93 
 
Guidance for Industry 
 
 
IMPURITIES IN NEW VETERINARY MEDICINAL 
PRODUCTS (REVISED)  
VICH GL11 (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.  FDA-1999-D-0048 (formerly 1999D-2145).   
 
For questions regarding this document, contact Dennis Bensley, Center for Veterinary Medicine, 
(HFV-140), 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/d
efault.htm .   
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
November 21, 2007 
 
Page 1 of 14  Contains Non-Binding Recommendations 
 
 
 
 
 
VICH GL11 (QUALITY) 
September 2007 
Revised at Step 9 
 
 
 
 
 
 
I N V M
MPURITIES IN  EW  ETERINARY  EDICINAL 
P (R )  
RODUCTS  EVISION  
 
 
 
 
 
 
 
Revised at Step 9 
by the VICH Steering Committee in September 2007 
 
 
 
 
 
 
 
 
 
 
 
This 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. 
 
 
 
 
 
Page 2 of 14  Contains Non-Binding Recommendations 
 
 
 
IMPURITIES IN NEW VETERINARY MEDICINAL PRODUCTS (REVISED)  
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION  4 
1.1  OBJECTIVE OF THE GUIDANCE  4 
1.2  BACKGROUND  4 
1.3  SCOPE OF THE GUIDANCE  4 
II.  RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION 
PRODUCTS  5 
III.  ANALYTICAL PROCEDURES  6 
IV  REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES  6 
V.      LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS  7 
VI  QUALIFICATION OF DEGRADATION PRODUCTS  8 
VII  GLOSSARY  10 
ATTACHMENT 1:  THRESHOLDS FOR DEGRADATION PRODUCTS IN NEW VETERINARY 
MEDICINAL PRODUCTS  12 
   
ATTACHMENT 2 :  DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A 
DEGRADATION PRODUCT  13 
Page 3 of 14  VICH GL- 11 (R) 
IMPURITIES IN NEW VETERINARY MEDICINAL PRODUCTS 
 
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.  
 
 
I.  INTRODUCTION 
 
1.1  Objective of the guidance 
 
This document provides guidance to registration applicants on the content and qualification of 
impurities in new veterinary medicinal products produced from chemically synthesized new 
veterinary  drug  substances  not  previously  registered  in  a  country,  region,  or  member  state. 
Alternative approaches may be used if such approaches satisfy the requirements of applicable 
statutes and regulations.  
 
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. 
 
 
1.2  Background 
 
This guidance is complementary to the VICH GL10(R) guidance Impurities in New Veterinary 
Drug Substances, which should be consulted for basic principles.  The VICH GL18 guidance, 
Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients 
should also be consulted, if appropriate.  
 
1.3  Scope of the guidance 
 
This guidance addresses only those impurities in new veterinary medicinal products classified as 
degradation products of the new veterinary drug substance or reaction products of the new 
veterinary  drug  substance  with  an  excipient  and/or  immediate  container  closure  system 
(collectively referred to as degradation products in this guidance). Generally, impurities present 
in the new veterinary drug substance need not be monitored or specified in the new veterinary 
medicinal  product unless they are also degradation  products  (see  guidance  VICH  GL39  on 
specifications). 
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Impurities arising from excipients present in the new veterinary medicinal product or extracted or 
leached from the container closure system are not addressed in this guidance. This guidance also 
does not address new veterinary medicinal products used during the clinical research stages of 
development.  The  following  types  of  products  are  not  addressed  in  this  guidance: 
biological/biotechnological  products,  peptides,  oligonucleotides,  radiopharmaceuticals, 
fermentation products and semi-synthetic products derived therefrom, herbal products, and crude 
products  of  animal  or  plant  origin.  Also  excluded  from  this  document  are:  (1)  extraneous 
contaminants  that  should  not  occur  in  new  veterinary  medicinal  products  and  are  more 
appropriately addressed as good manufacturing practice (GMP) issues, (2) polymorphic forms, 
and (3) enantiomeric impurities.  
 
II.  RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION 
PRODUCTS 
 
The  registration  applicant  should  summarize  the  degradation  products  observed  during 
manufacture and/or stability studies of the new veterinary medicinal product. This summary 
should be based on sound scientific appraisal of potential degradation pathways in the new 
veterinary medicinal product and impurities arising from the interaction with excipients and/or 
the immediate container closure system. In addition, the registration applicant should summarize 
any laboratory studies conducted to detect degradation products in the new veterinary medicinal 
product.  This  summary  should  also  include  test  results  of  batches  manufactured  during  the 
development process and batches representative of the proposed commercial process. A rationale 
should be provided for exclusion of those impurities that are not degradation products (e.g., 
process  impurities  from  the  new  veterinary  drug  substance  and  impurities  arising  from 
excipients). The impurity profiles of the batches representative of the proposed commercial 
process should be compared with the profiles of batches used in development and any differences 
discussed.  
Any degradation product observed in stability studies conducted at the recommended storage 
condition should be identified when present at a level greater than (>) the identification threshold 
of 1.0 % (Attachment 1). When identification of a degradation product is not feasible, a summary 
of the laboratory studies demonstrating the unsuccessful efforts to identify it should be included 
in the registration application.  
 
Degradation products present at a level of not more than () the identification threshold of 1.0 % 
generally would not need to be identified. However, analytical procedures should be developed 
for those degradation products that are suspected to be unusually potent, producing toxic or 
significant pharmacological effects at levels not more than () the identification threshold of 1.0 
%.  In  certain  circumstances,  technical  factors  (e.g.,  manufacturing  capability,  a  low  new 
veterinary drug substance to excipient ratio, or the use of excipients that are crude products of 
animal or plant origin) can be considered as part of the justification for selection of alternative 
thresholds based upon manufacturing experience with the proposed commercial process. 
 
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III.  ANALYTICAL PROCEDURES 
 
The registration application should include documented evidence that the analytical procedures 
have been validated and are suitable for the detection and quantitation of degradation products 
(see guidances VICH GL1 and GL2 on analytical validation).  In particular, analytical procedures 
should be validated to demonstrate specificity for the specified and unspecified degradation 
products. As appropriate, this validation should include samples stored under relevant stress 
conditions:  light,  heat,  humidity,  acid/base  hydrolysis,  and  oxidation.  When  an  analytical 
procedure reveals the presence of other peaks in addition to those of the degradation products 
(e.g.,  the  new  veterinary  drug  substance,  impurities  arising  from  the  synthesis  of  the  new 
veterinary drug substance, excipients and impurities arising from the excipients), these peaks 
should  be  labeled  in  the  chromatograms  and  their  origin(s)  discussed  in  the  validation 
documentation.   
 
The quantitation limit for the analytical procedure should be not more than () the reporting 
threshold (see attachment 1). 
 
Degradation product levels can be measured by a variety of techniques, including those that 
compare an analytical response for a degradation product 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  degradation  products  should  be  evaluated  and 
characterized according to their intended uses. The new veterinary drug substance can be used to 
estimate the levels of degradation products. In cases where the response factors are not close, this 
practice can still be used if a correction factor is applied or the degradation products are, in fact, 
being overestimated. Acceptance criteria and analytical procedures, used to estimate identified or 
unidentified degradation products, are often based on analytical assumptions (e.g., equivalent 
detector response). These assumptions should be discussed in the registration application. 
Differences between the analytical procedures used during development and those proposed for 
the commercial product should also be discussed. 
 
IV  REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES 
 
Analytical results should be provided in the registration application for all relevant batches of the 
new veterinary medicinal product used for clinical, safety, and stability testing, as well as batches 
that  are  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 
degradation product at a level greater than (>) the reporting threshold of 0.3 %(see Attachment 
1),  and  total  degradation  products  observed  in  the  relevant  batches  of  the  new  veterinary 
medicinal product, should be reported with the analytical procedures indicated.  The results 
should be reported to one decimal place (e.g., 0.4%, 1.3%).  Results should be rounded using 
conventional rules.  A tabulation (e.g., spreadsheet) of the data is recommended.  Degradation 
products 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 degradation 
products at a level greater than (>) the reporting threshold of 0.3% should be summed and 
reported as total degradation products.   
 
Page 6 of 14  Contains Non-Binding Recommendations 
 
 
Chromatograms with peaks labeled (or equivalent data if other analytical procedures are used) 
from  representative  batches,  including  chromatograms  from  analytical  procedure  validation 
studies and from long-term and accelerated stability studies, should be provided. The applicant 
should ensure that complete degradation product profiles (e.g., chromatograms) of individual 
batches are available, if requested.  
For each batch of the new veterinary medicinal product described in the registration application, 
the documentation should include: 
  Batch identity, strength, and size 
  Date of manufacture 
  Site of manufacture 
  Manufacturing process 
  Immediate container closure  
  Degradation product content, individual and total 
  Use of batch (e.g., clinical studies, stability studies)  
  Reference to analytical procedure used 
  Batch number of the new veterinary drug substance used in the new veterinary medicinal 
  product 
  Storage conditions for stability studies 
 
V.  LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS 
 
The specification for a new veterinary medicinal product should include a list of degradation 
products  expected  to  occur  during  manufacture  of  the  commercial  product  and  under 
recommended storage conditions. Stability studies, knowledge of degradation pathways, product 
development  studies,  and  laboratory  studies  should  be  used  to  characterize  the  degradation 
profile.    The  selection  of  degradation  products  in  the  new  veterinary  medicinal  product 
specification should be based on the degradation products found in batches manufactured by the 
proposed commercial process. Those individual degradation products with specific acceptance 
criteria included in the specification for the new veterinary medicinal product are referred to as 
"specified  degradation  products"  in  this  guidance.  Specified  degradation  products  can  be 
identified or unidentified.  A rationale for the inclusion or exclusion of degradation products in 
the  specification  should  be  presented.  This  rationale  should  include  a  discussion  of  the 
degradation profiles observed in the safety and clinical development batches and in stability 
studies, together with a consideration of the degradation profile of batches manufactured by the 
proposed commercial process. Specified identified degradation products should be included along 
with specified unidentified degradation products estimated to be present at a level greater than (>) 
the identification threshold of 1.0% (Attachment 1). For degradation products 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 degradation products should be controlled. For unidentified degradation products, the 
Page 7 of 14  Contains Non-Binding Recommendations 
 
 
procedure used and assumptions made in establishing the level of the degradation product should 
be  clearly  stated.    Specified  unidentified  degradation  products  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 of 1.0% (Attachment 1) for any unspecified degradation product and an acceptance 
criterion for total degradation products should also be included. 
 
For a given degradation product, its acceptance criterion should be established by taking into 
account its acceptance criterion in the new veterinary drug substance (if applicable), its qualified 
level, its increase during stability studies, and the proposed shelf life and recommended storage 
conditions for the new veterinary medicinal product.   Furthermore, each acceptance criterion 
should be set no higher than the qualified level of the given degradation product.   
Where there is no safety concern, degradation product acceptance criteria should be based on data 
generated from batches of the new veterinary medicinal product manufactured by the proposed 
commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical 
variation and the stability characteristics of the new veterinary medicinal product. Although 
normal manufacturing variations are expected, significant variation in batch-to-batch degradation 
product  levels  can  indicate  that  the  manufacturing process of the new  veterinary  medicinal 
product is not adequately controlled and validated (see guidance VICH GL39 on specifications 
and decision tree #2 for establishing an acceptance criterion for a specified degradation product in 
a new veterinary medicinal product).  
 
In  summary,  the  new  veterinary  medicinal  product  specification  should  include,  where 
applicable, the following list of degradation products: 
  Each specified identified degradation product 
  Each specified unidentified degradation product  
  Any unspecified degradation product with an acceptance criterion of not more than () the 
identification threshold of 1.0% (see Attachment 1) 
  Total degradation products. 
 
VI  QUALIFICATION OF DEGRADATION PRODUCTS 
 
Qualification is the process of acquiring and evaluating data that establishes the biological safety 
of an individual degradation product or a given degradation profile at the level(s) specified. The 
registration applicant should provide a rationale for establishing degradation product acceptance 
criteria that includes safety considerations. The level of any degradation product present in a new 
veterinary medicinal product that has been adequately tested in safety and/or clinical studies 
would be considered qualified. Therefore, it is useful to include any available information on the 
actual content of degradation products in the relevant batches at the time of use in safety and/or 
clinical studies.  Degradation products that are also significant metabolites present in animal 
and/or  human  studies  are  generally  considered  qualified.    Degradation  products  could  be 
Page 8 of 14  Contains Non-Binding Recommendations 
 
 
considered  qualified  at  levels  higher  than  those  administered  in  safety  studies  based  on  a 
comparison between actual doses given in the safety studies and the intended dose of the new 
veterinary medicinal product. Justification of such higher levels should include consideration of 
factors such as: (1) the amount of degradation product administered in previous safety and/or 
clinical studies and found to be safe; (2) the increase in the amount of the degradation product; 
and (3) other safety factors, as appropriate.   
 
If the qualification threshold of 1.0% given in Attachment 1 is exceeded and data are unavailable 
to qualify the proposed acceptance criterion of a degradation product, additional studies to obtain 
such data can be appropriate (see Attachment 2).  
 
Higher or lower thresholds for qualification of degradation products can be appropriate for some 
individual new veterinary medicinal products 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  degradation  products  in  certain  new  veterinary 
medicinal products or therapeutic classes have previously been associated with adverse reactions 
in animals and/or humans. In these instances, a lower qualification threshold can be appropriate. 
Conversely, a higher qualification threshold can be appropriate for individual new veterinary 
medicinal products when the level of concern for safety is less than usual based on similar 
considerations (e.g., animal species, drug class effects, and clinical considerations).  Proposals for 
alternative thresholds would be considered on a case-by-case basis. 
The "Decision Tree for Identification and Qualification of a Degradation Product" (Attachment 2) 
describes  considerations  for  the  qualification  of  degradation  products  when  thresholds  are 
exceeded.  In some cases, reducing the level of degradation product (e.g., use of a more protective 
container closure or modified storage conditions) 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 a degradation product. If neither is the case, additional safety testing 
should be considered. The studies considered appropriate to qualify a degradation product will 
depend on a number of factors, including the animal species, daily dose, and route and duration 
of new veterinary medicinal product administration. Such studies can be conducted on the new 
veterinary medicinal product or substance containing the degradation products to be controlled, 
although studies using isolated degradation products can sometimes be appropriate. 
Although this guidance is not intended to address the clinical research stage of development, in 
the later stages of development, the thresholds in this guidance can be useful in evaluating new 
degradation products observed in new veterinary medicinal product batches prepared by the 
proposed  commercial  process.    Any  new  degradation  product  observed  in  later  stages  of 
development should be identified (see the Decision Tree for Identification and Qualification of a 
Degradation Product in Attachment 2) if its level is greater than (>) the identification threshold 
of 1.0% given in Attachment 1. Similarly, qualification of the degradation product should be 
considered if its level is greater than (>) the qualification threshold of 1.0% given in Attachment 
1.  
Safety studies should provide a comparison of results of safety testing of the new veterinary 
medicinal product or new veterinary drug substance containing a representative level of the 
degradation  product  with  previously  qualified  material,  although  studies  using  the  isolated 
degradation products can also be considered. 
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VII  GLOSSARY 
 
(The following definitions are presented for the purpose of this Revised Guidance.) 
 
Degradation Product: An impurity resulting from a chemical change in the new veterinary drug 
substance brought about during manufacture and/or storage of the new veterinary medicinal 
product by the effect of, for example, light, temperature, pH, water, or by reaction with an 
excipient and/or the immediate container closure system. 
Degradation Profile: A description of the degradation products observed in the new veterinary 
drug substance or  new veterinary medicinal product. 
Development Studies: Studies conducted to scale-up, optimize, and validate the manufacturing 
process for a new veterinary medicinal product. 
Identification Threshold: A limit above (>) which a degradation product should be identified. 
Identified Degradation Product: A degradation product for which a structural characterization 
has been achieved. 
Impurity:    Any  component  of  the  new  veterinary  medicinal  product  that  is  not  the  new 
veterinary drug substance or an excipient in the new veterinary medicinal product.  
Impurity Profile: A description of the identified and unidentified impurities present in a new 
veterinary medicinal product. 
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 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. 
Qualification:  The process of acquiring and evaluating data that establishes the biological safety 
of an individual degradation product or a given degradation profile at the level(s) specified. 
Qualification Threshold: A limit above (>) which a degradation product should be qualified. 
Reporting Threshold: A limit above (>) which a degradation product should be reported. 
Specified Degradation Product: A degradation product that is individually listed and limited 
with a specific acceptance criterion in the new veterinary medicinal product specification. A 
specified degradation product can be either identified or unidentified. 
Unidentified  Degradation  Product:  A  degradation  product  for  which  a  structural 
characterization  has  not  been  achieved  and  that  is  defined  solely  by  qualitative  analytical 
properties (e.g., chromatographic retention time). 
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Unspecified  Degradation  Product:  A  degradation  product  that  is  limited  by  a  general 
acceptance criterion, but not individually listed with its own specific acceptance criterion, in the 
new veterinary medicinal product specification. 
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Attachment 1:  Thresholds for Degradation Products in New Veterinary Medicinal 
Products  
 
 
 
Identification1  1.0% 
 
Reporting1  0.3% 
 
Qualification1  1.0% 
 
 
 
 
 
 
1  Higher thresholds should be scientifically justified. 
 
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Attachment 2:  Decision Tree for Identification and Qualification of a Degradation Product 
 
                                                                                                                                                                                     
Is degradation 
product greater than 
identification / 
qualification 
thresholdc? 
Yes  No
No action
Any Yes 
Reduce to 
known human 
safe level 
or animal 
Structure  Yes  relevant risksd?
identified? 
No 
No
Reduce 
to not more than  Yes  No further 
() identification/  action 
qualification 
thresholdc? 
No 
 
 
Toxicity documented  Yes 
and sufficient / 
acceptable justification   
for relation to other 
substances with known 
toxicity? 
Consider animal species and duration of use and 
No  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 safe  Yes  clinically  No  
level or remove  relevant adverse  Qualified 
impurity or conduct  effects? 
additional safety 
studies 
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Notes on Attachment 2 
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 a degradation product. 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 degradation product is unusually toxic. 
d)  For example, do known safety data for this degradation product or its structural class 
preclude human or animal exposure at the concentration present? 
 
 
 
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