Elemental Impurities in 
Drug Products 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
August 2018 
Pharmaceutical Quality/CMC 
 
 
9073135 FNL 
8/1/2018   
Elemental Impurities in 
Drug Products 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
 
 
 
 
 
 
 
 
 
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) 
 
August 2018 
Pharmaceutical Quality/CMC 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  ICH Q3D ......................................................................................................................................... 2 
B.  USP General Chapters <232> and <233> .................................................................................... 2 
III.  IMPLEMENTATION ...................................................................................................... 3 
A.  New Compendial NDA or ANDA Drug Products ....................................................................... 4 
B.  New Noncompendial NDA and ANDA Drug Products .............................................................. 4 
C.  Compendial Drug Products Not Approved Under an NDA or ANDA ..................................... 4 
D.  Noncompendial Drug Products Not Approved Under an NDA or ANDA ............................... 4 
E.  Changes to Approved NDAs and ANDAs .................................................................................... 4 
F.  Documentation Related to the Control of Elemental Impurities ............................................... 5 
G.  Quantitative Analytical Procedures for Elemental Impurities .................................................. 6 
H.  Validation of Analytical Procedures ............................................................................................ 7 
i  Contains Nonbinding Recommendations 
 
Elemental Impurities in Drug Products 
Guidance for Industry1 
 
 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations regarding the control of elemental impurities of human 
drug products2 marketed in the United States consistent with implementation of International 
Council for Harmonisation (ICH) guidance for industry Q3D Elemental Impurities (ICH Q3D).3 
This guidance will also assist manufacturers of compendial drug products in responding to the 
issuance of the United States Pharmacopeia (USP) requirement4 for the control of elemental 
impurities.5 Specifically, with respect to implementation of ICH Q3D and of USP General 
Chapters <232> and <233>, this guidance makes recommendations on the following:  
 
  How applicants submitting new drug applications (NDAs) or abbreviated new drug 
applications (ANDAs) for noncompendial drug products should control elemental 
impurities as described in ICH Q3D. ICH Q3D contains recommendations on applying a 
risk-based approach to control elemental impurities and permitted daily exposure (PDE). 
 
  How manufacturers of compendial drug products that are not marketed under an 
approved NDA or ANDA can comply with USP General Chapters <232> Elemental 
ImpuritiesLimits and <233> Elemental ImpuritiesProcedures and the Federal Food, 
Drug, and Cosmetic (FD&C) Act.6 
 
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration.  
2 Prescription and nonprescription.  
3 The ICH guidance was adopted as an FDA guidance document. We update guidances periodically. To make sure 
you have the most recent version of a guidance, check the FDA Drugs or Biologics guidance Web pages at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
4 USP General Chapters <232> Elemental ImpuritiesLimits and <233> Elemental ImpuritiesProcedures. 
5 Note that control of elemental impurities for all finished drug products is also addressed in 21 CFR part 211. 
6 See section 501(b) of the FD&C Act (21 U.S.C. 351(b)). 
 
  1  Contains Nonbinding Recommendations 
 
  How holders of NDAs or ANDAs for compendial drug products should report changes in 
chemistry, manufacturing, and controls specifications to FDA to comply with General 
Chapters <232> and <233> and 21 CFR 314.70. 
  How manufacturers of noncompendial drug products7 that are marketed without an 
approved NDA or ANDA should control elemental impurities. 
  
This guidance does not include specific recommendations on the evaluation of toxicity data for 
potential elemental impurities, application of a risk-based approach to control elemental 
impurities in drug products, or PDE. For this information, please refer to ICH Q3D.  
Holders of approved or pending biologics license applications should refer to ICH Q3D. 
 
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 Agency guidances means that something is suggested or recommended, but 
not required. 
 
II.  BACKGROUND 
 
A.  ICH Q3D  
 
ICH guidance for industry Q3D Elemental Impurities contains recommendations for 
manufacturers of human drugs and biologics on applying a risk-based approach to control 
elemental impurities and PDE. 
 
ICH Q3D recommends that manufacturers conduct a product risk assessment by first identifying 
known and potential sources of elemental impurities. Manufacturers should consider all potential 
sources of elemental impurities, such as elements intentionally added, elements potentially 
present in the materials used to prepare the drug product, and elements potentially introduced 
from manufacturing equipment or container closure systems. Manufacturers should then evaluate 
each elemental impurity likely to be present in the drug product by determining the observed or 
predicted level of the impurity and comparing it with the established PDE. If the risk assessment 
fails to show that an elemental impurity level is consistently less than the control threshold 
(defined as being 30 percent of the established PDE in the drug product), additional controls 
should be established to ensure that the elemental impurity level does not exceed the PDE in the 
drug product. These additional controls could be included as in-process controls or in the 
specifications of the drug product or components. ICH Q3D also discusses options for different 
dosage forms and special circumstances that might affect the risk assessment conclusions. 
 
B.  USP General Chapters <232> and <233> 
 
USP introduced new limits and analytical procedures for elemental impurities in General 
Chapters <232> Elemental ImpuritiesLimits and <233> Elemental ImpuritiesProcedures. 
Their primary goals are to (1) set limits for acceptable levels of elemental impurities in finished 
                                                 
7 Including nonprescription (over-the-counter) products marketed under an FDA monograph. 
  2  Contains Nonbinding Recommendations 
 
drug products, and (2) update the methodology used to test for elemental impurities in drug 
products to include modern analytical procedures. 
 
USP worked closely with ICH to align its new General Chapters with ICH Q3D. General 
Chapter <232> endorses a risk-based approach to the control of elemental impurities as 
described in ICH Q3D.  
 
General Chapter <232> requires control of elemental impurities in finished drug products by 
setting limits for acceptable levels. General Chapter <232> also requires assurance of 
compliance to the specified levels when elemental impurities are known to be present, have been 
added, or have the potential for introduction. However, the chapter does not require routine 
testing of the drug product to ensure compliance. Depending on the source of an elemental 
impurity and the risk that its level in the finished drug product will exceed the PDE, alternative 
approaches to ensure compliance can be taken. For example, routine testing could be performed 
on the components (active pharmaceutical ingredient (API) and excipients) instead of the 
finished drug product. If the risk that the amount of an elemental impurity will exceed its PDE in 
the drug product is sufficiently low, it may not be necessary to test each lot of drug product for 
that impurity.  
 
General Chapters <232> and <233> are currently official, and the revised version of <232> that 
aligns with ICH Q3D became official on August 1, 2017 (first supplement to USP 40-NF 35).  
General Chapters <232> and <233> replaced General Chapter <231> Heavy Metals. Effective 
January 1, 2018, General Notices 5.60.30. Elemental Impurities in USP Drug Products and 
Dietary Supplements made General Chapter <232> applicable to all drug products with USP 
monographs except for those drug products specifically excluded in <232>.  USP may retain 
other specific metal limit tests (e.g., General Chapter <211> Arsenic) that appear in a particular 
monograph.8 In some cases, USP monographs and General Chapters may specify impurity limits 
that differ from General Chapter <232>. When specific limits are included in a monograph, or in 
a General Chapter referenced by a monograph, those limits are the official limits with which 
manufacturers must comply.9 
 
III.  IMPLEMENTATION   
 
Because elemental impurities pose toxicological concerns and do not provide any therapeutic 
benefit to the patient, their levels in drug products should be controlled within acceptable limits. 
In general, FDA recommends that the manufacturer of any U.S. marketed drug product follow 
ICH Q3D recommendations to establish appropriate procedures for identifying and controlling 
elemental impurities in the drug product based on risk assessment and product-specific 
considerations, unless the drug product must comply with USPNF requirements (see below). 
January 1, 2018, was the implementation date for the control of elemental impurities in new or 
existing drug products whether or not they are subject to a compendial monograph. 
 
   
                                                 
8 For USPs implementation plan, see http://www.usp.org. 
9 See FD&C Act section 501(b).  
  3  Contains Nonbinding Recommendations 
 
A.  New Compendial NDA or ANDA Drug Products  
 
With implementation of General Chapters <232> and <233>, all new NDAs and ANDAs for 
drug products with an official USP monograph are now expected to meet the requirements for 
control of elemental impurities described in General Chapters <232> and <233>.10  
 
B.  New Noncompendial NDA and ANDA Drug Products 
 
Applicants submitting new NDAs and ANDAs after January 1, 2018 for drug products without 
an official USP monograph should follow the recommendations for the control of elemental 
impurities as described in ICH Q3D. 
 
C.  Compendial Drug Products Not Approved Under an NDA or ANDA 
 
Marketed compendial drug products not approved under an NDA or ANDA are expected to meet 
the requirements for control of elemental impurities described in General Chapters <232> and 
<233>. Appropriate documentation demonstrating compliance, including detailed risk 
assessment, screenings, and validation data for release methods, must be maintained at the 
manufacturing site to be available for Agency review during an inspection.11 
 
D.  Noncompendial Drug Products Not Approved Under an NDA or ANDA 
 
Marketed drug products not approved under an NDA or ANDA that do not have an official USP 
monograph should follow the recommendations for the control of elemental impurities as 
described in ICH Q3D. Appropriate documentation demonstrating compliance such as detailed 
risk assessment, screenings, and validation data for release methods, must be maintained at the 
manufacturing site to be available for Agency review during an inspection.12 
 
E.  Changes to Approved NDAs and ANDAs 
 
An applicant with a drug product already approved under an NDA or ANDA may have to change 
conditions established in the approved application13 to comply with General Chapter <232> (if 
the product has an official USP monograph) or to follow the recommendations in ICH Q3D (if 
the product does not have an official USP monograph). Any changes to conditions established in 
the approved application should be reported in accordance with applicable regulations and 
guidances ( 314.70 and the guidance for industry Changes to an Approved NDA or ANDA14).   
 
FDA anticipates that most approved drug products marketed in the United States do not contain 
any elemental impurities that exceed the PDEs described in General Chapter <232> and ICH 
                                                 
10 See section 501(b) of the FD&C Act (21 U.S.C. 351(b)).  
11 21 CFR parts 211. 
12 Ibid. 
13 Section 314.70(a)(1)(i) states that, other than the exceptions or alternatives provided in  314.70(a)(1)(ii), an 
applicant must notify FDA about each change in each condition established in an approved application beyond the 
variations already provided for in an application. 
14 See also guidances for industry Changes to an Approved NDA or ANDA Questions and Answers and CMC 
Postapproval Manufacturing Changes To Be Documented in Annual Reports.  
  4  Contains Nonbinding Recommendations 
 
Q3D. For drug products that do not exceed the PDEs, complying with General Chapters <232> 
and <233> or following the recommendations in ICH Q3D will involve performing a risk 
assessment and perhaps implementing changes, such as establishing new in-process controls or 
including additional controls in the specifications of the drug product or drug product 
components (e.g., APIs, excipients, container closure system components). Such changes made 
to comply with General Chapters <232> and <233> are considered to have a minimal potential to 
have an adverse effect on the identity, strength, quality, purity, or potency of the drug product 
and must be documented by the applicant in the next annual report in accordance with 21 CFR 
314.81(b)(2).15 Similarly, such changes made to follow the recommendations in ICH Q3D must 
also be documented by the applicant in the next annual report.16  
 
If a drug product approved under an NDA or ANDA does not meet the requirements described in 
General Chapter <232> or the recommendations in ICH Q3D, documenting changes in an annual 
report is not appropriate. Applicants should consider whether higher limits for elemental 
impurities should apply to the drug product or whether manufacturing changes could reduce 
elemental impurity amounts. Manufacturing changes implemented to reduce the amounts of 
elemental impurities should be submitted according to existing postapproval CMC change 
guidance documents.17 FDA recognizes that the requirements described in General Chapter 
<232> and the recommendations in ICH Q3D are not appropriate for all drug products. (For 
example, they may not be applicable for radiopharmaceuticals or products to which metals have 
been intentionally added.) Applicants should discuss drug products that do not meet General 
Chapter <232> or ICH Q3D with the appropriate review division. 
 
Applicants must have made changes to comply with General Chapter <232> by the 
implementation date. Applicants should have made changes to follow the recommendations in 
ICH Q3D by January 1, 2018. 
 
F.  Documentation Related to the Control of Elemental Impurities 
 
As described in ICH Q3D and General Chapter <232>, the first step in a risk-based approach to 
the control of elemental impurities is performing a risk assessment. Manufacturers should use the 
results from the risk assessment to determine which elemental impurities are likely to be present 
in the drug product and whether current controls for those elemental impurities are adequate. If 
additional controls should be put in place, the results of the risk assessment can also help 
determine which types of controls should be used. For example, the risk assessment can help 
                                                 
15 See also  314.70(d). 
16 Normally, adding to a specification or changing the methods or controls to provide increased assurance that the 
drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it 
purports or is represented to possess are considered changes that have a moderate potential to have an adverse effect 
and therefore should be documented in changes being effected (CBE) supplements ( 314.70(c)(6)(i)). However, the 
changes described above have a reduced potential to have an adverse effect on the drug product compared with other 
potential changes covered by these regulations because (1) in the situation described above, the elemental impurities 
in the drug product do not exceed the PDEs listed in ICH Q3D, and (2) the changes are being made to follow ICH 
Q3D, which, because it has been adopted as an FDA guidance document, reflects current Agency thinking on the 
control of elemental impurities. 
17 See footnote 15 and  314.70. 
 
  5  Contains Nonbinding Recommendations 
 
determine whether establishing new in-process controls or including additional controls in the 
specifications of components would be adequate or whether manufacturers should include 
additional controls in the specifications of the drug product.  
 
Because the risk assessment is important to the justification of the manufacturers controls on 
elemental impurities, manufacturers should include the risk assessment (or a summary of the risk 
assessment18) in the documentation related to the control of elemental impurities. 
 
  For new drug products submitted under an NDA or ANDA, applicants should include a 
summary of the risk assessment in any new application to which General Chapters <232> 
and <233> or ICH Q3D apply. (For information about the implementation schedule for 
new applications, see sections III.A and III.B). The P.2 section (Pharmaceutical 
Development) is an appropriate location for the risk assessment summary, hyperlinked to 
appropriate sections of the application. When additional controls are warranted, 
supporting material should be appropriately cited in the summary. 
 
  For drug products already approved under an NDA or ANDA, if changes are made to the 
controls on elemental impurities to comply with General Chapters <232> and <233> or to 
follow the recommendations in ICH Q3D, applicants should include a summary of the 
risk assessment in any supplemental application or annual report describing those 
changes. Even if no changes are made, FDA recommends that applicants include a 
summary of the risk assessment in the next annual report following the completion of the 
risk assessment. 
 
  For drug products not approved under an NDA or ANDA, manufacturers should include 
the risk assessment in the documentation maintained at the manufacturing site for  
Agency review during an inspection. 
 
Documentation on the control of elemental impurities should also include descriptions of the 
controls. This should include acceptance criteria associated with any analytical testing and, if 
appropriate, the analytical procedures and validation information. If the controls include routine 
testing of drug product components (e.g., APIs, excipients, container closure system 
components), these tests can be performed by the drug product manufacturer or, if applicable, by 
properly qualified suppliers as described in 21 CFR 211.84(d)(2). The full risk assessment 
should be maintained at the drug product manufacturing site.  
 
G.  Quantitative Analytical Procedures for Elemental Impurities 
 
For drug products with an official USP monograph, General Chapter <233> describes the 
analytical procedures that ordinarily would be used to determine the amount of elemental 
impurities in drug products or drug product components. These analytical procedures can be used 
for routine testing of materials or for performing a risk assessment. 
 
                                                 
18 See training materials for ICH Q3D available at www.ICH.org.  
  6  Contains Nonbinding Recommendations 
 
General Chapter <233> also describes criteria for acceptable analytical procedures. If the 
analytical procedures described in General Chapter <233> cannot be used for a specific item 
associated with the drug product or its components (e.g., APIs, excipients, container closure 
system components), USP permits the use of alternative procedures in accordance with General 
Notices and Requirements 6.30, Alternative and Harmonized Methods and Procedures. Any 
analytical procedure must meet the validation requirements described in General Chapter <233>. 
Alternative procedures should be properly described, and if used for routine testing, their 
suitability must be verified under actual conditions of use as described in 21 CFR 211.165(e) and 
211.194(a)(2) or, if applicable, 212.70(b). 
 
For drug products without an official USP monograph, manufacturers should follow the 
recommendations in ICH Q3D. ICH Q3D does not describe specific analytical procedures for 
routine testing of materials or for performing a risk assessment. FDA recommends that 
manufacturers use the analytical procedures described in General Chapter <233> or, if those 
analytical procedures cannot be used for a specific item, analytical procedures that meet the 
validation requirements described in General Chapter <233>. Any analytical procedure used to 
test for elemental impurities should be properly described, and if used for routine testing, its 
suitability must be verified under actual conditions of use as described in  211.165(e) and 
211.194(a)(2) or, if applicable, 212.70(b). 
 
H.  Validation of Analytical Procedures 
 
Validation is the process of demonstrating that an analytical procedure is suitable for its intended 
purpose. Analytical procedures for both risk assessments and routine testing should be validated, 
but the validation criteria (e.g., accuracy, precision, detection limits) can depend on the analytical 
procedures intended purpose.  
 
ICH guidance for industry Q2(R1) Validation of Analytical Procedures: Text and Methodology 
and FDA guidance for industry Analytical Procedures and Methods Validation for Drugs and 
Biologics provide recommendations pertaining to the validation of analytical procedures. These 
recommendations were developed for analytical procedures used for routine testing of drug 
products and drug product components. In addition, General Chapter <233> describes factors 
that should be considered during the validation of these analytical procedures. The suitability of 
an analytical procedure (e.g., the analytical procedures described in General Chapter <233>) 
should be verified under actual conditions of use.19 
 
Manufacturers should establish that the analytical procedures used during risk assessments 
possess characteristics (e.g., accuracy, precision, specificity) such that the manufacturers can be 
reasonably certain (e.g., at the 95-percent confidence level) that the measurements can be relied 
upon to decide whether to include routine testing of materials in the control strategy. This 
decision depends on whether the amounts of the elemental impurities in the materials are 
consistently below control thresholds. The analytical procedures should be validated with this 
goal in mind. 
 
                                                 
19 See  211.165(e), 211.194(a)(2), and 212.70(b); USP General Chapter <1226> Verification of Compendial 
Procedures; and guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics.  
  7  Contains Nonbinding Recommendations 
 
I.  Deletion of USP <231>  
 
Upon adoption of General Chapters <232> and <233>, drug products and any components are 
not expected to demonstrate compliance with General Chapter <231>.  
  8