#255 
 
Elemental Impurities in Animal Drug 
Products 
Questions and Answers 
 
Guidance for Industry 
 
Submit comments on this guidance at any time. Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 
20852.  All comments should be identified with the docket number FDA-2018-D-0943. 
 
For further information regarding this document, contact AskCVM@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish 
Place, Rockville MD 20855, and may be viewed on the Internet at either 
https://www.fda.gov/animal-veterinary or https://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
November 2020  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 4 
II.  BACKGROUND AND SCOPE ....................................................................................... 4 
III.  RECOMMENDATIONS .................................................................................................. 5 
Q1.  What elements should be evaluated? .................................................................. 5 
Q2.  Is it necessary to test investigational and approved animal drug products   
for elemental impurities? ..................................................................................... 5 
Q3.  How should drug product components be evaluated for their potential to 
introduce elemental impurities into the finished drug products? .................... 6 
Q4.  How should the potential for the container closure and manufacturing 
equipment to leach elemental impurities into the drug product be  
addressed? ............................................................................................................. 6 
Q5.  Can a non-specific test, such as the test for heavy metals previously  
described in USP <231>, be used to test a component, or should  
instrumental methods, such as those described in USP <233> be used? ......... 7 
Q6.  For approved products, should we continue to perform the USP <231>      
test for heavy metals where it is included in the approved specifications for 
components of a drug product? ........................................................................... 7 
Q7.  Some USP monographs contain limits for specific elements and, in some 
cases, a different general chapter, such as USP <211>, Arsenic, or USP 
<251>, Lead, is referenced.  Do these limits apply to veterinary products?.... 7 
Q8.  If a certificate of analysis for an excipient or drug substance contains test 
results for specific elements using an instrumental method per USP <233>, 
do these tests need to be confirmed as part of vendor qualification? .............. 7 
Q9.  When specified elements are known to be present in one or more of the 
excipients or the drug substance, how should the elemental impurity daily 
exposure from the drug product be assessed? .................................................... 8 
Q10.  Even in cases where the COA includes results for elemental impurities      
and a specific risk factor has been identified, often the excipient or drug 
substance make up a small percentage of the drug product or the COA 
results demonstrate that the elements are controlled at low levels.  Is       
there a threshold at which we would not be expected to confirm the COA 
results? ................................................................................................................... 8 
Q11.  What information should be submitted to the file? ........................................... 8 
Q12.  How should updates to the test methods and limits be reported to the file? ... 9 
Q13.  Does this guidance apply to Type A medicated articles? .................................. 9 
Q14.  What if the drug product contains elements that are for therapeutic   
benefit? ................................................................................................................... 9 
2  Contains Nonbinding Recommendations 
 
Q15.  When is it necessary to reassess the risk for the drug product? ....................... 9 
Q16.  By what date should we have completed risk assessments for elemental 
impurities in our products? ................................................................................. 9 
IV.  Appendix I  Example decision tree for the components of the animal drug   
product. ............................................................................................................................ 11 
3  Contains Nonbinding Recommendations 
 
 
Elemental Impurities in Animal Drug Products 
Questions and Answers 
 
Guidance for Industry 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
I.  INTRODUCTION 
 
This guidance is intended to assist sponsors of animal drug products in addressing changes in the 
United States Pharmacopeia (USP)1 requirements for the control of elemental impurities in drug 
products marketed in the United States.   
 
In general, FDAs guidance documents 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 Agencys guidances means that something is suggested or recommended, but 
not required. 
 
II.  BACKGROUND AND SCOPE 
 
USP General Chapter <231>, Heavy Metals, was deleted with the implementation of General 
Chapters <232>, Elemental Impurities  Limits, and <233>, Elemental Impurities  Procedures.  
While USP <232> does not apply to animal drug products, the Center for Veterinary Medicine 
(CVM) expects sponsors of animal drug products to continue to apply a risk-based control 
strategy for elemental impurities and establish appropriate acceptance criteria and test methods 
for elemental impurities where necessary.  Ensuring that elemental impurities in the final drug 
product are controlled within safe limits remains the responsibility of the sponsor of the animal 
drug product. 
 
This document provides recommendations to sponsors regarding the control of elemental 
impurities in animal drug products, including pending and approved applications for all dosage 
forms and routes of administration.  The information to be maintained on-site and information to 
be submitted to CVM is also clarified.  The submission of information regarding components 
and composition, as well as manufacturing methods, facilities, and controls is required under 21 
CFR 514.1(b)(4) and (5) for new animal drug applications and under section 512(n)(1)(G) of the 
Federal Food, Drug, and Cosmetic Act for abbreviated new animal drug applications.  The 
                                                 
1 http://www.usp.org/ 
4  Contains Nonbinding Recommendations 
 
submission of manufacturing changes to an approved application is required under 21 CFR 
514.8(b)(1)(i). 
 
Approaches other than those set forth in this guidance may be applicable and acceptable. 
 
III.  RECOMMENDATIONS 
 
CVM recommends that animal drug product sponsors perform a thorough evaluation of the 
component materials of the drug product (e.g., drug substance, excipients, and primary 
packaging), including communication with the suppliers of sourced materials, and an evaluation 
of the manufacturing process for the drug product to identify risk factors that could potentially 
lead to significant levels of one or more elemental impurities in the drug product.  CVM will 
only expect test methods and limits for elemental impurities in cases where a specific risk is 
identified based on the evaluation of the components, including the primary packaging, and the 
manufacturing process for the product. 
 
This section includes CVMs answers to the following questions regarding control of elemental 
impurities. 
 
Q1.  What elements should be evaluated? 
 
A.  Typically, the greatest emphasis should be placed on arsenic, lead, mercury, cadmium, and 
any additional elements used in the excipient, drug substance, and drug product 
manufacturing process, such as catalysts; however, any elements that could be present at 
levels that may be of toxicological concern for the target species and, where relevant, the 
consumer, should be considered.  Refer to International Council for Harmonisation (ICH) 
Q3D, Elemental Impurities,2 for details. 
 
Q2.  Is it necessary to test investigational and approved animal drug products for 
elemental impurities? 
 
A.  CVM recommends that animal drug product sponsors evaluate the components of the drug 
product, including the primary packaging, and the drug product manufacturing process to 
identify any risk factors that could potentially lead to significant levels of one or more 
elemental impurities in the drug product (see Q3 and Q4 below).  Some examples of risk 
factors for introduction of elemental impurities into the drug product include the use of a 
catalyst or inorganic reagent in the manufacture of a component or the drug product, and 
the use of high concentrations of inorganic components, including mined materials, in the 
drug product formulation.  See ICH Q3D for more information on performing risk 
assessments.  In cases where a specific risk factor has been identified based on this 
assessment, CVM would expect a test method and limit for elemental impurities in either 
the component or the drug product to ensure that they are adequately controlled (see 
Appendix I for more information). 
 
                                                 
2 https://www.fda.gov/media/135956/download. 
5  Contains Nonbinding Recommendations 
 
Q3.  How should drug product components be evaluated for their potential to introduce 
elemental impurities into the finished drug products? 
 
A.  The considerations may include, but are not limited to: 
  Knowledge of the source and production process for drug product components (drug 
substance, excipients, and primary packaging), including information or data from 
suppliers; 
  The concentration of the component (drug substance or excipient) in the drug product 
formulation; 
  The quality of any water used in the production of the component; 
  Published data; 
  Test results generated by the animal drug product sponsor. 
The principles described in ICH Q9, Quality Risk Management,3 and ICH Q3D should 
be considered.  Control approaches should be proportional to the level of risk (see Q5, Q9, 
Q10, and Appendix I). 
 
Q4.  How should the potential for the container closure and manufacturing equipment to 
leach elemental impurities into the drug product be addressed? 
 
A.  CVM considers the risk of elemental impurities from the container closure to be low in 
most cases.  The probability of elemental leaching into solid dosage forms is minimal and 
does not require further evaluation in the risk assessment.  For liquid and semi-solid 
dosage forms, if the primary container closure components may introduce elemental 
impurities into the drug product at levels that present a safety concern, adequate controls 
should be in place.  If the supplier certifies that the materials of construction of the 
primary packaging meet the applicable requirements of the USP and the U.S. Code of 
Federal Regulations (CFR), the animal drug product sponsor will not be asked to confirm 
the COA results for extractable metals.  If a statement or data are unavailable from the 
manufacturer of the primary packaging regarding elemental impurities, CVM recommends 
performing at a minimum a test for heavy metals, such as the procedure previously 
described in USP <231>, for containers used for liquid and semi-solid dosage forms.  The 
probability of elemental leaching into solid dosage forms is minimal and does not require 
further evaluation in the risk assessment.  If the primary container closure components are 
expected to introduce elemental impurities into the drug product at levels that present a 
safety concern, adequate controls should be in place or testing of the drug product may be 
necessary. 
 
CVM considers the risk from manufacturing equipment to be low in most cases if 
appropriate, qualified equipment is selected for the process and GMP requirements (21 
CFR parts 210, 211, and 226) are met.  Unless an unusual amount of chemical corrosion 
                                                 
3 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9-quality-risk-management. 
6  Contains Nonbinding Recommendations 
 
or mechanical erosion of equipment results from the manufacturing process, no further 
assessment is expected. 
 
Q5.  Can a non-specific test, such as the test for heavy metals previously described in USP 
<231>, be used to test a component, or should instrumental methods, such as those 
described in USP <233> be used? 
 
A.  Procedures with selectivity and sufficient sensitivity for individual elements, such as the 
procedures described in USP <233>, should be used where controls for individual 
elements are necessary based on the risk assessment (see Appendix I for additional 
guidance).  Non-specific tests, such as the procedures previously described in USP <231>, 
are unsuitable for controlling elemental impurities below acceptable limits.  Non-specific 
tests for components determined to be low risk based on the risk assessment may be 
maintained at the sponsors discretion.  Previously reported non-specific tests can 
typically be deleted (see Q6 below).  If you choose to maintain a non-specific test, it can 
be kept on site and should not be submitted to the file. 
 
Q6.  For approved products, should we continue to perform the USP <231> test for heavy 
metals where it is included in the approved specifications for components of a drug 
product? 
 
A.  The USP <231> test for heavy metals has significant limitations and we therefore do not 
recommend that it be used for controlling elemental impurities below acceptable limits 
where controls for individual elements are necessary based on the risk assessment.  The 
heavy metals test and limit may be deleted, and the change may be reported in the next 
Minor Changes and Stability Report (MCSR).  If the test method is maintained, it can be 
kept on site and should not be submitted to the file. 
 
Q7.  Some USP monographs contain limits for specific elements and, in some cases, a 
different general chapter, such as USP <211>, Arsenic, or USP <251>, Lead, is 
referenced.  Do these limits apply to veterinary products? 
 
A.  At a minimum, these materials should continue to meet the requirements in the 
monograph, including the limits for specified elements, unless a risk-based justification 
supports their omission.  An instrumental method consistent with those described in USP 
<233> may be used as an alternative to the referenced procedure. 
 
Q8.  If a certificate of analysis for an excipient or drug substance contains test results for 
specific elements using an instrumental method per USP <233>, do these tests need to 
be confirmed as part of vendor qualification? 
 
A.  This depends on the risk assessment.  Communication with the supplier regarding the 
reason for including limits for specific elements is recommended.  The results should be 
confirmed by the animal drug product sponsor only when deemed necessary by the risk 
assessment (see Q10 and Appendix I). 
 
7  Contains Nonbinding Recommendations 
 
Q9.  When specified elements are known to be present in one or more of the excipients or 
the drug substance, how should the elemental impurity daily exposure from the drug 
product be assessed? 
 
A.  The daily exposure to the elements should be calculated based on the suppliers limit, the 
amount of the excipient or drug substance in the drug product, and the maximum daily 
dose.  If the same element may be introduced by more than one component of the drug 
product, the total exposure should be calculated.  CVM generally considers the Permitted 
Daily Exposures (PDEs) for humans established in ICH Q3D in units of g/day acceptable 
for the safety of animal drug products.  The calculated elemental impurity daily exposure 
should result in a level equal to or below the ICH Q3D PDE for the drug product; 
however, CVM recognizes that the PDEs in ICH Q3D are for humans.  If the calculated 
elemental impurity content of the animal drug product exceeds the PDE in ICH Q3D, the 
animal drug product sponsor may provide a justification or contact CVM to discuss the 
product and veterinary-specific considerations. 
 
Q10.  Even in cases where the COA includes results for elemental impurities and a specific 
risk factor has been identified, often the excipient or drug substance make up a small 
percentage of the drug product or the COA results demonstrate that the elements are 
controlled at low levels.  Is there a threshold at which we would not be expected to 
confirm the COA results? 
 
A.  If the elemental impurity content listed on the COA will lead to a daily exposure that is 
not more than 30% of the PDE for an element, the risk from the component can usually be 
considered below the threshold at which additional testing by the drug product 
manufacturer is necessary (see Appendix I), and confirmation of the COA values for 
elemental impurities will not be requested.  If the 30% control threshold will be applied, 
the total daily exposure should not exceed 30% of the PDE in cases where the same 
element may be introduced by multiple components of the drug product. 
 
If the 30% threshold is exceeded but the elements are below the PDE, the drug product 
manufacturer should confirm the component COA results for vendor qualification, or, 
alternatively, test every lot of the drug product to ensure that the element does not exceed 
the PDE.  A test that is selective for the element should be used unless an alternative 
approach can be justified.  The test method(s) and limit(s) should be submitted to the file 
(see Q11 below).  Reduced testing may be appropriate for a qualified supplier in 
accordance with 21 CFR 211.84(d)(2).  The test may also be discontinued if sufficient 
data are generated to support that the element remains below 30% of the PDE. 
 
Q11.  What information should be submitted to the file? 
 
A.  If test methods and limits for elemental impurities in components or the drug product are 
deemed necessary based on the risk assessment, they should be submitted to the file.  If 
the drug product will be tested for elemental impurities, the method validation should also 
be submitted to the file.  If one of the compendial procedures described in USP <233> is 
used, the animal drug product sponsor may simply reference that chapter for the method.  
8  Contains Nonbinding Recommendations 
 
The risk assessment, any calculations, and any method validations for methods for 
elemental impurities in components, where applicable, should be kept on site to provide to 
an investigator upon request (see 21 CFR parts 210, 211, and 226).  CVM may request 
additional information on a case-by-case basis. 
 
Q12.  How should updates to the test methods and limits be reported to the file?  
 
A.  For approved products, this information can be provided in an annual MCSR unless a new 
testing facility is requested.  A new testing facility should be reported in a supplement 
(please see CVM Guidance for Industry #83, Chemistry, Manufacturing, and Controls 
Changes to an Approved NADA or ANADA4). 
 
Q13.  Does this guidance apply to Type A medicated articles? 
 
A.  Yes.  When a specific risk factor has been identified that may lead to introduction of 
elemental impurities into the Type A medicated article, any calculations of the daily 
exposure should take into account the ultimate dilution of the Type A to produce a 
medicated feed. 
 
Q14.  What if the drug product contains elements that are for therapeutic benefit? 
 
A.  This guidance does not apply to elements that are present in a form that is for therapeutic 
benefit (e.g., as part of the active pharmaceutical ingredient).  However, the sponsors risk 
assessment should consider the potential for elemental impurities to be present at elevated 
levels based on the composition of the active pharmaceutical ingredient. 
 
Q15.  When is it necessary to reassess the risk for the drug product? 
 
A.  The potential sources of elemental impurities in the drug product should be reevaluated 
where necessary throughout the product lifecycle, for example: 
  With changes to the components and composition of the drug product; 
  With changes to the drug product manufacturing process; 
  With changes to the drug product manufacturing facility or equipment; 
  With changes to the source or manufacturing process for the drug substance or 
excipients; or 
  With changes to the primary packaging components. 
 
Q16.  By what date should we have completed risk assessments for elemental impurities in 
our products?  
 
                                                 
4 https://www.fda.gov/media/70323/download  
9  Contains Nonbinding Recommendations 
 
A.  We ask that completed risk assessments for investigational and approved products be 
available on site to provide upon request by January 2023.  Potential sources of unsafe 
levels of elemental impurities in the product should be controlled even prior to this 
requested date, and CVM may request additional information from drug product sponsors 
in cases where there appears to be an inadequately controlled potential source of elemental 
impurities in a product. 
10  Contains Nonbinding Recommendations 
 
IV.  Appendix I  Example decision tree for the components of the animal drug product. 
 
 
 
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