STABILITY TESTING STABILITY TESTING

   Dr. Laila Khairy PhD,Dr. Laila Khairy PhD,Chairman, NODCARChairman, NODCAR

NATIONAL ORGANIZATION FORNATIONAL ORGANIZATION FOR DRUG CONTROL AND RESEARCHDRUG CONTROL AND RESEARCH

PURPOSE OF STABILITY PURPOSE OF STABILITY STUDIESSTUDIES

OBJECTIVEOBJECTIVE TYPE OF TYPE OF STUDYSTUDY

FORFOR

-To select adequate To select adequate formulation & formulation & container closure container closure

AcceleratedAccelerated Development of Development of productproduct

-To determine shelf To determine shelf life and storage life and storage conditionsconditions

Accelerated Accelerated and / or real-and / or real-timetime

Development of Development of product and product and registration dossierregistration dossier

-To substantiate the To substantiate the claimed shelf life claimed shelf life

Real-timeReal-timeRegistration dossierRegistration dossier

-To verify that no To verify that no changes have been changes have been introduced in the introduced in the formulation or formulation or manufacturing manufacturing process.process.

Accelerated and Accelerated and real timereal time

Quality assurance in Quality assurance in general including general including quality control.quality control.

Intended MarketIntended MarketFour climatic zones can be Four climatic zones can be distinguished for the purpose of distinguished for the purpose of worldwide stability testingworldwide stability testing

Climatic Climatic zonezone

TypeType Measured Measured data in open data in open (C (Coo) (RH) (RH

%)%)IITemperate Temperate 10.910.9 757518.7 4518.7 45

18.818.8

IIIISub-tropicSub-tropic17.017.0 707021.121.1 5252

IIIIIIHot / dryHot / dry24.4 3924.4 3926.026.0 5454

IVIVHot / Hot / humidhumid

26.5 7726.5 7728.428.4 7070

Points of Consideration Points of Consideration During A Stability StudyDuring A Stability Study

• Storage Conditions.Storage Conditions.

• Container Closure Container Closure

• Extreme Temperature FluctuationsExtreme Temperature Fluctuations

• Storage TemperaturesStorage Temperatures

• Microbial QualityMicrobial Quality

• Degradation Degradation

• Statistical consideration Statistical consideration

On-going stability studies – WHOOn-going stability studies – WHO

One batch every other year may be One batch every other year may be tested for formulations considered to tested for formulations considered to be stable be stable ( otherwise one batch per year) ( otherwise one batch per year)

One batch every 3 – 5 years may be One batch every 3 – 5 years may be tested for formulations when the tested for formulations when the stability profile has been established stability profile has been established unless a major product change has unless a major product change has been made.been made.

CONTENT OF STABILITY CONTENT OF STABILITY

REPORTSREPORTS A.A. General Product Information.General Product Information.

B.B. Specifications and test methodology.Specifications and test methodology.

C.C. Study Design and Study Conditions.Study Design and Study Conditions.

D.D. Stability Data / Information.Stability Data / Information.

E.E. Analytical MethodsAnalytical Methods

F.F. Data Analysis and Conclusions.Data Analysis and Conclusions.

Before You Start Before You Start

Rugged and robust methods.Rugged and robust methods.

Trained analysts. Trained analysts.

Effective technology transfer. Effective technology transfer.

Qualified equipment and instruments.Qualified equipment and instruments.

Pre-Determined and Written.Pre-Determined and Written.

- Protocol Protocol

- Acceptance Criteria Acceptance Criteria

Pre-validation Assay Pre-validation Assay

Acceptance CriteriaAcceptance Criteria • Assay Characterized for:Assay Characterized for:

– Accuracy Accuracy

- SpecificitySpecificity

- RuggednessRuggedness

- RobustnessRobustness

- Precision and other parameters as appropriatePrecision and other parameters as appropriate

- SST parameters.SST parameters.

• Passes repeated SST SETS Passes repeated SST SETS

Quantitation LimitQuantitation Limit

• Lowest amount of analyte in a samples Lowest amount of analyte in a samples which can be quantitatively determined which can be quantitatively determined with suitablewith suitable - Precision.Precision.

- Accuracy.Accuracy.

• Approaches.Approaches.- Visual evaluation.Visual evaluation.

- By signal to noise ratio (10:1)By signal to noise ratio (10:1)

- Based on SD and slope of response.Based on SD and slope of response.

AccuracyAccuracy

• Closeness to reference value.Closeness to reference value.

• Methods.Methods.

-Assay of reference material.Assay of reference material.

-Comparison of results to reference Comparison of results to reference procedure.procedure.

-Infer from precision, linearity, and Infer from precision, linearity, and specificity data. specificity data.

Specificity for ID TestsSpecificity for ID Tests

• Discrimination may be shown by.Discrimination may be shown by.• ObtainingObtaining

- Positive results from samples containing Positive results from samples containing the analyte.the analyte.

ANDAND

• Negative results from samples not Negative results from samples not containing the analyte.containing the analyte.- Obtaining negative results on materials Obtaining negative results on materials

similar in structure to the analytes.similar in structure to the analytes.

Specificity for Assay Specificity for Assay & Impurity Tests & Impurity Tests

• Spike with impurities and Spike with impurities and demonstrate resolution.demonstrate resolution.- From active From active - From each otherFrom each other

• Spike with degradation product Spike with degradation product standards standards

• Perform peak purity testsPerform peak purity tests- Collection and analysisCollection and analysis- Detection (DAD.MS)Detection (DAD.MS)

Ruggedness and RobustnessRuggedness and Robustness

• Ruggedness: ability of assay to perform.Ruggedness: ability of assay to perform.

- Person to personPerson to person

- Instrument to instrument Instrument to instrument

- Day –to dayDay –to day

• Robustness: capacity to remain unaffectedRobustness: capacity to remain unaffected

- By small, deliberate changes in parametersBy small, deliberate changes in parameters

LinearityLinearity

• Ability to obtain test results which are Ability to obtain test results which are directly proportional to the concentration directly proportional to the concentration of analyte in the sample.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.

Reproducibility Reproducibility

• Expresses precision between Expresses precision between laboratories.laboratories.

• Inter – laboratory trial.Inter – laboratory trial.

• Used for assay standardization.Used for assay standardization.

• Not necessarily part of marketing Not necessarily part of marketing application dossier.application dossier.

RepeatabilityRepeatability ( AKA intra-assay precision)( AKA intra-assay precision)

• Precision underPrecision under

- Same operating conditionsSame operating conditions

- Over a short time intervalOver a short time interval

• MethodsMethods

- 9 determinations (minimum) covering range9 determinations (minimum) covering range

- 6 determinations at 100% test concentration 6 determinations at 100% test concentration

Generally Acceptable Design Generally Acceptable Design

ConsiderationsConsiderations 1.Tablets:1.Tablets: A stability study should include A stability study should include

tests for the following characteristics of tests for the following characteristics of the tablet: Appearance, friability, the tablet: Appearance, friability, hardness, color, odor, moisture, strength, hardness, color, odor, moisture, strength, disintegration and dissolution. disintegration and dissolution.

etc…… capsules …………………………etc…… capsules …………………………

Cli

part

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