Elemental Impurities inDrug 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 inDrug 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/orOffice of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
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 CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2A.

ICH Q3D ......................................................................................................................................... 2B.

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 .............................................................. 4C.

Compendial Drug Products Not Approved Under an NDA or ANDA ..................................... 4D.

Noncompendial Drug Products Not Approved Under an NDA or ANDA ............................... 4E.

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 ............................................................................................ 7i

Contains Nonbinding Recommendations

Elemental Impurities in Drug Products
Guidance for Industry 1
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 thetitle page.

I.

INTRODUCTION

This guidance provides recommendations regarding the control of elemental impurities of human
drug products 2 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 theissuance of the United States Pharmacopeia (USP) requirement 4 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 arisk-based approach to control elemental impurities and permitted daily exposure (PDE).

•

How manufacturers of compendial drug products that are not marketed under anapproved NDA or ANDA can comply with USP General Chapters <232> Elemental
Impurities—Limits and <233> Elemental Impurities—Procedures and the Federal Food,
Drug, and Cosmetic (FD&C) Act. 6

1This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch 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 athttps://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm andhttps://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
4
USP General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures.
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)).

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Contains Nonbinding Recommendations••

How holders of NDAs or ANDAs for compendial drug products should report changes inchemistry, manufacturing, and controls specifications to FDA to comply with General
Chapters <232> and <233> and 21 CFR 314.70.
How manufacturers of noncompendial drug products 7 that are marketed without anapproved NDA or ANDA should control elemental impurities.

This guidance does not include specific recommendations on the evaluation of toxicity data forpotential 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, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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.

BACKGROUNDA.

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 potentiallypresent in the materials used to prepare the drug product, and elements potentially introduced
from manufacturing equipment or container closure systems. Manufacturers should then evaluateeach 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 thespecifications 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 Impurities—Limits and <233> Elemental Impurities—Procedures.
Their primary goals are to (1) set limits for acceptable levels of elemental impurities in finished7

Including nonprescription (over-the-counter) products marketed under an FDA monograph.

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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 bysetting limits for acceptable levels. General Chapter <232> also requires assurance ofcompliance 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 performedon the components (active pharmaceutical ingredient (API) and excipients) instead of thefinished 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 forthat impurity.
General Chapters <232> and <233> are currently official, and the revised version of <232> thataligns 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 andDietary 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 particularmonograph. 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-specificconsiderations, unless the drug product must comply with USP–NF requirements (see below).
January 1, 2018, was the implementation date for the control of elemental impurities in new orexisting drug products whether or not they are subject to a compendial monograph.

89

For USP’s implementation plan, see http://www.usp.org.
See FD&C Act section 501(b).

3Contains Nonbinding RecommendationsA.

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 forcontrol 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 meetthe 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 application 13 to comply with General Chapter <232> (ifthe product has an official USP monograph) or to follow the recommendations in ICH Q3D (ifthe 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 andguidances (§ 314.70 and the guidance for industry Changes to an Approved NDA or ANDA 14).
FDA anticipates that most approved drug products marketed in the United States do not containany 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)).
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 thevariations 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.
11

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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 productcomponents (e.g., APIs, excipients, container closure system components). Such changes madeto comply with General Chapters <232> and <233> are considered to have a minimal potential tohave an adverse effect on the identity, strength, quality, purity, or potency of the drug productand 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 mustalso 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 ofelemental 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. (Forexample, they may not be applicable for radiopharmaceuticals or products to which metals havebeen 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 tothe control of elemental impurities is performing a risk assessment. Manufacturers should use theresults 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).
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 effectand therefore should be documented in changes being effected (CBE) supplements (§ 314.70(c)(6)(i)). However, thechanges described above have a reduced potential to have an adverse effect on the drug product compared with otherpotential 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 thecontrol of elemental impurities.
17
See footnote 15 and § 314.70.
16

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determine whether establishing new in-process controls or including additional controls in thespecifications 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 manufacturer’s controls on
elemental impurities, manufacturers should include the risk assessment (or a summary of the risk
assessment 18) in the documentation related to the control of elemental impurities.
•

For new drug products submitted under an NDA or ANDA, applicants should include asummary 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 toappropriate 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 thecontrols on elemental impurities to comply with General Chapters <232> and <233> or tofollow the recommendations in ICH Q3D, applicants should include a summary of therisk assessment in any supplemental application or annual report describing thosechanges. Even if no changes are made, FDA recommends that applicants include asummary of the risk assessment in the next annual report following the completion of therisk 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 forAgency review during an inspection.

Documentation on the control of elemental impurities should also include descriptions of thecontrols. 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 systemcomponents), these tests can be performed by the drug product manufacturer or, if applicable, byproperly 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 theanalytical 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.

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General Chapter <233> also describes criteria for acceptable analytical procedures. If theanalytical 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 closuresystem 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, theirsuitability 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 therecommendations in ICH Q3D. ICH Q3D does not describe specific analytical procedures forroutine testing of materials or for performing a risk assessment. FDA recommends that
manufacturers use the analytical procedures described in General Chapter <233> or, if thoseanalytical procedures cannot be used for a specific item, analytical procedures that meet thevalidation requirements described in General Chapter <233>. Any analytical procedure used totest for elemental impurities should be properly described, and if used for routine testing, itssuitability 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 analyticalprocedure’s 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 andBiologics 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 factorsthat should be considered during the validation of these analytical procedures. The suitability ofan 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 bereasonably 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. Thisdecision depends on whether the amounts of the elemental impurities in the materials are
consistently below control thresholds. The analytical procedures should be validated with thisgoal 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.

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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