Guidance for Industry 

Q3A Impurities in New Drug 

Substances

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 
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 

I. INTRODUCTION (1)....................................................................................................... 1

II. CLASSIFICATION OF IMPURITIES (2)..................................................................... 2

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. 

I. INTRODUCTION (1) 

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. 

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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 

II. CLASSIFICATION OF IMPURITIES (2) 

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. 

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Contains Nonbinding Recommendations

III. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES (3) 

A. Organic Impurities (3.1) 

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. 

B. Inorganic Impurities (3.2) 

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. 

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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. REPORTING IMPURITY CONTENT OF BATCHES (5) 

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) 

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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 

VI. LISTING OF IMPURITIES IN SPECIFICATIONS (6) 

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 

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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. 

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Contains Nonbinding Recommendations

7

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. 

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 

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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 

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Contains Nonbinding Recommendations

ATTACHMENT 1: THRESHOLDS 

Maximum 

Daily Dose1

Reporting 

Threshold2,3

Identification 

Threshold3

Qualification 

Threshold3

≤ 2g/day 0.05% 0.10% or 1.0 mg per day 

intake (whichever is 

lower) 

0.15% or 1.0 mg per day 

intake (whichever is 

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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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” Action 

Result 

(%) 

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?) 

0.044 Not reported 0.2 None None 

0.0963 0.10 0.5 None None 

0.12 0.121) 0.6 Yes None1

0.1649 0.161) 0.8 Yes Yes1

Example 2: 0.8 g Maximum Daily Dose 

Reporting threshold = 0.05% 

Identification threshold = 0.10% 

Qualification threshold = 1.0 mg TDI 

 “Raw” Action 

Result 

(%) 

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 1.0 mg TDI 

exceeded?) 

0.066 0.07 0.6 None None 

0.124 0.12 1.0 Yes None1, 2

0.143 0.14 1.1 Yes Yes1

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.

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Contains Nonbinding Recommendations

ATTACHMENT 3: DECISION TREE FOR IDENTIFICATION AND QUALIFICATION 

Is impurity greater 

than identification

thresholdc? 

Yes No

No action 

Yes 

No 

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 

Yes 

Yes 

No

Structure 

identified? 

Any

clinically 

relevant adverse 

effects?

Qualified 

No 

Greater

than qualification

thresholdc? 

Any

known human 

relevant risksd

?

Yes

No

Reduce to 

safe level 

Yes 

No 

Reduce 

to not more than 

(≤) identification 

thresholdc

? 

No further 

action

Reduce

to not more than 

(≤) qualification 

thresholdc

? 

Yes

No

No action 

Reduce to 

safe level 

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Contains Nonbinding Recommendations

14

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) 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. 

c) Lower thresholds can be appropriate if the impurity is unusually toxic. 

d) For example, do known safety data for this impurity or its structural class preclude human 

exposure at the concentration present?