92 
 
Guidance for Industry 
 
IMPURITIES IN NEW VETERINARY 
 DRUG SUBSTANCES (Revision) 
VICH GL10(R) 
 
 
REVISED FINAL GUIDANCE 
 
 
 
Comments and suggestions regarding the document should be submitted to Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  Submit electronic comments to http://www.regulations.gov.  All comments should be identified 
with the Docket No. 1999D-2215.   
 
For questions regarding this document, contact Dennis Bensley, Center for Veterinary Medicine, (HFV-
143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 240-276-8268, e-mail:  
dennis.bensley@fda.hhs.gov. 
Additional copies of this final guidance document may be requested from the Communications Staff 
(HFV-12),  Center  for  Veterinary  Medicine,  Food  and  Drug  Administration,  7519  Standish  Place, 
Rockville,  MD    20855,  and  may  be  viewed  on  the  Internet  at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.ht
m.    
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
November 26, 2007   
VICH GL10 (QUALITY) 
September 2007 
Revision at Step 9 
 
 
 
 
 
I N V D
MPURITIES IN  EW  ETERINARY  RUG 
S (R )  
UBSTANCES  EVISION  
 
 
 
 
 
 
 
Revised at Step 9 
by the VICH Steering Committee in September 2007 
 
 
 
 
 
 
 
 
 
 
 
 
This revised Guidance has been developed by the appropriate VICH Expert Working Group and is subject 
to consultation by the parties, in accordance with the VICH Process.  At Step 9 of the Process the final 
draft will be recommended for adoption to the regulatory bodies of the European Union, Japan and USA. 
  Contains Non-Binding Recommendations 
 
TABLE OF CONTENTS 
 
1.  INTRODUCTION      4 
2.  CLASSIFICATION OF IMPURITIES      5 
3.  RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES      5 
3.1      Organic Impurities     5 
3.2      Inorganic Impurities      6 
3.3      Solvents      6 
4.  ANALYTICAL PROCEDURES  6 
5.  REPORTING IMPURITY CONTENT OF BATCHES      7 
6.   LISTING OF IMPURITIES IN SPECIFICATIONS    8 
7.  QUALIFICATION OF IMPURITIES        9 
8.  GLOSSARY     11 
Attachment 1 - Thresholds  13 
Attachment 2 - Illustration of Reporting Impurity Results for Identification and 
Qualification in an Application  14 
Attachment 3 - Decision Tree for Identification and Qualification  15
3  Contains Non-Binding Recommendations 
 
 
VICH GL10(R) 
 Impurities in New Veterinary Drug Substances (Revision) 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on the subject 
matter.  It does not create or confer any rights for or on any person and does not operate to bind FDA or   
the public.  You can use an alternative approach if the approach satisfies the requirements of the 
applicable statute(s) and regulation(s).  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.  
 
 
1.  INTRODUCTION 
This document is intended to provide guidance to registration applicants on the content and 
qualification of impurities in new veterinary drug substances intended to be used for new 
veterinary medicinal products, produced by chemical syntheses and not previously registered in a 
country, region, or member state.  This guidance does not address new veterinary drug substances 
used during the clinical research stage of development. The following types of new veterinary 
drug substances are not covered in this guidance: biological/biotechnological, peptide, 
oligonucleotide, radiopharmaceutical, fermentation products and semi-synthetic products derived 
therefrom, herbal products, and crude products of animal or plant origin.   
Impurities in new veterinary drug substances are addressed from two perspectives: 
Chemistry Aspects including classification and identification of impurities, report 
generation, listing of impurities in specifications, and a brief discussion of analytical 
procedures; and 
Safety Aspects including specific guidance for qualifying those impurities that were not 
present, or were present at substantially lower levels, in batches of a new veterinary drug 
substance used in safety and clinical studies.  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidances means that 
something is suggested or recommended, but not required. 
 
 
4  Contains Non-Binding Recommendations 
 
 
2.  CLASSIFICATION OF IMPURITIES 
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 
veterinary drug substance. They can be identified or unidentified, volatile or non-volatile, 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 veterinary drug substance. Since these are generally of 
known toxicity, the selection of appropriate controls is easily accomplished (see guidance VICH 
GL18, Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients). 
This document does not address: (1) extraneous contaminants that should not occur in new 
veterinary 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 registration applicant should summarize the actual and potential impurities most likely to 
arise during the synthesis, purification, and storage of the new veterinary 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 veterinary drug substance, and possible degradation products. This discussion can be 
5  Contains Non-Binding Recommendations 
 
 
limited  to  those  impurities  that  might  reasonably  be  expected  based  on  knowledge  of  the 
chemical reactions and conditions involved. 
In addition, the registration applicant should summarize the laboratory studies conducted to 
detect impurities in the new veterinary 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 guidance VICH GL3, Stability 
Testing  of  New  Veterinary  Drug  Substances  and  Medicinal  Products)  used  to  identify  potential 
impurities arising during storage. The impurity profile of the new veterinary 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  the  new 
veterinary  drug  substance  at  a  level  greater  than  (>)  the  identification  threshold  given  in 
Attachment 1 (e.g., calculated using the response factor of the new veterinary 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.  
3.2  Inorganic Impurities 
Inorganic  impurities  are  normally  detected  and  quantified  using  pharmacopoeial  or  other 
appropriate procedures. Carry-over of catalysts to the new veterinary drug substance should be 
evaluated during development. The need for inclusion or exclusion of inorganic impurities in the 
new veterinary drug substance specification should be discussed. 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 veterinary 
drug  substance  should  be  discussed  and  presented  (see  guidance  VICH  GL18  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 guidances VICH 
GL1 and GL2 for Analytical Validation). Technical factors (e.g., manufacturing capability and 
6  Contains Non-Binding Recommendations 
 
 
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 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 () the reporting 
threshold (see Attachment 1). 
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 veterinary 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 new veterinary drug substance can be used as a standard to estimate the levels 
of impurities. In cases where the response factors of the new veterinary 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 veterinary 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  as 
opposed to 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 veterinary 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 
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.  
7  Contains Non-Binding Recommendations 
 
 
A tabulation should be provided that links the specific new veterinary drug substance batch to 
each safety study and each clinical study in which the new veterinary drug substance has been 
used. 
For each batch of the new veterinary 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  
6.  LISTING OF IMPURITIES IN SPECIFICATIONS 
The specification for a new veterinary 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 
veterinary  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  veterinary  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 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 
() the identification threshold (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  the  new  veterinary  drug  substance  manufactured  by  the  proposed 
commercial  process,  allowing  sufficient  latitude  to  deal  with  normal  manufacturing  and 
8  Contains Non-Binding Recommendations 
 
 
analytical  variation  and  the  stability  characteristics  of  the  new  veterinary  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 veterinary drug substance 
is not adequately controlled and validated (see guidance VICH GL39 on Specifications and 
Decision Tree #1 for establishing an acceptance criterion for a specified impurity in a new 
veterinary drug substance). The use of two decimal places for thresholds does not necessarily 
indicate the precision of the acceptance criteria for specified impurities and total impurities. 
In summary, the new veterinary 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 
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 veterinary 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 veterinary 
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  animals.  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., 
9  Contains Non-Binding Recommendations 
 
 
animal species, 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 animal 
species, daily dose, and route and duration of drug administration. Such studies can be conducted 
on the new veterinary drug substance containing the impurities to be controlled, although studies 
using isolated impurities can sometimes be appropriate. 
Although this guidance does not address 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 the new veterinary 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 
veterinary  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. 
10  Contains Non-Binding Recommendations 
 
 
8.  GLOSSARY  
(The following definitions are presented for the purpose of this Revised Guidance.) 
Chemical  Development  Studies:  Studies  conducted  to  scale-up,  optimize,  and  validate  the 
manufacturing process for a new veterinary drug substance. 
Degradation Product: An impurity resulting from a chemical change in the drug substance 
brought  about  during  its  manufacture  and/or  storage  by  the  effect  of,  for  example,  light, 
temperature, pH or water. 
Enantiomeric Impurity:  A compound with the same molecular formula as the new veterinary 
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 veterinary drug substance that is not the chemical entity 
defined as the new veterinary drug substance. 
Impurity Profile:  A description of the identified and unidentified impurities present in a new 
veterinary drug substance. 
Intermediate:  A material produced during steps of the synthesis of a new veterinary drug 
substance that undergoes further chemical transformation before it becomes a new veterinary 
drug substance. 
Ligand:  An agent with a strong affinity to a metal ion. 
New  Veterinary  Drug  Substance:    The  designated  therapeutic  moiety  that  has  not  been 
previously registered in a region or member state in a veterinary medicinal product (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. 
New  Veterinary  Medicinal  Product:    A  pharmaceutical  product  type,  for  example,  tablet, 
capsule,  solution,  cream,  etc.,  containing  a  new  or  existing  drug  substance  which  has  not 
previously been registered in a region or member state, and which contains a drug ingredient 
generally, but not necessarily, in association with excipients. 
Polymorphic Forms:  Different crystalline forms of the same new veterinary drug substance. 
These can include solvation or hydration products (also known as pseudo-polymorphs) and 
amorphous forms. 
11  Contains Non-Binding Recommendations 
 
 
Potential Impurity:  An impurity that theoretically can arise during manufacture or storage. It 
may or may not actually appear in the new veterinary 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 veterinary drug substance. 
Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting 
threshold is the same as reporting level in VICH GL2, Guidance on Validation of Analytical 
Procedures. 
Solvent:  An inorganic or an organic liquid used as a vehicle for the preparation of solutions or 
suspensions in the synthesis of a new veterinary drug substance. 
Specified  Impurity:    An  impurity  that  is  individually  listed  and  limited  with  a  specific 
acceptance criterion in the new veterinary drug substance specification. A specified impurity can 
be either identified or unidentified. 
Starting Material:  A material used in the synthesis of a new veterinary drug substance that is 
incorporated as an element into the structure of an intermediate and/or of the new veterinary 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  veterinary  drug 
substance specification. 
12  Contains Non-Binding Recommendations 
 
 
Attachment 1: Thresholds  
 
              New Veterinary Drug Substance 
Identification 2  As per ICH* 
0.20%** 
Reporting 1,2  As per ICH* 
0.10%** 
Qualification 2  0.50% 
 
* new veterinary drug substance used in veterinary and human medicine 
** new veterinary drug substance not used in human medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________ 
1 Higher reporting thresholds should be scientifically justified. 
2 Lower thresholds can be appropriate if the impurity is unusually toxic. 
13  Contains Non-Binding Recommendations 
 
 
 
Attachment  2:  Illustration  of  Reporting  Impurity  Results  for  Identification  and 
Qualification  in  an  Application  (substances  used  in  veterinary  medicine  only  (see 
attachment 1); for substances used in human and veterinary medicine see also relevant ICH 
guidance) 
 
Raw Result  Reported Result  Action 
(%)  (%)  Identification  Qualification 
(Threshold 0.20%)  (Threshold 0.50%) 
0.166  0.17  None  None 
0.1963  0.20  None  None 
0.22  0.22*  Yes  None 
0.649  0.65*  Yes  Yes* 
 
* * 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).  
 
14  Contains Non-Binding Recommendations 
 
 
Attachment 3:  Decision Tree for Identification and Qualification 
 
 
Is impurity greater 
than identification 
thresholdc? 
Yes  No
No action 
Any
known human   Yes  Reduce to 
Yes  or animal 
safe level 
Structure  relevant risksd?
identified? 
No 
No
Reduce 
to not more than  Yes No further 
() identification  action
thresholdc? 
Yes
No 
Reduce Yes  No 
No  Greater
to not more than 
() qualification  than qualification  No action 
thresholdc?  thresholdc? 
Toxicity documented 
and sufficient/acceptable 
Yes 
justification for relation to 
other substances with known 
toxicity? 
Consider  animal  species,  duration  of  use  and 
consider conducting: 
  Genotoxicity  studies  (point  mutation, 
No  chromosomal aberration)a 
  General toxicity studies (one species, usually 
14 to 90 days)b 
  Other  specific  toxicity  endpoints,  as 
appropriate 
Any
Reduce to safe level or  Yes  clinically  No
relevant adverse   
remove impurity or 
effects? Qualified 
conduct additional 
safety studies 
15  Contains Non-Binding 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 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. 
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 
or animal exposure at the concentration present? 
16