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 
 
1
Guidance for Industry  
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.  
  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   
 
 
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. 
  2 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.  
  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.  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) 
  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 
 
 
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 
  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  Reporting  Identification  Qualification 
Daily Dose1  Threshold2,3  Threshold3  Threshold3 
 2g/day  0.05%  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  
  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  Reported Result  Calculated Total Daily Intake  Action 
Result  (%)  (TDI) (mg) of the impurity  Identification  Qualification 
(%)  Reporting  (rounded result in mg)  (Threshold 0.10%  (Threshold 0.15% 
threshold =0.05%  exceeded?)  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  Reported Result  Calculated Total Daily Intake  Action 
Result  (%)  (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?) 
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. 
  12 Contains Nonbinding Recommendations 
 
ATTACHMENT 3:  DECISION TREE FOR IDENTIFICATION AND QUALIFICATION 
 
 
Is impurity greater 
than identification 
thresholdc? 
Yes  No
No action 
Any
Structure  Yes  known human  Yes  Reduce to 
identified?  relevant risksd? safe level 
No 
No
Reduce 
to not more than  Yes  No further 
() identification  action
thresholdc? 
Yes
No 
Reduce
Greater
to not more than  Yes No 
than qualification  No action 
() qualification 
thresholdc?  thresholdc? 
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 
Any
Reduce to  Yes  clinically  No  
relevant adverse  Qualified 
safe level 
effects?
  13 Contains Nonbinding Recommendations 
 
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? 
 
  14