should be conducted on at least one primary conducted on at least one primary batch of the product if appropriate. batch of the product if appropriate. The standard conditions were The standard conditions were described by ICHdescribed by ICH

Selection of BatchesSelection of Batches

For NCE stability data should be For NCE stability data should be provided on at least 3 primary provided on at least 3 primary batches of the drug productsbatches of the drug products

For generic and variations;For generic and variations;- For conventional dosage forms - For conventional dosage forms (immediate release solid and (immediate release solid and solutions), when the drug substances solutions), when the drug substances are known to be stable stabiliy data are known to be stable stabiliy data on at least 2 pilot scale batches are on at least 2 pilot scale batches are acceptableacceptable

Selection of Batches (contd)Selection of Batches (contd)

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

Testing parameterTesting parameter

Stability study should include testing of Stability study should include testing of those attributes of the drug product that those attributes of the drug product that are susceptible to change during storage are susceptible to change during storage and are likely to influence quality, safety and are likely to influence quality, safety and/or efficacy.and/or efficacy.

The testing should cover, the physical, The testing should cover, the physical, chemical, biological and microbiological chemical, biological and microbiological attributes, preservatives content attributes, preservatives content (antioxidant & antimicrobial) and (antioxidant & antimicrobial) and functionality test (dose delivery system)functionality test (dose delivery system)

Testing parameter (contd)Testing parameter (contd)

The analytical procedures should be The analytical procedures should be fully validated and stability fully validated and stability indicating according to ASEAN indicating according to ASEAN guideline on Analytical validation.guideline on Analytical validation.

1.1. TabletTabletShould be evaluated for Should be evaluated for appearance, odor, color, assay, appearance, odor, color, assay, degradation products, dissolution, degradation products, dissolution, moisture and hardness/friabilitymoisture and hardness/friability


2. Capsules2. Capsules

Hard gelatin capsules: appearance (incl Hard gelatin capsules: appearance (incl brittleness), odor, color, assay, brittleness), odor, color, assay, degradation products, dissolution, mosture degradation products, dissolution, mosture and microbial content.and microbial content.

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


3. Emulsions : 3. Emulsions :

Appearance (incl. phase separation), Appearance (incl. phase separation), color, odor, assay, degradation color, odor, assay, degradation products, pH, viscosity, microbial products, pH, viscosity, microbial limits, preservative content, and limits, preservative content, and mean size and distribution of mean size and distribution of dispersed globulesdispersed globules


4. Oral solutions and Suspensions4. Oral solutions and SuspensionsAppearance (incl. formation of precipitate, Appearance (incl. formation of precipitate, clarity for solutions), color, odor, assay, clarity for solutions), color, odor, assay, degradation products, pH, viscosity, degradation products, pH, viscosity, preservative content and microbial limits.preservative content and microbial limits.Additional for suspensions: redispersibility, Additional for suspensions: redispersibility, rheological properties, mean size and rheological properties, mean size and distrib of particles. After storage sample of distrib of particles. After storage sample of suspensions should be prepared for assay suspensions should be prepared for assay according to the recommended labelling according to the recommended labelling (shake well before using).(shake well before using).


5. Oral powders for reconstitution5. Oral powders for reconstitution

Oral powders: appearance, color, Oral powders: appearance, color, odor, assay, degradation products, odor, assay, degradation products, moisture and reconstitution time.moisture and reconstitution time.

Reconstituted products Reconstituted products (suspensions): as described in oral (suspensions): as described in oral solutions and suspensions above, solutions and suspensions above, after preparationafter preparation


6. Metered dose inhalations and Nasal aerosols6. Metered dose inhalations and Nasal aerosols

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


7. Nasal Sprays: Solutions and Suspensions7. Nasal Sprays: Solutions and SuspensionsAppearance, color, clarity for solution, Appearance, color, clarity for solution, assay, degrad. Products, preservative and assay, degrad. Products, preservative and antioxidant content, microbial limits, pH, antioxidant content, microbial limits, pH, particulate matter, unit spray medication particulate matter, unit spray medication content uniformity, number of actuations content uniformity, number of actuations meeting unit spray content uniformity per meeting unit spray content uniformity per container, droplet and/or particle size container, droplet and/or particle size distrib., weight loss, pump delivery, distrib., weight loss, pump delivery, microscopic evaluation, foreign particulate microscopic evaluation, foreign particulate matter, bleachable form plastic and closure matter, bleachable form plastic and closure & pump.& pump.


8. Topical, Ophtalmic and Otic preparations8. Topical, Ophtalmic and Otic preparations(included ointments, cream, lotions, paste, (included ointments, cream, lotions, paste, gel, solutions and non-metered aerosols gel, solutions and non-metered aerosols for application to the skin)for application to the skin)Topical prep: appearance, clarity, color, Topical prep: appearance, clarity, color, homogenity, odor, pH, resuspendability homogenity, odor, pH, resuspendability (for lotions), consistency, viscosity, (for lotions), consistency, viscosity, particle size distrib, assay, degrag. particle size distrib, assay, degrag. Products, preservative and antioxidant Products, preservative and antioxidant content, microbial limits/sterility and content, microbial limits/sterility and weight lossweight loss


Ophtalmic or otic products: Ophtalmic or otic products: additionally sterility, particulate additionally sterility, particulate matter and extractablematter and extractable

Non-metered topical aerosols: Non-metered topical aerosols: appearance, assay, degrad. Products, appearance, assay, degrad. Products, pressure, weight loss, net weight pressure, weight loss, net weight dispensed, delivery rate, microbial dispensed, delivery rate, microbial limits, spray pattern, water content, limits, spray pattern, water content, and particle size distrib.and particle size distrib.


9. Suppositories9. Suppositories

- appearance, color, assay, - appearance, color, assay, degradation products, particle size, degradation products, particle size, softening range, dissolution (at 37softening range, dissolution (at 37ooC) C) and microbial limits.and microbial limits.


10. Small Volume Parenterals (SVPs)10. Small Volume Parenterals (SVPs)

appearance, clarity, color, assay, appearance, clarity, color, assay, preservative content (if present), preservative content (if present), degradation products, particulate degradation products, particulate matter, pH, sterility and matter, pH, sterility and pyrogen/endotoxin.pyrogen/endotoxin.

(additional for injectable (additional for injectable suspension/emulsion as in suspension/emulsion as in suspension/emulsion)suspension/emulsion)


11. Large Volume Parenterals (LVPs)11. Large Volume Parenterals (LVPs)

appearance, color, assay, appearance, color, assay, preservative content (if present), preservative content (if present), degradation products, particulate degradation products, particulate matter, pH, sterility, matter, pH, sterility, pyrogen/endotoxin, clarity and pyrogen/endotoxin, clarity and volumevolume


12. Drug Admixture12. Drug Admixtureshould be evaluated for stability and should be evaluated for stability and compatibility in admixture with the other compatibility in admixture with the other drug products or with dilents, both in drug products or with dilents, both in upright and in inverted orrientations.upright and in inverted orrientations.A stability protocols should be conducted A stability protocols should be conducted at 0-, 6- to 8- and 24 hour time points. at 0-, 6- to 8- and 24 hour time points. Tests include appearance, color, clarity, Tests include appearance, color, clarity, assay, degradation products, pH, assay, degradation products, pH, particulate matter, interaction w/ particulate matter, interaction w/ container, sterility.container, sterility.


13. Transdermal Patches13. Transdermal Patches

appearance, assay, degradation appearance, assay, degradation products, in-vitro release rates, products, in-vitro release rates, leakage, sterility, peel and adhesive leakage, sterility, peel and adhesive forces, and the drug release ratesforces, and the drug release rates


14. Freeze-dried Products14. Freeze-dried Products

appearance for both freeze-dried and appearance for both freeze-dried and its reconstituted products, pH, water its reconstituted products, pH, water content and rate of solution.content and rate of solution.

Testing FrequencyTesting Frequency

Storage Storage ConditionCondition

ProductsProducts Testing Testing FrequencyFrequency

Real TimeReal Time NCE, NCE, Generics, and Generics, and variationsvariations

0, 3, 6, 9, 12, 18, 24 0, 3, 6, 9, 12, 18, 24 months and annually months and annually through the proposed through the proposed shelf-lifeshelf-life

AcceleratedAccelerated NCE, NCE, Generics, and Generics, and variationsvariations

0, 3 and 6 0, 3 and 6 monthsmonths

Alternatives Alternatives to accelerated to accelerated studystudy

NCE, NCE, Generics, and Generics, and variationsvariations

0, 1 and 3 0, 1 and 3 monthsmonths

Storage ConditionStorage Condition

Type of Type of container/studycontainer/study

Storage ConditionStorage Condition

Products in primary containers Products in primary containers permeable to water vapourpermeable to water vapour

3030ooC C ++ 2 2ooC/75% RH C/75% RH ++ 5% RH5% RH

Products in primary containers Products in primary containers impermeable to water vapourimpermeable to water vapour

3030ooC C ++ 2 2ooC/RH not C/RH not specified specified

Accelerated studiesAccelerated studies 4040ooC C ++ 2 2ooC/75% RH C/75% RH ++ 5% RH 5% RH

Stress studiesStress studies 4040ooC C ++ 2 2ooC/75% RH C/75% RH ++ 5% RH5% RH

For NCE Drug ProductsFor NCE Drug Products

StudyStudy Storage Storage ConditionCondition

Minimum time Minimum time period period covered by covered by data at data at submissionsubmission

Number Number of of BatchesBatches

Real TimeReal Time 3030ooC C ++ 22ooC/75% RH C/75% RH ++ 5% RH 5% RH

12 12 monthsmonths

Min. 3Min. 3

AcceleratAccelerateded

4040ooC C ++ 22ooC/75% RH C/75% RH ++ 5% RH 5% RH

6 months6 months Min. 3Min. 3

For generics and variation For generics and variation productsproducts




Real TimeReal Time 3030ooC C ++ 22ooC/75% RH C/75% RH ++ 5% RH 5% RH

12 12 monthsmonths

12 12 monthsmonths

Min.2 for Min.2 for conventional & conventional & stable drug stable drug subssubs

Min 3 for critical Min 3 for critical dosage form or dosage form or unstable drug sunstable drug s



6 months6 months Min 2Min 2

Drug Products Intended for storage in a Drug Products Intended for storage in a refrigeratorrefrigerator




Real TimeReal Time 55ooC C ++ 3 3ooCC 12 12 monthsmonths

Min. 3Min. 3



6 months6 months Min. 3Min. 3

Drug Products Intended for storage in Drug Products Intended for storage in a Freezera Freezer



Real TimeReal Time -20-20ooC C ++ 5 5ooCC 12 months12 months

stability trials asean guidelines. the objective of a stability study to determine the shelf life,...

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