Stability – Regulatory Requirements

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  • J. B. Chemicals & Pharmaceuticals Ltd.

    www.jbcpl.com Copyright 2005 J. B. Chemicals Pvt. Ltd.

    Stability Regulatory Requirements

    Dr. Milind JoshiPresident - Global Regulatory Management

  • Stability requirements in Drug Substances / Drug Products for Submission to Regulated / Unregulated Markets

    J. B. Chemicals & Pharmaceuticals Ltd.www.jbcpl.com. Copyright 2005 J. B. Chemicals Pvt. Ltd.

    Semi

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    Stability Retest Period / Shelf Life

    Minimum Period till when the product Is safe to useRetains its qualityRetains its efficacy

    For chemicals retest period For formulations shelf life (no reprocessing)

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    STABILITY CONSIDERATIONS IN DISPENSING PRACTICE

    Criteria for Acceptable Levels of Stability

    No significant increase in toxicity occurs.Toxicological

    The therapeutic effect remains unchanged.Therapeutic

    Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.

    Microbiological

    The original physical properties,includingappearance, palatability, uniformity, dissolution and suspendability are retained.

    Physical

    Each active ingredient retains its chemical integrity and labeled potency, within the specified limits.

    Chemical

    Conditions Maintained Throughout the Shelf Life of the Drug Product

    Type of Stability

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    Stability Requirements - Proof

    Stability data To prove the quality of the product till expiry Evaluation of quality of

    product under extreme conditions for definite timeproduct under normal conditions for life timeproduct under intermediate conditions for definite timeproduct under particular conditions plausible for

    definite time

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    Stability and Storage

    Primary packagingFactors affecting integrity of Primary PackagingFactors affecting packaged formulations

    Storage conditions Environmental factorsStorage condition requirements

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    Storage & Environment Regional Aspects

    Different environmental conditions in different part of the globeEffect on primary packaging will be differentDiscussions, Consensus, Differences of OpinionsGlobal stability requirements harmonisation ?Zones and sub-zones ICH + WHO

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    30C / 75% RH> 22C / > 27 hPaHot and veryhumid climate

    IVB

    30C / 65% RH> 22C / > 15 to 27 hPaHot and humid climate

    IVA

    30C / 35% RH> 22C / 15 hPaHot and dryclimate

    III

    25C / 60% RH> 15 to 22C / > 11 to 18 hPaSubtropicaland Mediterranean Climate

    II

    21C / 45% RH 15C / 11 hPaTemperateclimate

    I

    Long-term Testingconditions

    CriteriaMean annual temperature/ Mean annual partial waterVapour Pressure

    DefinitionCZ

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    Analysis and Stability Data

    Sampling pointsMatrixing and Reduced TestingDuration of Stability StudyExtrapolation of DataTrend AnalysisDetermination of Shelf Life / Re-test PeriodStability Commitment

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    Stability Guidance

    WHOICH

    USAEUJapan

    BrazilASEAN

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    ICH

    Exhaustive guidanceJoint group of with the help of and three regulatory bodies USA, EU, JapanGuidance for Drug Substance and Drug ProductGuidance for dosage forms, package style (permiable / semi-permiable-non-permiable, transparent / light resistant)Stress testingDuration of studySampling pointsMatrixing and bracketing (reduced testing)

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    ICH

    ProtocolSpecificationReporting styleTabular summaryData compilationStatistics and derivationShelf life / re-test periodStability commitment

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    USA

    Exhibit batch stability data as per ICH guidanceAccelerated API 6 M / Formulation 3 MIntermediate API 6 M / Formulation 3 MLong Term API 6 M / Formulation 3 MStability CommitmentStability of Validation BatchesAnnual Stability Commitment

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    EU

    Stability data for 3 batches (2+1)As per ICH guidanceAccelerated Formulation 6 M Intermediate Formulation 6 MLong Term Formulation 6 MStability CommitmentStability of Validation BatchesPackaging Validation / StabilityAnnual Stability CommitmentIndividual country requirements ?

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    JAPAN

    Follows ICH guidanceUsed to require stability data on three batches right before submission for approvalLanguage and cultural barrier

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    JAPAN

    International Stability Testing David J Mazzo

    Matrixing and Bracketing general case

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    BRAZIL

    Many sub-conditions are present (e.g. weigh-loss calculation of semi-solid at 75% RH)

    5C 3C25C 2C / 60 % RH 5% RH

    Semi-permeable

    2C - 8C

    5C 3C25C 2CImpermeable2C - 8CAll Dosage Forms

    30C 2C40C 2CImpermeable15C - 30CGases

    30C 2C40C 2CImpermeable15C - 30CFluids

    30C 2C / 75% RH 5% RH

    40C 2C / 75% RH 5% RH

    Semi-permeable

    15C - 30C

    30C 2C40C 2CImpermeable15C - 30C

    30C 2C / 75% RH 5% RH

    40C 2C / 75% RH 5% RH

    Semi-permeable

    15C - 30CSemi-solid

    30C 2C40C 2CImpermeable15C - 30C

    30C 2C / 75% RH 5% RH

    40C 2C / 75% RH 5% RH

    Semi-permeable

    15C - 30CSolidLong-Term Accelerated

    Temperature and Humidity criteria PackagingStorage Conditions

    Dosage Form

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    ASEAN

    Exhaustive as ICHAll points as in ICH coveredStorage conditions differentData on minimum 2 batches (for standard products)3 batches for NCE, modified dosage forms, unstable APIsFormats for Protocol, Report, Summary etcBracketing :

    T

    T

    1

    100 mg

    3

    T

    T

    3 1

    75 mg

    2

    T

    T

    2

    TTT500

    100

    TTT15Container size(ml)

    321Batch

    50 mgStrength

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    INDIA

    Schedule MPoint 16.10 -The Quality Control Department shall conduct stability studies of the products to ensure and assign their shelf-life at the prescribed conditions of storage. All records of such studies shall be maintained.

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    Case Study - Srilanka

    Co-relation of labeling and stability dataData at temperature condition of 25C unacceptable for label stating Store below 30CLong time stability study at 30C

    Case Study - Sudan

    Temperature conditions requirement 50 C

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    Stability Specifications

    Some countries insist on some specific tests to be included in the Stability SpecificationHardnessPreservative efficacyMicrobial Purity

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    Labeling

    Store in dry conditionHighly hygroscopic pharmaceutical products

    Store & transport always below 30CPharmaceutical products that cannot tolerate excessive heat, e.g. suppositories

    Protect from lightLight-sensitive pharmaceutical products

    Do not freezePharmaceutical products that cannot tolerate freezing

    Do not refrigerate or freezePharmaceutical products that cannot tolerate refrigerating

    Additional labeling statement, where relevant

    Limiting factors

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    Stability and Packaging

    USA HDPE BottlesEU Blisters / HDPE BottlesIndia No bottles

    Primary / Secondary PackagingInjectableSpecial PackagingSilica Gel

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    Stability - Various

    Shipping StabilityHold Time Study

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    DRUG PRODUCT STABILITY TESTING SYSTEM MAJOR FACTORS PLANNING OF STABILITY TESTING

    Laboratory batches Stress stability Accelerated stability Long-term stability

    Primary batches three (3) batches Accelerated stability Long-term stability Intermediate stability

    Validated test

    methodsProduction batches First three (3) batches According to application for MA

    Guidelines

    Stability protocol

    Storage conditions for samples

    Bracketing Matrixing

    Evaluation of results

    Products on the market One (1) batch each year Follow-up stability Intermediates three (3) batches

    Change control procedure

    In case of variation

    Individual requirements

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    Thank you !!!milind@jbcpl.com

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