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`Guidance for Industry
`Q3A Impurities in New Drug
`Substances
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`June 2008
`ICH
`
`Revision 2
`
`Azurity Pharmaceuticals, Inc. EXHIBIT - 1033
`
`

`

`Guidance for Industry
`Q3A Impurities in New Drug
`Substances
`
`
`
`
`
`Additional copies are available from:
`
`Office of Training and Communication
`Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10903 New Hampshire Ave.
`Bldg. 51, Room 2201
`Silver Spring, MD 20993-0002
` (Tel) 301-796-3400
` http://www.fda.gov/cder/guidance/index.htm
`
`and/or
`
` Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
` http://www.fda.gov/cber/guidelines.htm.
`Fax: 1-888-CBERFAX or 301-827-3844
` (Tel) 800-835-4709 or 301-827-1800
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`June 2008
`ICH
`
`Revision 2
`
`
`
`
`
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`
`
`
`INTRODUCTION (1)....................................................................................................... 1
`I.
`CLASSIFICATION OF IMPURITIES (2)..................................................................... 2
`II.
`III. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES (3).... 3
`A. Organic Impurities (3.1)................................................................................................................3
`B.
`Inorganic Impurities (3.2) .............................................................................................................3
`C. Solvents (3.3)...................................................................................................................................4
`IV. ANALYTICAL PROCEDURES (4)................................................................................ 4
`V.
`REPORTING IMPURITY CONTENT OF BATCHES (5).......................................... 4
`VI.
`LISTING OF IMPURITIES IN SPECIFICATIONS (6) .............................................. 5
`VII. QUALIFICATION OF IMPURITIES (7)...................................................................... 6
`GLOSSARY................................................................................................................................... 9
`ATTACHMENT 1: THRESHOLDS........................................................................................ 11
`ATTACHMENT 2: ILLUSTRATION OF REPORTING IMPURITY RESULTS FOR
`
`IDENTIFICATION AND QUALIFICATION IN AN APPLICATION ................... 12
`ATTACHMENT 3: DECISION TREE FOR IDENTIFICATION
`
`AND QUALIFICATION................................................................................................ 13
`
`
`
`

`

`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`Q3A Impurities in New Drug Substances
`
`
`
`
`
`
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.
`It does not create or confer any rights for or on any person and does not operate to bind FDA or the
`public. An alternative approach may be used if such approach satisfies the requirements of the
`applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
`staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
`the appropriate number listed on the title page of this guidance.
`
`
`INTRODUCTION (1)
`
`
`
`
`I.
`
`This document is intended to provide guidance for registration applications on the content and
`qualification of impurities in new drug substances produced by chemical syntheses and not
`previously registered in a region or member state. Impurities in new drug substances are
`addressed from two perspectives:
`
` •
`
` Chemistry aspects include classification and identification of impurities, report generation,
`listing of impurities in specifications, and a brief discussion of analytical procedures
`
`• Safety aspects include specific guidance for qualifying those impurities that were not present,
`or were present at substantially lower levels, in batches of a new drug substance used in
`safety and clinical studies.
`
`
`This is the second revision of the Q3A guidance, which was published in 1996 and revised in
`2003. In revision 2, Attachment 2 is retitled “Illustration of Reporting Impurity Results for
`Identification and Qualification in an Application” and includes clarifying information and an
`additional example.
`
`
`
`1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
`subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been
`endorsed by the ICH Steering Committee at Step 4 of the ICH process (October 2006). At Step 4 of the process, the
`final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United
`States.
`
`Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at
`Step 4 of the ICH process, October 2006.
`
`
`
`1
`
`

`

`Contains Nonbinding Recommendations
`
`
`This guidance is not intended to apply to new drug substances used during the clinical research
`stage of development. The following types of drug substances are not covered in this guidance:
`
`
`• biological/biotechnological
`• peptide
`• oligonucleotide
`•
`radiopharmaceutical
`•
`fermentation products and semisynthetic products derived therefrom
`• herbal products
`• crude products of animal or plant origin
`
`CLASSIFICATION OF IMPURITIES (2)
`
`
`
`II.
`
`Impurities can be classified into the following categories:
`
`
`• Organic impurities (process- and drug-related)
`•
`Inorganic impurities
`• Residual solvents
`
`
`Organic impurities can arise during the manufacturing process and/or storage of the new drug
`substance. They can be identified or unidentified, volatile or nonvolatile, and include:
`
`
`• Starting materials
`• By-products
`•
`Intermediates
`• Degradation products
`• Reagents, ligands, and catalysts
`
`
`Inorganic impurities can result from the manufacturing process. They are normally known and
`identified and include:
`
`
`• Reagents, ligands and catalysts
`• Heavy metals or other residual metals
`•
`Inorganic salts
`• Other materials (e.g., filter aids, charcoal)
`
`
`Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or
`suspensions in the synthesis of a new drug substance. Since these are generally of known
`toxicity, the selection of appropriate controls is easily accomplished (see ICH Q3C on Residual
`Solvents).
`
`Excluded from this document are: (1) extraneous contaminants that should not occur in new drug
`substances and are more appropriately addressed as good manufacturing practice (GMP) issues,
`(2) polymorphic forms, and (3) enantiomeric impurities.
`
`
`
`2
`
`

`

`Contains Nonbinding Recommendations
`
`
`
`
`III. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES (3)
`
`
`Organic Impurities (3.1)
`
`A.
`
`The applicant should summarize the actual and potential impurities most likely to arise during
`the synthesis, purification, and storage of a new drug substance. This summary should be based
`on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities
`associated with raw materials that could contribute to the impurity profile of the new drug
`substance, and possible degradation products. This discussion can be limited to those impurities
`that might reasonably be expected based on knowledge of the chemical reactions and conditions
`involved.
`
`In addition, the applicant should summarize the laboratory studies conducted to detect impurities
`in the new drug substance. This summary should include test results of batches manufactured
`during the development process and batches from the proposed commercial process, as well as
`the results of stress testing (see ICH Q1A(R) on stability) used to identify potential impurities
`arising during storage. The impurity profile of the drug substance batches intended for marketing
`should be compared with those used in development, and any differences discussed.
`
`The studies conducted to characterize the structure of actual impurities present in a new drug
`substance at a level greater than (>) the identification threshold given in Attachment 1 (e.g.,
`calculated using the response factor of the drug substance) should be described. Note that any
`impurity at a level greater than (>) the identification threshold in any batch manufactured by the
`proposed commercial process should be identified. In addition, any degradation product
`observed in stability studies at recommended storage conditions at a level greater than (>) the
`identification threshold should be identified. When identification of an impurity is not feasible, a
`summary of the laboratory studies demonstrating the unsuccessful effort should be included in
`the application. Where attempts have been made to identify impurities present at levels of not
`more than (≤) the identification thresholds, it is useful also to report the results of these studies.
`
`Identification of impurities present at an apparent level of not more than (≤) the identification
`threshold is generally not considered necessary. However, analytical procedures should be
`developed for those potential impurities that are expected to be unusually potent, producing toxic
`or pharmacological effects at a level not more than (≤) the identification threshold. All impurities
`should be qualified as described later in this guidance.
`
`
`Inorganic Impurities (3.2)
`
`B.
`
`Inorganic impurities are normally detected and quantified using pharmacopoeial or other
`appropriate procedures. Carry-over of catalysts to a new drug substance should be evaluated
`during development. The need for inclusion or exclusion of inorganic impurities in a new drug
`substance specification should be discussed. Acceptance criteria should be based on
`pharmacopoeial standards or known safety data.
`
`
`
`3
`
`

`

`
`
`
`Contains Nonbinding Recommendations
`
`C.
`
`Solvents (3.3)
`
`
`The control of residues of the solvents used in the manufacturing process for a new drug
`substance should be discussed and presented according to ICH Q3C Impurities: Residual
`Solvents.
`
`
`IV. ANALYTICAL PROCEDURES (4)
`
` A
`
` registration application should include documented evidence that the analytical procedures are
`validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B
`on analytical validation). Technical factors (e.g., manufacturing capability and control
`methodology) can be considered as part of the justification for selection of alternative thresholds
`based on manufacturing experience with the proposed commercial process. The use of two
`decimal places for thresholds (see Attachment 1) does not necessarily reflect the precision of the
`analytical procedure used for routine quality control purposes. Thus, the use of lower precision
`techniques (e.g., thin-layer chromatography) can be appropriate where justified and
`appropriately validated. Differences in the analytical procedures used during development and
`those proposed for the commercial product should be discussed in the registration application.
`The quantitation limit for the analytical procedure should be not more than (≤) the reporting
`threshold.
`
`Organic impurity levels can be measured by a variety of techniques, including those that
`compare an analytical response for an impurity to that of an appropriate reference standard or to
`the response of the new drug substance itself. Reference standards used in the analytical
`procedures for control of impurities should be evaluated and characterized according to their
`intended uses. The drug substance can be used as a standard to estimate the levels of impurities.
`In cases where the response factors of a drug substance and the relevant impurity are not close,
`this practice can still be appropriate, provided a correction factor is applied or the impurities are,
`in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate
`identified or unidentified impurities can be based on analytical assumptions (e.g., equivalent
`detector response). These assumptions should be discussed in registration applications.
`
`
`V.
`
`Analytical results should be provided in an application for all batches of a new drug substance
`used for clinical, safety, and stability testing, as well as for batches representative of the
`proposed commercial process. Quantitative results should be presented numerically, and not in
`general terms such as “complies” or “meets limit.” Any impurity at a level greater than (>) the
`reporting threshold (see Attachment 1) and total impurities observed in these batches of the new
`drug substance should be reported with the analytical procedures indicated. Below 1.0 percent,
`the results should be reported to two decimal places (e.g., 0.06 percent, 0.13 percent); at and
`above 1.0 percent, the results should be reported to one decimal place (e.g., 1.3 percent). Results
`should be rounded using conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet)
`
`REPORTING IMPURITY CONTENT OF BATCHES (5)
`
`
`
`4
`
`

`

`Contains Nonbinding Recommendations
`
`
`of the data is recommended. Impurities should be designated by code number or by an
`appropriate descriptor (e.g., retention time). If a higher reporting threshold is proposed, it should
`be fully justified. All impurities at a level greater than (>) the reporting threshold should be
`summed and reported as total impurities.
`
`
`When analytical procedures change during development, reported results should be linked to the
`procedure used, with appropriate validation information provided. Representative
`chromatograms should be provided. Chromatograms of representative batches from analytical
`validation studies showing separation and detectability of impurities (e.g., on spiked samples),
`along with any other impurity tests routinely performed, can serve as the representative impurity
`profiles. The applicant should ensure that complete impurity profiles (e.g., chromatograms) of
`individual batches are available, if requested.
`
` A
`
` tabulation should be provided that links the specific new drug substance batch to each safety
`study and each clinical study in which the new drug substance has been used.
`For each batch of the new drug substance, the report should include:
`• Batch identity and size
`• Date of manufacture
`• Site of manufacture
`• Manufacturing process
`•
`Impurity content, individual and total
`• Use of batches
`• Reference to analytical procedure used
`
`LISTING OF IMPURITIES IN SPECIFICATIONS (6)
`
`
`
`VI.
`
`The specification for a new drug substance should include a list of impurities. Stability studies,
`chemical development studies, and routine batch analyses can be used to predict those impurities
`likely to occur in the commercial product. The selection of impurities in a new drug substance
`specification should be based on the impurities found in batches manufactured by the proposed
`commercial process. Those individual impurities with specific acceptance criteria included in the
`specification for a new drug substance are referred to as specified impurities in this guidance.
`Specified impurities can be identified or unidentified.
`
` A
`
` rationale for the inclusion or exclusion of impurities in a specification should be presented.
`The rationale should include a discussion of the impurity profiles observed in the safety and
`clinical development batches, together with a consideration of the impurity profile of batches
`manufactured by the proposed commercial process. Specified identified impurities should be
`included along with specified unidentified impurities estimated to be present at a level greater
`than (>) the identification threshold given in Attachment 1. For impurities known to be unusually
`potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit
`of the analytical procedures should be commensurate with the level at which the impurities
`should be controlled. For unidentified impurities, the procedure used and assumptions made in
`establishing the level of the impurity should be clearly stated. Specified, unidentified impurities
`
`
`
`5
`
`

`

`Contains Nonbinding Recommendations
`
`
`should be referred to by an appropriate qualitative analytical descriptive label (e.g., “unidentified
`A,” “unidentified with relative retention of 0.9”). A general acceptance criterion of not more
`than (≤) the identification threshold (see Attachment 1) for any unspecified impurity and an
`acceptance criterion for total impurities should be included.
`
`Acceptance criteria should be set no higher than the level that can be justified by safety data and
`should be consistent with the level achievable by the manufacturing process and the analytical
`capability. Where there is no safety concern, impurity acceptance criteria should be based on
`data generated on batches of a new drug substance manufactured by the proposed commercial
`process, allowing sufficient latitude to deal with normal manufacturing and analytical variation
`and the stability characteristics of the new drug substance. Although normal manufacturing
`variations are expected, significant variation in batch-to-batch impurity levels can indicate that
`the manufacturing process of the new drug substance is not adequately controlled and validated
`(see ICH Q6A guidance on specifications, Decision Tree #1, for establishing an acceptance
`criterion for a specified impurity in a new drug substance). The use of two decimal places for
`thresholds (see Attachment 1) does not necessarily indicate the precision of the acceptance
`criteria for specified impurities and total impurities.
`
`In summary, a new drug substance specification should include, where applicable, the following
`list of impurities:
`
`
`Organic Impurities
`• Each specified identified impurity
`• Each specified unidentified impurity
`• Any unspecified impurity with an acceptance criterion of not more than (≤) the
`identification threshold
`• Total impurities
`Residual Solvents
`Inorganic Impurities
`
`
`
`
`
`
`VII. QUALIFICATION OF IMPURITIES (7)
`
`Qualification is the process of acquiring and evaluating data that establishes the biological safety
`of an individual impurity or a given impurity profile at the level(s) specified. The applicant
`should provide a rationale for establishing impurity acceptance criteria that includes safety
`considerations. The level of any impurity present in a new drug substance that has been
`adequately tested in safety and/or clinical studies would be considered qualified. Impurities that
`are also significant metabolites present in animal and/or human studies are generally considered
`qualified. A level of a qualified impurity higher than that present in a new drug substance can
`also be justified based on an analysis of the actual amount of impurity administered in previous
`relevant safety studies.
`
`
`
`
`6
`
`

`

`Contains Nonbinding Recommendations
`
`
`If data are unavailable to qualify the proposed acceptance criterion of an impurity, studies to
`obtain such data can be appropriate when the usual qualification thresholds given in Attachment
`1 are exceeded.
`
`Higher or lower thresholds for qualification of impurities can be appropriate for some individual
`drugs based on scientific rationale and level of concern, including drug class effects and clinical
`experience. For example, qualification can be especially important when there is evidence that
`such impurities in certain drugs or therapeutic classes have previously been associated with
`adverse reactions in patients. In these instances, a lower qualification threshold can be
`appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs
`when the level of concern for safety is less than usual based on similar considerations (e.g.,
`patient population, drug class effects, clinical considerations). Proposals for alternative
`thresholds would be considered on a case-by-case basis.
`
`The "Decision Tree for Identification and Qualification" (see Attachment 3) describes
`considerations for the qualification of impurities when thresholds are exceeded. In some cases,
`decreasing the level of impurity to not more than the threshold can be simpler than providing
`safety data. Alternatively, adequate data could be available in the scientific literature to qualify
`an impurity. If neither is the case, additional safety testing should be considered. The studies
`considered appropriate to qualify an impurity will depend on a number of factors, including the
`patient population, daily dose, and route and duration of drug administration. Such studies can be
`conducted on the new drug substance containing the impurities to be controlled, although studies
`using isolated impurities can sometimes be appropriate.
`
`Although this guidance is not intended to apply during the clinical research stage of
`development, in the later stages of development, the thresholds in this guidance can be useful in
`evaluating new impurities observed in drug substance batches prepared by the proposed
`commercial process. Any new impurity observed in later stages of development should be
`identified if its level is greater than (>) the identification threshold given in Attachment 1 (see
`the “Decision Tree for Identification and Qualification” in Attachment 3). Similarly, the
`qualification of the impurity should be considered if its level is greater than (>) the qualification
`threshold given in Attachment 1. Safety assessment studies to qualify an impurity should
`compare the new drug substance containing a representative amount of the new impurity with
`previously qualified material. Safety assessment studies using a sample of the isolated impurity
`can also be considered.
`
`
`
`
`7
`
`

`

`

`

`
`
`Contains Nonbinding Recommendations
`
`GLOSSARY
`
`
`
`Chemical Development Studies: Studies conducted to scale-up, optimize, and validate the
`manufacturing process for a new drug substance
`
`Enantiomeric Impurity: A compound with the same molecular formula as the drug substance
`that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable
`mirror image
`
`Extraneous Contaminant: An impurity arising from any source extraneous to the
`manufacturing process
`
`
`Herbal Products: Medicinal products containing, exclusively, plant material and/or vegetable
`drug preparations as active ingredients. In some traditions, materials of inorganic or animal
`origin can also be present.
`
`Identified Impurity: An impurity for which a structural characterization has been achieved
`
`Identification Threshold: A limit above (>) which an impurity should be identified
`
`Impurity: Any component of the new drug substance that is not the chemical entity defined as
`the new drug substance
`
`Impurity Profile: A description of the identified and unidentified impurities present in a new
`drug substance
`
`Intermediate: A material produced during steps of the synthesis of a new drug substance that
`undergoes further chemical transformation before it becomes a new drug substance
`
`Ligand: An agent with a strong affinity to a metal ion
`
`New Drug Substance: The designated therapeutic moiety that has not been previously
`registered in a region or member state (also referred to as a new molecular entity or new
`chemical entity). It can be a complex, simple ester, or salt of a previously approved drug
`substance.
`
`Polymorphic Forms: Different crystalline forms of the same drug substance. These can include
`solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms.
`
`Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It
`may or may not actually appear in the new drug substance.
`
`Qualification: The process of acquiring and evaluating data that establishes the biological
`safety of an individual impurity or a given impurity profile at the level(s) specified
`
`
`
`
`9
`
`

`

`Contains Nonbinding Recommendations
`
`
`Qualification Threshold: A limit above (>) which an impurity should be qualified
`
`Reagent: A substance other than a starting material, intermediate, or solvent that is used in the
`manufacture of a new drug substance
`
`Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting
`threshold is the same as reporting level in Q2B.
`
`Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of solutions or
`suspensions in the synthesis of a new drug substance
`
`Specified Impurity: An impurity that is individually listed and limited with a specific
`acceptance criterion in the new drug substance specification. A specified impurity can be either
`identified or unidentified.
`
`Starting Material: A material used in the synthesis of a new drug substance that is incorporated
`as an element into the structure of an intermediate and/or of the new drug substance. Starting
`materials are normally commercially available and of defined chemical and physical properties
`and structure.
`
`Unidentified Impurity: An impurity for which a structural characterization has not been
`achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic
`retention time)
`
`Unspecified Impurity: An impurity that is limited by a general acceptance criterion, but not
`individually listed with its own specific acceptance criterion, in the new drug substance
`specification
`
`
`
`
`
`
`
`10
`
`

`

`Contains Nonbinding Recommendations
`
`ATTACHMENT 1: THRESHOLDS
`
`Maximum
`Daily Dose1
`≤ 2g/day
`
`Reporting
`Threshold2,3
`0.05%
`
`> 2g/day
`
`0.03%
`
`Identification
`Threshold3
`0.10% or 1.0 mg per day
`intake (whichever is
`lower)
`0.05%
`
`Qualification
`Threshold3
`0.15% or 1.0 mg per day
`intake (whichever is
`lower)
`0.05%
`
`
`
`
`
`
`
`
` 1
`
` The amount of drug substance administered per day
`2 Higher reporting thresholds should be scientifically justified
`3 Lower thresholds can be appropriate if the impurity is unusually toxic
`
`
`
`11
`
`

`

`
`
`Contains Nonbinding Recommendations
`
`ATTACHMENT 2: ILLUSTRATION OF REPORTING IMPURITY RESULTS FOR
`IDENTIFICATION AND QUALIFICATION IN AN APPLICATION
`
`
`The attachment is only illustrative and is not intended to serve as a template for how results on
`impurities should be presented in an application file. Normally, raw data are not presented.
`
`Example 1:
`
`
`
`
`
`0.5 g Maximum Daily Dose
`Reporting threshold = 0.05%
`Identification threshold = 0.10%
`Qualification threshold = 0.15%
`
`“Raw”
`Result
`(%)
`
`0.044
`0.0963
`0.12
`0.1649
`
`Reported Result
`(%)
`Reporting
`threshold =0.05%
`Not reported
`0.10
` 0.121)
` 0.161)
`
`Calculated Total Daily Intake
`(TDI) (mg) of the impurity
`(rounded result in mg)
`
`0.2
`0.5
`0.6
`0.8
`
`Action
`
`Identification
`(Threshold 0.10%
`exceeded?)
`None
`None
`Yes
`Yes
`
`Qualification
`(Threshold 0.15%
`exceeded?)
`None
`None
` None1
`Yes1
`
`
`Example 2:
`
`
`
`
`
` “Raw”
`Result
`(%)
`
` 0.8 g Maximum Daily Dose
`Reporting threshold = 0.05%
`Identification threshold = 0.10%
`Qualification threshold = 1.0 mg TDI
`
`Action
`
`Reported Result
`Calculated Total Daily Intake
`(%)
`(TDI) (mg)
`Identification
`Qualification
`Reporting
`of the impurity
`(Threshold 0.10%
`(Threshold 1.0 mg TDI
`threshold =0.05%
`(rounded result in mg)
`exceeded?)
`exceeded?)
`None
`None
`0.6
`0.07
`0.066
` None1, 2
`Yes
`1.0
`0.12
`0.124
`Yes1
`Yes
`1.1
`0.14
`0.143
`1 After identification, if the response factor is determined to differ significantly from the original assumptions, it
`may be appropriate to remeasure the actual amount of the impurity present and reevaluate against the qualification
`threshold (see Attachment 1).
`2 To verify if a threshold is exceeded, a reported result should be evaluated against the thresholds as follows: When
`the threshold is described in %, the reported result rounded to the same decimal place as the threshold should be
`compared directly to the threshold. When the threshold is described in TDI, the reported result should be converted
`to TDI, rounded to the same decimal place as the threshold, and compared to the threshold. For example, the
`amount of impurity at 0.12% level corresponds to a TDI of 0.96 mg (absolute amount), which is then rounded up to
`1.0 mg; so the qualification threshold expressed in TDI (1.0 mg) is not exceeded.
`
`
`
`12
`
`

`

`Contains Nonbinding Recommendations
`
`
`ATTACHMENT 3: DECISION TREE FOR IDENTIFICATION AND QUALIFICATION
`
`
`
`Is impurity greater
`than identification
`thresholdc?
`
`Yes
`
`No
`
`No action
`
`Structure
`identified?
`
`Yes
`
`Any
`known human
`relevant risksd?
`
`Yes
`
`Reduce to
`safe level
`
`No
`
`Reduce
`to not more than
`(≤) identification
`thresholdc?
`
`No
`
`Yes
`
`No further
`action
`
`Yes
`
`Reduce
`to not more than
`(≤) qualification
`thresholdc?
`
`No
`
`No
`
`Yes
`
`Greater
`than qualification
`thresholdc?
`
`No
`
`No action
`
`Consider patient population and duration of use
`and consider conducting:
`• Genotoxicity studies (point mutation,
`chromosomal aberration)a
`• General toxicity studies (one species, usually
`14 to 90 days)b
`• Other specific toxicity endpoints, as
`appropriate
`
`Reduce to
`safe level
`
`Yes
`
`Any
`clinically
`relevant adverse
`effects?
`
`
`Qualified
`
`No
`
`13
`
`
`
`

`

`Contains Nonbinding Recommendations
`
`
`Notes on Attachment 3
`
`If considered desirable, a minimum screen (e.g., genotoxic potential) should be conducted.
`A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are
`considered an appropriate minimum screen.
`
`If general toxicity studies are desirable, one or more studies should be designed to allow
`comparison of unqualified to qualified material. The study duration should be based on
`available relevant information and performed in the species most likely to maximize the potential
`to detect the toxicity of an impurity. On a case-by-case basis, single-dose studies can be
`appropriate, especially for single-dose drugs. In general, a minimum duration of 14 days and a
`maximum duration of 90 days would be considered appropriate.
`
`Lower thresholds can be appropriate if the impurity is unusually toxic.
`
`For example, do known safety data for this impurity or its structural class preclude human
`exposure at the concentration present?
`
`
`a)
`
`
`b)
`
`
`c)
`
`d)
`
`
`
`14
`
`