Impurity guidance Table FDA

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    3.2.S DRUG SUBSTANCE

    3.2.S.3 Characterization

    All potential impurities should be listed in a tabular format as given below

    Listing of Potential Impurities

    IUPAC

    Chemical Name

    Code # Chemical

    Structure

    Process

    /Degradation

    Impurity

    Source/mechanism

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    Section 2.3.S.4.5- Justification of Specifications

    In addition to other tests, controls for drug substance should include specifications for specifiedidentified specified unidentified, unspecified, and total impurities.

    Please refer to theGuidance for Industry ANDAs: Impurities in Drug Substances

    Specified Identified Impurities:

    Justification for the acceptance criteria (AC) for all specified identified impurities along with

    identification threshold (IT) and qualification threshold (QT) should be provided in a tabular

    format as given below:

    Chemical

    Name*

    Code

    #

    MDD IT QT TDI of

    Impurity

    Proposed

    AC for

    Unspecified

    Impurities

    Proposed AC

    for Specified

    Impurities

    Justification if

    AC >QT for

    Specified

    Impurities**

    *If applicable**Reference the section if supportive data is provided for justification. This justification may

    include the following types of data and should be included directly in the application (not byreference to DMF)

    1. The observed level and proposed acceptance criterion for the impurity do not exceed the level

    observed in the reference listed drug product.

    2. The impurity is a significant metabolite of the drug substance.

    3 The observed level and the proposed acceptance criterion for the impurity are adequatelyjustified by the scientific literature.

    4. The observed level and proposed acceptance criterion for the impurity do not exceed the levelthat has been adequately evaluated in toxicity studies.

    If drug substance has a USP monograph that contains acceptance criteria forspecified impurities, then all USP monograph impurities along with other

    potential impurities should be listed in drug substance impurities specifications.

    Specified Unidentified Impurities: These should be listed by relative retention times and

    acceptance criteria for these impurities should not be more than IT or higher level should be

    qualified by comparison with RLD.

    Unspecified Impurities: Acceptance criteria for these impurities should not be more than IT.

    IT and QT should be based on maximum daily dose (MDD) of the drug and total daily intake ofimpurities. These thresholds should be reported as percentage and percentages must be based on

    lower total daily intake (TDI) of impurities per ICH guidance tables for all impurities.

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    3.2.P DRUG PRODUCT

    3.2.P.5.5 Characterization of Impurities

    All potential degradation products should be listed in a tabular format as given below

    Listing of Potential Degradation Products

    IUPAC

    Chemical Name

    Code # Chemical

    Structure

    Degradation

    product

    Source/mechanism

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    Section 3.2.P.5.6- Justification of Specifications

    In addition to other tests, controls for drug product should include specifications for specifiedidentified, specified unidentified, unspecified and total degradation products.

    Please refer to the Guidance for Industry ANDAs: Impurities in Drug Products

    Specified Degradation Products (Shelf Life)Justification for the acceptance criteria (AC) for all specified degradation products along with

    identification threshold (IT) and qualification threshold (QT) should be provided in a tabularformat as given below.

    Chemical

    Name*

    Code

    #

    MDD IT QT TDI of

    Degradation

    Product

    Proposed

    AC for

    UnspecifiedDegradation

    Product

    Proposed

    AC for

    SpecifiedDegradation

    Product

    Justification if

    AC >QT for

    SpecifiedDegradation

    Product**

    *If applicable**Reference the section if supportive data is provided for justification. This justification may

    include the following types of data and should be included directly in the application

    1. The observed level and proposed acceptance criterion for the degradation product do not exceed

    the level observed in the reference listed drug product.

    2. The degradation product is a significant metabolite of the drug substance.

    3. The observed level and the proposed acceptance criterion for the degradation product are

    adequately justified by the scientific literature.4. The observed level and proposed acceptance criterion for the degradation product do not exceedthe level that has been adequately evaluated in toxicity studies.

    If drug product has a USP monograph that contains acceptance criteria for specified impurities,

    then all USP monograph impurities along with other potential degradation products should be

    listed in drug product degradation product specifications.Process impurities should not be included in the specifications.

    Specified Unknown Degradation Products: These should be listed by relative retention timesand acceptance criteria for these degradation products should not be more than IT or higher level

    should be qualified by comparison with RLD.

    Unspecified Degradation Products: Acceptance criteria for these should not be more than IT.

    IT and QT thresholds should be reported as percentage and percentages must be based on lower

    TDI of degradation products per ICH guidance tables for all degradation products.


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