INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
`
`REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
`USE
`
`ICH HARMONISED TRIPARTITE GUIDELINE
`
`IMPURITIES IN NEW DRUG SUBSTANCES
`
`Q3A(R2)
`
`Current Step 4 version
`
`dated 25 October 2006
`
`This Guideline has been developed by the appropriate ICH Expert Working Group and
`has been subject to consultation by the regulatory parties, in accordance with the ICH
`Process. At Step 4 of the Process the final draft is recommended for adoption to the
`regulatory bodies of the European Union, Japan and USA.
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`
`First
`Codification
`
`Q3A(R2)
`Document History
`
`History
`
`Approval by the Steering Committee under Step 2 and
`release for public consultation.
`
`Approval by the Steering Committee under Step 4 and
`recommendation for adoption to the three ICH regulatory
`bodies.
`
`Q3 was renamed Q3A.
`
`Approval by the Steering Committee of the first Revision
`under Step 2 and release for public consultation.
`
`15
`March
`1994
`
`30
`March
`1995
`
`7
`October
`1999
`
`Approval by the Steering Committee of the first Revision
`under Step 4 and recommendation for adoption to the three
`ICH regulatory bodies.
`
`6
`February
`2002
`
`Current Step 4 version
`
`New
`Codification
`
`November
`2005
`
`Q3A
`
`Q3A(R1)
`
`Q3A(R1)
`
`Q3A(R2)
`
`Approval by the Steering Committee of the revision of the
`Attachment 2 directly under Step 4 without further public
`
`consultation.
`
`25 October
`2006
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`IMPURITIES IN NEW DRUG SUBSTANCES
`
`ICH Harmonised Tripartite Guideline
`
`Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
`on 7 February 2002, this guideline is recommended for
`adoption to the three regulatory parties to ICH.
`
`Attachment 2 has been revised on 25 October 2006.
`
`TABLE OF CONTENTS
`
`1.
`
`PREAMBLE ............................................................................................................ ..1
`
`2. CLASSIFICATION OF IMPURITIES ................................................................... ..1
`
`3. RATIONALE FOR THE REPORTING AND CONTROL
`OF IMPURITIES .................................................................................................... ..2
`
`3.1 Organic Impurities .......................................................................................... ..2
`
`3.2 Inorganic Impurities ........................................................................................ ..2
`
`3.3 Solvents ............................................................................................................ ..3
`
`4. ANALYTICAL PROCEDURES .............................................................................. ..3
`
`5. REPORTING IMPURITY CONTENT OF BATCHES .......................................... ..3
`
`6. LISTING OF IMPURITIES IN SPECIFICATIONS ............................................. ..4
`
`7. QUALIFICATION OF IMPURITIES ..................................................................... ..5
`
`8. GLOSSARY ............................................................................................................. ..6
`
`ATTACHMENT 1 ........................................................................................................... ..8
`
`ATTACHMENT 2 ........................................................................................................... ..9
`
`ATTACHMENT 3 ......................................................................................................... ..10
`
`1
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`IMPURITIES IN NEW DRUG SUBSTANCES
`
`1.
`
`PREAMBLE
`
`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. It 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 guideline:
`biological/biotechnological,
`peptide,
`oligonucleotide,
`radiopharmaceutical,
`fermentation product and semi-synthetic products derived therefrom, herbal products,
`and crude products of animal or plant origin.
`
`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; and
`
`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.
`
`2.
`
`CLASSIFICATION OF IMPURITIES
`
`Impurities can be classified into the following categories:
`
`0
`
`0
`
`0
`
`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 non-volatile,
`and include:
`
`0
`
`0
`
`o
`
`0
`
`0
`
`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:
`
`0
`
`0
`
`0
`
`0
`
`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
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`Impurities in New Drug Substances
`
`the selection of appropriate controls
`generally of known toxicity,
`accomplished (see ICH Guideline Q3C on Residual Solvents).
`
`is easily
`
`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.
`
`3.
`
`RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES
`
`3.1
`
`Organic Impurities
`
`The applicant should summarise the actual and potential impurities most likely to
`arise during the synthesis, purification, and storage of the 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 summarise 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
`Guideline Q1A 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 characterise the structure of actual impurities present in the
`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 (S) 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 (S) 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
`(S) the identification threshold. All impurities should be qualified as described later in
`this guideline.
`
`3.2
`
`Inorganic Impurities
`
`Inorganic impurities are normally detected and quantified using pharmacopoeial or
`other appropriate procedures. Carry-over of catalysts to the new drug substance
`should be evaluated during development. The need for inclusion or exclusion of
`inorganic impurities in the new drug substance specification should be discussed.
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`Impurities in New Drug Substances
`
`Acceptance criteria should be based on pharmacopoeial standards or known safety
`data.
`
`3.3
`
`Solvents
`
`The control of residues of the solvents used in the manufacturing process for the new
`drug substance should be discussed and presented according to the ICH Q3C
`Guideline for Residual Solvents.
`
`4.
`
`ANALYTICAL PROCEDURES
`
`The 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 Guidelines for 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 acceptable 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 (S) 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 characterised 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 the 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 the
`registration application.
`
`5.
`
`REPORTING IMPURITY CONTENT OF BATCHES
`
`Analytical results should be provided in the application for all batches of the 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”, “meets limit” etc.
`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%, the results should be
`reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results
`should be reported to one decimal place (e.g., 1.3%). Results should be rounded using
`conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet) 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
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`Impurities in New Drug Substances
`
`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:
`
`0
`0
`
`0
`
`0
`
`0
`0
`
`0
`
`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
`
`6.
`
`LISTING OF IMPURITIES IN SPECIFICATIONS
`
`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 the 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
`the new drug substance are referred to as "specified impurities" in this guideline.
`Specified impurities can be identified or unidentified.
`
`A rationale for the inclusion or exclusion of impurities in the specification should be
`presented. This 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 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 (S)
`the
`identification threshold (Attachment
`1)
`for any unspecified impurity and an
`acceptance criterion for total impurities should be included.
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`Impurities in New Drug Substances
`
`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 the 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 Guideline 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, the new drug substance specification should include, where applicable,
`the following list of impurities:
`
`Organic Impurities
`
`0
`
`0
`
`Each specified identified impurity
`
`Each specified unidentified impurity
`
`0 Any unspecified impurity with an acceptance criterion of not more than (S) the
`identification threshold
`
`0
`
`Total impurities
`
`Residual Solvents
`
`Inorganic Impurities
`
`7.
`
`QUALIFICATION OF IMPURITIES
`
`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.
`
`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
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`
`Impurities in New Drug Substances
`
`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" (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 guideline is not intended to apply during the clinical research stage of
`development, in the later stages of development the thresholds in this guideline 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.
`
`8.
`
`GLOSSARY
`
`Chemical Development Studies: Studies conducted to scale-up, optimise, 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 characterisation 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.
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`Impurities in New Drug Substances
`
`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.
`
`The designated therapeutic moiety that has not been
`New Drug Substance:
`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.
`
`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 characterisation 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.
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`
`Impurities in New Drug Substances
`
`ATTACHMENT 1
`
`Thresholds
`
`Maximum
`Daily Dose‘
`
`Reporting
`Threshold“
`
`5 2g/day
`
`0.05%
`
`
`
`Identification
`Thresholda
`
`Qualification
`Threshold“
`
`0.10% or 1.0 mg per day 0.15% or 1.0 mg per day
`intake
`(whichever
`is
`intake
`(whichever
`is
`lower)
`lower)
`
`> 2g/day
`
`0.03%
`
`0.05%
`
`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
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`
`Impurities in New Drug Substances
`
`ATTACHMENT 2
`
`Illustration of Reporting Impurity Results
`Qualification in an Application
`
`for
`
`Identification and
`
`The attachment is only illustrative and is not intended to serve as template how
`results on impurities should be presented in an application file. Normally raw data
`are not presented.
`
`Exa.mple 1:
`
`0.5 g Maximum Daily Dose
`
`Reporting threshold = 0.05%
`Identification threshold = 0.10%
`
`Qualification threshold = 0.15%
`
`Reported
`Result
`(%)
`Reporting
`threshold
`=0.05%
`
`Calculated Total Daily
`Intake (TDI) (mg) of the
`impurity
`(rounded result in mg)
`
`Identification
`(Threshold 0.10%
`exceeded?)
`
`Qualification
`(Threshold 0.15%
`exceeded?)
`
`Yesl)
`
`0-044mm
`0.0963
`s
`mm
`0.1649
`0.161)
`Yes
`
`Example 2:
`
`0.8 g Maximum Daily Dose
`
`Reporting threshold = 0.05%
`Identification threshold = 0.10%
`
`Qualification threshold = 1.0 mg TDI
`
`Reported
`Result
`(%)
`Reporting
`threshold
`
`Calculated Total Daily
`Intake (TDI) (mg)
`of the impurity
`(rounded result in mg)
`
`=0.05%
`
`Identification
`(Threshold 0.10%
`exceeded?)
`
`Qualification
`(Threshold 1.0 mg
`TDI exceeded?)
`
`1) After identification, if the response factor is determined to differ significantly from
`the original assumptions, it may be appropriate to re-measure the actual amount of
`the impurity present and re-evaluate against
`the qualification threshold (see
`Attachment 1).
`
`2) To verify if a threshold is exceeded, a reported result has to 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.
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`|PR2016-00006
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`

`
`Impurities in New Drug Substances
`
`ATTACHMENT 3
`
`Decision Tree for Identification and Qualification
`
`
`
`
`
`10
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`

`
`Impurities in New Drug Substances
`
`Notes on Attachment 3
`
`a)
`
`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.
`
`b)
`
`c)
`
`d)
`
`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 maximise 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?
`
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